International J. Pharm CMPD'G May - June 2002

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I N T E R N AT I O N A L J O U R N A L
COMPOUNDING
COMPOUNDING FOR HEALTH, WELLNESS, AND GERIATRIC PATIENTS Page 171 Estrogen Replacement Therapy in the Treatment of Alzheimers Disease Page 178 Lollipops: The Evolution of a Dosage Form Page 186 How To Perform a Study in Your Pharmacy
VOLUME 6
Page 194 Basics of Compounding: Iontophoresis, Part 1 Page 210 The Treatment of Canine Atopic Disease Page 216 A Review of pH and Osmolarity
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DEPARTMENTS 163 PreScription From the Editor 163 Erratum 236 Index of Advertisers 237 Calculations Shelly J. Prince, PhD, RPh 238 Continuing Education Questions 240 PostScription Patsy Angelle, PD, FIACP, FACA
COMPOUNDING FOR HEALTH, WELLNESS, AND GERIATRIC PATIENTS
164 Healthful Living: Good Practices for Good Health Kathy Jackson, RPh, FIACP 168 Compounding for Geriatric Patients Eldon Armstrong, RPh, CGP, FIACP, FACA, FASCP 171 Estrogen Replacement Therapy in the Treatment of Alzheimers Disease Jennifer Osburn, PharmD (Candidate) 178 Lollipops: The Evolution of a Dosage Form Dave Mason, DPh, FIACP; and Shannon Fields, PhTech 180 Book Reviews: Wellness, Nutrition, and Geriatrics Dana Reed-Kane, PharmD, FIACP, FACA; and Lisa D. Ashworth, RPh
GENERAL INTEREST
FORMULATIONS
199 Anhydrous Emollient Dry Skin Lotion 200 Antiseptic Protective Ointment 201 Camphor, Menthol, and Eucalyptol Rubefacient Ointment 202 Carbidopa 2-mg/mL and Levodopa 250-mg/mL Oral Suspension 203 Ergoloid Mesylates 15 mg/mL and Selegiline HCl 6.25 mg/mL in Pluronic Lecithin Organogel 204 Misoprostol 0.0024%, Metronidazole 2%, and Pentoxifylline 5% Decubitus Ulcer Cream 205 Nicotine 2-mg Lollipops 206 Nicotine Medication Stick 207 Podophyllum, Lactic Acid, and Salicylic Acid Wart Mixture 208 Vitamin B12 1-mg/mL Nasal Spray PEER REVIEWED 226 Stability of Ampicillin Sodium, Nafcillin Sodium, and Oxacillin Sodium in AutoDose Infusion System Bags Yanping Zhang, BS; and Lawrence A. Trissel, BS, RPh 230 Compatibility Screening of Precedex During Simulated Y-Site Administration with Other Drugs Lawrence A. Trissel, BS, RPh; Christopher A. Saenz; Delshalonda S. Ingram; Kimberly Y. Williams; and Julie P. Retzinger, RN 234 Stability of Cefotaxime Sodium After Reconstitution in 0.9% Sodium Chloride Injection and Storage in Polypropylene Syringes for Pediatric Use V. Das Gupta, PhD
Cover Photo by MARK RUTLEDGE 2002
184 Compounding in History: The Road to Wellville Dennis B. Worthen, PhD 186 How To Perform a Study in Your Pharmacy with Little or No Effort Dana Reed-Kane, PharmD, FIACP, FACA 188 Technology Spotlight: Electric Mixing Machines Gary Schneider, RPh 189 Treatment of Pain with a Topically Applied Combination of Indomethacin and Piroxicam Eric R. Vetter, RPh, PharmD (Candidate); and Lawrence Curtis, RPh 193 Medications Discontinued in the United States Lisa D. Ashworth, RPh 194 Basics of Compounding: Iontophoresis, Part 1 Loyd V. Allen, Jr, PhD, RPh
SPECIALTY COMPOUNDING
210 The Treatment of Canine Atopic Disease Gigi Davidson, BS, RPh, DICVP 216 A Review of pH and Osmolarity Marc Stranz, PharmD; and Eric S. Kastango, RPh, MBA, FASHP
COMPOUNDING SUPPORT & QUALITY CONTROL
221 Featured Excipient: The Sorbitan Esters Loyd V. Allen, Jr, PhD, RPh 224 Standard Operating Procedure: Developing Standard Operating Procedures Loyd V. Allen, Jr, PhD, RPh
International Journal of Pharmaceutical Compounding 161 Vol. 6 No. 3 May/June 2002
F R O M
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Editorial Editor-in-Chief Executive Editor Medical Editor Assistant to Editor-in-Chief Contributing Authors Loyd V. Allen, Jr, PhD, RPh Shelly Capps Jane Vail LaVonn Williams Lisa D. Ashworth, RPh
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Gigi Davidson, BS, RPh, FSVHP, DICVP Eric S. Kastango, RPh, MBA, FASHP Shelly J. Prince, PhD, RPh Dennis B. Worthen, PhD Contributing Editor Peter R. Ford, BSPharm, FACA, FIACP ADDRESS: 122 N. Bryant, Edmond, OK 73034-6301 USA TEL: 800-757-4572 FAX: 405-330-5622 Design Design Director Subscription & Reader Services Circulation Director Interactive Media & Special Projects Designer Andy Bernick Jordana Ford Carolyn Rose
ADDRESS: PO Box 340205, Austin, TX 78734 USA TEL: (toll free) 888-588-4572, 512-261-3179 FAX: 512-608-9828 Advertising Director of Advertising Lauren Bernick
ADDRESS: PO Box 340205, Austin, TX 78734 USA TEL: 800-661- 4572 FAX: 800-494-4572 EMAIL: lbernick@ijpc.com Board of Directors Jake Beckel , RPh Shelly Capps Mike Collins, RPh Pat Downing, RPh Bob Scarbrough , RPh Editorial Board Harvey Ahl, RPh Diane Boomsma , RPh Marianna Foldvari, PhD, RPh Peter R. Ford, BSPharm, FACA, FIACP Paul F. Grassby, PhD, MRPharmS Hetty A. Lima, RPh, FASHP Dave Mason, RPh, FIACP John Preckshot , RPh, FIACP Lawrence A. Trissel, BS, RPh, FASHP David J. Woods, MPharm, MRPharmS, FHPA
Isnt it great to be alive? Health and wellness are the themes of this issue of the journal, in addition to compounding for the special health needs of geriatric patients. Never in the history of the world has so much money been spent in the pursuit of health and wellness. Health and wellness can be maintained or regained. It is easiest and best to maintain a state of health and well-being by eating a healthful diet, exercising, and adopting a healthful lifestyle. Those practices often obviate the time, effort, and money spent trying to regain good health. I have often wondered why we seem to spend the first half of life burning the candle at both ends and the last half trying to put the drops of wax back together. Developing and maintaining healthful habits can result in healthier and happier mature adults. We as compounding pharmacists can individualize patient care by offering our patients nutritional supplements, recommendations for lifestyle changes, and counseling about medication use. We can help patients maintain good health by addressing minor ailments or discomforts as they arise and by helping our clients eliminate harmful habits such as smoking or overeating. In many cases, innovative dosage forms (nicotine lollipops, troches, gummy gels, sublingual drops, etc) can be used effectively in smoking cessation or weight reduction programs. Our clients will benefit from our efforts
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to ensure their health and wellness, and we have probably been neglecting those services too long. Promoting the vital components of good health may be just the niche for those of us who want to expand the scope of their services and better serve their patients.
Loyd V. Allen, Jr, PhD, RPh
Erratum: In the article, Bacterial Endotoxins and Pyrogens, which was published in IJPC volume 5, number 4 (July/August 2001), page 262, column 2, in the section Intrathecal Limits for Pyrogens, the third sentence should read: The EU limit would then be 13 EU/hr, or 13 EU/0.042 mL, or a 312 EU/mL critical endotoxin load allowed for a nonpyrogenic intrathecal drug product.
The International Journal of Pharmaceutical Compounding (IJPC), ISSN No. 10924221, is published 6 times per year by IJPC, 122 N. Bryant St, Edmond OK 73034, USA. ANNUAL SUBSCRIPTION RATES (All rates in US dollars) North America Standard: $125, institutional: $150, student: $ 90. All other destinations Standard: $190, institutional: $ 215, student: $95. Electronic issue downloads (no print copy) Standard: $125, institutional: $ 150, student: $90. Back issues are available Nine or fewer for $20 per issue, 10 or more for $15 per issue. Call 888-588-4572 to order back issues or subscriptions. All rights reserved. Permission is granted for libraries and others registered with the Copyright Clearance Center, Inc, 222 Rosewood Drive, Danvers, MA 01923 USA, to photocopy articles for a base fee of $5 per copy of the article plus $2 per page. Requests for bulk orders should be addressed to the editor. Copyright 2002 by the International Journal of Pharmaceutical Compounding.
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International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002
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HEALTHFUL LIVING:
GOOD PRACTICES for GOOD HEALTH

Kathy Jackson, RPh, FIACP The Family Pharmacy Compounding Pharmacy LaPorte, Texas The body is the temple in which we live. Adopting a healthful lifestyle often requires rediscovering common sense and taking the initiativeevery dayto maintain well-being. Regular health maintenance enables the human body to work best and last longer. The body, which is a product of the nutrients it receives, is composed of 60% water, 20% body fat, and a 20% mix of proteins and carbohydrates, related organic compounds, and minerals.1 Healthful nutrition is vital to maintaining ideal body composition. What we eat is what we are and how we feel. The quality of the nutrients consumed can make the difference between good health and illness. America is the most agriculturally productive nation in the history of the world. We as Americans also benefit from the most expensive and technologically advanced healthcare system available. In spite of those factors, many of us today are victims of dietrelated obesity and heart disease. We love fast food, and our grocery stores are packed with junk food. We choose our food according to preferences of taste, cost, convenience, and psychologic gratification, all of which are independent of the purpose of nutrition, which is to provide the materials necessary to grow, repair, and fuel the body. We often process, blend, hydrogenate, refine, and disassemble our food until very little nourishment remains. Through years of inactivity, many of us morph a fit physique into the habitus of a couch potato. We pollute our food, air, and water supply with a frightening array of contaminants. Then, when poor nutrition evolves into poor health, we use potent drugs to subdue the symptoms of illness.
The Importance of Diet

A healthful diet is an essential component of lasting good health. Poor eating habits lead to an increased risk of obesity, diabetes, high blood pressure, and heart disease. Understanding the basic principles of nutrition is important in ensuring compliance with healthful eating habits. Proteins, carbohydrates, and fats are the components of food. The body requires proteins for growth and muscle development. Carbohydrates and fats supply energy. Vitamins and minerals do not provide calories, but they facilitate the conversion of other elements into energy. Thousands of magazines and a vast array of diet books outline successful methods of shedding fat and decreasing weight.
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Manufacturers of special diet foodsfrom liquid high-protein meal substitutes to appetite-killing bars and snacksmake extravagant claims to sell hope to weight-conscious consumers. Many overthe-counter ephedrine-containing products are touted to help consumers burn fat and decrease body weight without much effort. Patients are often the victims of advertising that leads them to believe in a quick-fix pill purported to conquer any of a variety of diseases. Even vitamins have been promoted as substances that can counteract the effects of a junk-food diet. Fad diets can be very dangerous. The pharmacist can help educate patients about the dangers of quick-weight-loss products that do not address the need for a nutritious diet and a lifestyle that includes regular exercise. The most sensible approach to good nutrition is to adopt (for a lifetime) a diet that is low in refined carbohydrates, includes adequate proteins and fats, and is rich in fruits and vegetables. Combining a healthful diet with a regular exercise program and a positive mental attitude is the best approach to achieving and maintaining good health.
The Essential Role of Glucose and Insulin

Glucose
Glucose is the bodys major source of energy; it is also the only form of energy that the brain can use effectively. During digestion and metabolism, the liver converts all of the carbohydrates and about half of the protein from a meal into glucose, which is then released into the bloodstream. In response to an increasing glucose level, the pancreas secretes extra insulin, which is the hormone that enables cells to convert glucose into energy. 2 Excessive carbohydrate consumption can negatively affect the bodys endocrine function and can lead to hyperinsulinemia and eventually to insulin resistance. 3
ulate insulin release. It is safe to assume that highly processed foods have a higher glycemic index. 7 Patients should be advised to avoid processed, refined, or enriched foods8 because refining can deplete important nutrients that are essential to a healthful diet.9 Rened sugar and processed grain products such as candies, cookies, pies, cakes, and pastries are almost immediately absorbed by the gastrointestinal tract and produce a rapid secretion of large quantities of insulin. An increased insulin level promotes fat deposition and other undesirable effects. The long-term consumption of a diet that consists predominantly of high-glycemic-index carbohydrates can lead to the development of insulin resistance. 9,10 However, unrefined carbohydrates such as fruits, vegetables, whole grains, and dried beans require further digestive alteration before they are absorbed. This subsequently causes a proportionate reduction in the rate and quantity of insulin secretion, which results in less fat storage and less weight gain. Studies9,11 have indicated that in 6 weeks, low-glycemic-index diets produced a 7% decrease in the level of cholesterol in non-insulindependent diabetic patients and a 15% decrease in that level in nondiabetic patients.
The Keys to Good Health

Physical Activity
Regular physical activity is tremendously beneficial to overall health. Thirty minutes of vigorous aerobic exercise daily is essential to lowering the level of insulin; it also increases circulation and reduces fibrinogen production and the levels of triglycerides and cholesterol. In addition, exercise also decreases the blood glucose level and increases peripheral tissue sensitivity to insulin.10,12
Vitamins
Vitamin supplementation is also essential to good health. The human body requires approximately 60 minerals, 16 vitamins, 12 amino acids, and 3 essential fatty acids daily to regulate key metabolic processes. If those nutrients are not supplied by food or vitamin supplementation, vitamin deficiencies that could lead to serious health problems will occur.
Insulin
Insulin, the bodys master hormone, has an essential role in the use, storage, and metabolism of every nutrient in the human body. It affects membrane permeability, protein and fat synthesis, mineral and micronutrient use and storage, glucose uptake, and the metabolism of every cell. It also plays an important role in the flow of nutrients into and waste products out of cells. 4 Insulin resistance is a decrease in the response of peripheral tissues to insulin.5 Excess insulin release plays a role in the development of hypertension, diabetes, an elevated level of triglycerides, and obesity. 6 Other health problems caused by excess insulin include blood coagulation disorders, cancer, gout, sleep apnea, iron-overload disease, gastroesophageal reflux, peptic ulcer disease, and polycystic ovary disease. 4 The glycemic index is used to classify foods according to their effect on the blood glucose level. Not all carbohydrates are equal in their stimulation of insulin release. Carbohydrates that stimulate the most insulin secretion are termed high-glycemic-index carbohydrates. Low-glycemic-index carbohydrates do not stim-
Antioxidants
Antioxidants are key to the fight against free radicals, which are linked to heart disease, cancer, cataracts, stroke, Parkinsons disease, and many other disorders. Antioxidants act as free-radical scavengers that help to prevent disease.13 Important antioxidants include vitamins C, E, and A; -carotene; selenium; coenzyme Q10; -lipoic acid; mixed tocopherols; and mixed carotenoids. Fresh fruits and vegetables are an excellent source of essential antioxidants. Biotin is used to improve glycemic response by improving the metabolism of carbohydrates, fats, and amino acids. 3 Insulin production requires zinc, 14 and chromium is important for glucose metabolism and insulin production. 14
Proteins
Proteins control metabolism and provide the structural basis for tissues such as muscle and skin. They enable the body to grow
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and repair itself and are essential to the function of the immune system. Protein-rich foods are of animal origin (meat, fish, poultry, eggs, milk) or plant origin (wheat, rice, nuts, beans, lentils). Individual protein requirements are often calculated according to body weight measured in kilograms. The body weight in kilograms must be multiplied by 0.8 to determine the daily number of grams of protein required daily to maintain health. The amount of protein needed daily may vary among individuals. Pregnant women and highly trained athletes have a high daily protein requirement.1
ing more than following a consistent pattern of good choices made one at a time. Small changes in dietary habits, incorporating regular exercise into the daily routine, minimizing stress, and ensuring adequate rest produce a visible improvement in overall health and well-being. Pharmacists, as well as other healthcare professionals, have a unique opportunity and responsibility to model and promote a sound plan for wellness.
References
1. 2. 3. 4. 5. 6. 7. Whitney E, Hamilton E. Understanding Nutrition . 4th ed. New York:West Publishing Company; 1987:2-3, 83, 171. Eades M, Eades M. Protein Power . New York:Bantam Books; 1999:12, 28. Werbach M, Moss J. Textbook of Nutritional Medicine . Tarzana, CA:Third Line Press; 1999:8, 10-11, 320, 328. Eades M, Eades M. The Protein Power Life Plan . New York:Warner Books; 2000:11, 22-25, 132, 168. Hardman J, Limbird L, eds. Goodman and Gilmans The Pharmacological Basis of Therapeutics . 9th ed. New York: McGraw-Hill; 1996:1495. Wolever TM, Jenkins DJ, Vuksan V, et al. Beneficial effect of low-glycemic index diet in overweight NIDDM subjects. Diabetes Care 1992;15:562-564. Jenkins DJ, Wolever TM, Taylor RH, et al. Glycemic index of foods: A physiological basis for carbohydrate exchange. Am J Clin Nutr 1981;34: 362-366. Liu S, Manson JE, Stampfer MJ, et al. A prospective study of whole-grain intake and risk of type 2 diabetes mellitus in US women. Am J Public Health 2000;90:1409-1415. Steward H, Bethea M, Andrews S. Sugar Busters! New York:Ballantine Publishing Group; 1998:19, 41, 58-60. Liu S, Manson JA. Dietary carbohydrates, physical inactivity, obesity, and the metabolic syndrome as predictors of coronary heart disease. Curr Opin Lipidol 2001;12:395-404. Jenkins DJ, Wolever TM, Kalmusky J, et al. Low-glycemic index diet in hyperlipidemia: Use of traditional starchy foods. Am J Clin Nutr 1987; 46:66-71. Kanaley J, Weinstock R. Nonpharmacologic therapy in the treatment of insulin resistance. Curr Opin Endocrinol Diabetes 2001;8:219-225. Azen S, Qian D, Mack W, et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation 1996;94:2369-2372. Pelton R, LaValle J, Hawkins E. Drug-Induced Nutrient Depletion . 2nd ed. Cincinnati:Natural Health Resources; 200:9, 320, 370. American Gastroenterological Association. American Gastroenterological Association Position Statement: Impact of dietary fiber on colon cancer occurrence. Gastroenterology 2000;118:1233-1234. Ludwig D, Pereira MA, Kroenke CH, et al. Dietary fiber, weight gain, and cardiovascular disease risk factors in young adults. JAMA 1999;282: 1539-1546. Young-In K. AGA technical review: Impact of dietary fiber on colon cancer occurrence. Gastroenterology 2000;118:1235-1237. Salmeron J, Ascherio A, Rimm EB, et al. Dietary fiber, glycemic load, and risk of NIDDM in men. Diabetes Care 1997;20:545-550.
Fats
Fats, especially essential fatty acids, are vital to good health. They facilitate the absorption of fat-soluble vitamins, are involved in producing hormones, help support and protect vital organs, and insulate the body from cold. Fats are also an excellent source of energy. However, excessive consumption of foods high in saturated fats has been linked to heart disease and certain types of cancer. Linoleic acid, which is an omega-6 fatty acid obtained from plantbased sources such as evening primrose oil or flaxseed oil, exerts a cardioprotective effect. Linolenic acid, an omega-3 fatty acid found in all fish and seafood (especially cold-water fish such as salmon, sardines, and lake trout), may help to prevent blood clots that cause myocardial infarction or stroke. The Western diet consists primarily of saturated fats that are detrimental to health and often lacks the essential fatty acids mentioned above.
8.
Fiber
Fiber intake is also important to good health. A daily intake of natural fiber is crucial to good health and energy. Dietary fiber is most abundant in plant products such as fruits, grains, and vegetables. The American Gastroenterological Association recommends the consumption of 30 to 35 g of fiber daily. 15 An increased intake of dietary fiber ensures the timely transit of foods through the gastrointestinal tract and thus alleviates constipation and hemorrhoids. A high-fiber diet has been shown clinically to reduce atherosclerosis; dietary fats and cholesterol bind with fiber in the digestive system and are eliminated via defecation. 16 Evidence indicates that an increased intake of dietary fiber can exert a protective effect on the colon and may decrease the risk of colorectal cancer.17 High-fiber diets are helpful in controlling the blood glucose level in patients with type 2 diabetes. Fiber can also lower insulin secretion by reducing the absorption of carbohydrates.9,18
9. 10.
11.
12. 13.
14. 15.
Water
Water is a requirement of all living cells. The type and the amount of liquid consumed are as important as the intake of nutrients to maintaining good health. Water is the basis of essential body fluids such as blood and lymph. It lubricates joints, is a constituent of saliva, provides a protective cushion for tissues, and helps to eliminate toxic waste products from the body. At least 8 glasses of water purified by the reverse-osmosis process should be consumed daily.
16.
17. 18.
Rules To Remember
Good health is our most valuable earthly asset; what we do with it is our responsibility. Building a more healthful lifestyle is noth-
Address correspondence to: Kathy Jackson, RPh, FIACP, Family Pharmacy, Kathy Jackson, RPh, FIACP, 10406 W. Main, Suite B, La Porte, TX 77571-4300. E-mail: K a t h y @ f a m i l y p h a r m a c y. c c .
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Compounding for
Geriatric Patients
Eldon Armstrong, RPh, CGP, FIACP, FACA, FASCP Sandlapper Consultant Pharmacists, Columbia, South Carolina Today, older Americans visit their doctors 22% more often than they did in the mid-1980s, and according to statistics 1 released by the Centers for Disease Control and Prevention, physicians are prescribing more drugs for patients of all ages. Many elderly patients experience multiple illnesses and a diminished physical capacity, for which they frequently take medications. Those patients have a much higher risk of experiencing disabling side effects from treatment, as well as adverse drug reactions. Almost 25% of all hospital and nursing home admissions of older adults are caused by the improper use of medications by patients.2
The role of the consultant pharmacist has been designed to use the expertise of the pharmacist to prevent the misuse of medications (such as major tranquilizers) in treating elderly patients. The American Society of Consultant Pharmacists (ASCP) has been the leading national organization in geriatric pharmacy since 1969. The ASCP promotes the role of senior-care pharmacists who practice in community settings and provide care for ambulatory senior citizens. That organization provides training in pharmacotherapy for pharmacists who treat patients with disorders such as Parkinsons disease or Alzheimers disease. It also offers training in the medication management of geriatric patients with psychiatric disorders and in skin and wound care for elderly patients. In addition, the ASCP assisted in launching the Commission for Certification in Geriatric Pharmacy, which offers a demanding certication process to pharmacists specializing in health care for the elderly.
Practice Communication
Medication counseling must be well-documented and then orally communicated effectively to the patient and to selected members of his or her healthcare team (if warranted). We have found it effective to summarize the information orally to the patient and to provide a detailed written report to the primary caregiver. Patient involvement should be encouraged throughout the process. Historically, the pharmacist has served as the patient-physician liaison. Pharmacists can simplify a physicians orders into language understandable to the patient. In that role, we are the guardians of both the patient and the prescribing healthcare practitioner.
Changes in the American Healthcare System

Efforts to reform our healthcare system to meet the demands of geriatric patients must certainly be made. Many older patients are literally dying for the system to change. The following recommendations for healthcare reform were issued by the Alliance for Aging Research in August 1998 3: Provide a list of medications that are potentially inappropriate for the treatment of older patients. Require manufacturers to perform premarketing and postmarketing studies of medication effects in frail elderly patients. Provide geriatric-relevant labeling for nonprescription medications. Coordinate data collection, monitoring, and analysis of medication-related problems by age group. Encourage healthcare professionals to be competent in geriatric pharmacotherapy. Many healthcare professionals are making special efforts to meet the needs of elderly patients. The pharmacist who is active in community service, knowledgeable about the medications used to treat the elderly, and has good communication skills can ensure better health for elderly patients.
The Practice Site

The goal of the Medication Checkup Center (MCC) of Columbia, South Carolina, is to provide a stand-alone pharmacy practice in which the art and science of pharmacy are practiced primarily for elderly clients. It includes a working knowledge of dosage alternatives and a command of communication techniques, as well as an evaluation of the patients drug regimen and a clinical evaluation of treatment options. It does not include an inventory of medications. People need to gather up all their prescription drugs and show their doctors and pharmacists what theyre [taking]. These professionals can work up a suitable drug regimen for the patient, said Harold J. Washington, Jr, a Los Angeles pharmacist and president of the California Pharmacists Association. 3 Mr. Washingtons statement, although true, tends to simplify a complex process.
Consider the Possibilities

The pharmacists at MCC consider whether the clients illnesses may have been misdiagnosed, overlooked, or dismissed as part of the normal aging process. Many healthcare professionals are not trained to recognize the effects of diseases and drugs on senior citizens. 4 Determining the appropriateness of treatment includes identifying the effects of overuse, misuse, and underuse of medications. Often, the pharmacist will refer the patient to other healthcare professionals. For example, we at MCC have often referred patients to sleep evaluation centers. The effects of sleep disorders, some of which produce symptoms similar to those of muscle movement disorders, can undermine a treatment plan. Sleep
Practice Competence
The pharmacist may choose to provide medication counseling services to elderly patients and to others. He or she must be able to perform clinical evaluations, conduct medical sleuthing by using interview techniques, and recognize opportunities for nonchemical interventions. Having experience in drug regimen review and disease state management in nursing home settings is invaluable.
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apnea, which is most common in men and the obese, has only recently been regarded as a serious problem.5 The symptoms of sleep apnea can often be easily recognized, and the patient who feels tired all the time may not be suffering adverse drug effects. Some sufferers of another sleep disorder, restless leg syndrome (RLS), are often overlooked. Self-treatment often includes taking doses of diphenhydramine or acetaminophen. Diphenhydramine has been listed for more than a decade as inappropriate for use by the elderly.6 It is also essential that physicians and pharmacists know the recommendations for using acetaminophen to treat elderly individuals with impaired liver function. Optional therapy for the muscle cramps associated with RLS may involve the local application of transdermal ointments and gels. This obviates the hazards of using systemic drug therapies such as clonazepam, a long-acting benzodiazepine that can cause falling and confusion in the elderly patient. Transdermal medications recommended for the treatment of minor episodes of RLS include ketoprofen, cyclobenzaprine, gabapentin, or lorazepam. At MCC, we often suggest treatment with a specific medication for the prescribers consideration. For example, most patients with Peyronies disease do not always mention that problem to their physician and erroneously assume that no treatment is available for that condition. We identified Peyronies disease in several
patients who discussed their symptoms with us. The physicians of those patients responded positively to our recommendation of using verapamil, a topically applied calcium channel blocker, as treatment, although that therapy is not listed in standard drug reference books. Those who followed the directions for using verapamil experienced reduced discomfort during intercourse. The medication checkup should include a review of the patients drug therapy. The pharmacist must be knowledgeable about dosing parameters, contraindications, and drug interactions. For example, a thiazide-type diuretic that is ineffective because of a patients low creatinine clearance rate may be replaced by a loop diuretic such as furosemide. The use of a compounded formulation of slow-release furosemide helped to improve the compliance of one of our patients who followed a complex polypharmacy regimen for the treatment of congestive heart failure. A 93-year-old man who is our client recently wanted to discuss options for treating impotence. His primary care physician had denied this patient, who has a cardiac condition, treatment with sildenafil. The patient did not like the alternative of using a penile erection pump, which we first suggested. We ultimately recommended treatment with a sterile mixture of three medications administered as penile injections. The doctor agreed with our suggestion and trained the patient to self-administer that combination treatment.
Table 1. Sample of a Precounseling Questionnaire for Elderly Patients.

Name of your practice site To our patients: We are dedicated to helping you obtain the very best possible healthcare management. Please indicate your reasons for scheduling a checkup at ( practice site name here). Patient name Do you think that you may be experiencing drug interactions? Are your current medications not as effective as you wish they were? Do you want a better understanding of your medicines? Do you think that you may be experiencing adverse drug reactions? Do you want to develop a vitamin or herbal medication plan? Do you want to control the cost of your medications?
Please describe all suspected side effects that may be caused by your treatment.
Please describe any concerns about particular medicines.
Other
Add the name, mailing and e-mail addresses, and fax and telephone numbers of the practice site.
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Practice Education
The pharmacist must also analyze the learning ability of the client and his or her understanding of the treatment. The goal of education has always been to empower the student. It is no longer judicious for the medical team to continue the past practice of shrouding the treatment plan in secrecy and excluding active participation by the patient. The term high-maintenance patient refers to those who never seem satisfied, are well-read, and are always inquiring about changes and improvements. That type of patient (such as the typical patient with osteoporosis who is treated at MCC) is fast becoming the norm. Such patients are often confused about the intentions of the medical team. Many have benefited from the use of bioidentical hormone therapy instead of expensive treatments such as selective-estrogen-receptor modulators or antiresorptive therapies. We offer to evaluate the diet of our clients to ensure that their consumption of calcium and magnesium is adequate. By suggesting combinations of vitamins or herbal products, we may be able to reduce the total number of medications taken daily by some patients.
The Patients Medicine Cabinet

Medication counseling must also include a review of the patients over-the-counter medications, herbal preparations, and nutraceuticals. Clients are asked to bring the contents of their medicine cabinet, including medications for the treatment of hemorrhoids, to the counseling session so that we can identify possible drug interactions or medication-related side effects. 7 Reviewing the patients medicines also provides an indication about his or her more private concerns such as impotence, loss of memory, and anxiety or depression. The current popularity of herbal remedies has increased the demand for more knowledgeable pharmacists. The kavalactones (the active muscle relaxant in kava), are associated with hepatic toxicity that can be harmful to the elderly patient. Recent reports 8 have now resulted in the removal of kava from the market in Switzerland, and similar action may be taken in Germany. A trained pharmacist, however, can recommend customized doses in transdermal gel formulations that pose fewer risks to the elderly patient.
in local publications. However, none of those methods is successful without intense community networking. The pharmacist should establish a practice site that is separate from the dispensing pharmacy practice. Physicians and patients value the pharmacist who is objective and is not merely a promoter of products. Perhaps the practice site will be used to provide service only a few days each week. A pharmacist specialist might also be hired to provide additional service at the practice site. The decision to affix a sufficient charge for services is essential to success. Paying a fair price for the services of a skilled compounding pharmacist is acceptable to most patients and to the medical community. Consumers are already expressing a willingness to pay for pharmacists services that reduce the risk of medication-related problems.9 Our experiences at the MCC indicate that most are willing to pay even more when the results include a better quality of life. The goals of drug therapy in the elderly10 include alleviating pain, suffering, and disability; improving functional capacity; promoting the patients quality of life; and prolonging his or her life. Those goals can be accomplished if the current US healthcare system is retooled and rededicated so that care for geriatric patients is more important. Most pharmacists have been trained to focus on the drugs used in treatment and on providing service to physicians rather than on the needs of their patients and the intent of therapy. Encouraging patient compliance is critical to the success of treatment. Pharmacists are proven and respected professionals. Those of us who commit to providing service to the elderly must integrate changes into our practice of pharmacy as we apply our knowledge of all possible drug-related interventions.
References
[No author listed.] Older Americans seeing physicians more often. Reuters Medical News. 2001. Available at: http://www.medscape.com/reuters/prof/ 2001/07/07.18/20010717publ002.html. [Accessed July 26, 2001.] 2. Marsa L. Improved medications have a downside for seniors. LA Times. October 22, 2001: S1. 3. [No author listed]. Panel cites policies for prevention of medication misuse in elderly. Am J Health Syst Pharm 1998;55:1654. 4. Murphy J. Senate Committee on Aging. Washington Post. May 30, 1999. 5. Margen S, Lasnof J, Chaput L. A lot of night music. UC Berkley Wellness Letter 2000;May:5. 6. General Accounting Office/HEHS. Prescription Drugs and the Elderly. Washington, DC: United States General Accounting Office. 7. Halas C. Optimizing drug use in elderly patients. American Druggist 1999;October:56. 8. Shaver K, Jellin JM, Burson SC. Supplements, kavas days may be numbered. Pharmacists Letter 2002;18:6. 9. Dong-Chur S. Consumers willingness to pay for pharmacy services that reduce risk of medication-related problems. J Am Pharm Assoc 2000;40:818-827. 10. Sloan R. Principles of drug therapy in geriatric patients. Am Fam Physician 1992; June:10. 1.
Dene Essential Goals for Your Patients and Your Practice

The pharmacist is a positive part of the healthcare team for elderly patients, and the needs of that population will increase. The first decision in the process of becoming a more effective pharmacist for elderly patients is that of making a commitment. That commitment involves spending more time reading pertinent literature, obtaining additional training in compounding for the elderly, and developing assessment ability and communication skills that apply to older patients. The pharmacist must also select the best vehicles for patient education, such as brochures, advertisements, and presenting talks on pertinent subjects. Partnerships with local senior centers and organizations that provide benevolent services may yield free advertising for the practice or the opportunity to write guest columns
Address correspondence to: Eldon Armstrong, RPh, CGP, FIACP, FACA, FASCP, 1518 Taylor Street, Columbia, SC. E-mail: medicinecheckup@cs.com.
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Estrogen Replacement Therapy in the Treatment of

Introduction
Alzheimers disease (AD), which is one of the most common neurodegenerative disorders, has become a focus of clinical research as the lifespan for men and women in developed countries increases. AD is characterized by a progressive loss of memory and other cognitive abilities.1 It occurs 2 to 3 times more frequently in women than in men. Increasing age, a family history of the disease, and prior head trauma are risk factors for the development of AD. 2 The exact mechanism of action of AD is not completely understood. -Amyloid, a proteolytic fragment of the -amyloid precursor protein (APP), accumulates intracranially in patients with AD and forms senile plaques. As the disease progresses, neurofibrillary tangles and neuritic plaques form, a central core of -amyloid protein develops in the neurons of the cerebrum, and the level of acetylcholine (ACh) in the brain decreases. A chronic inflammatory process that is induced by the reaction of microglia and astrocytes to -amyloid also occurs in those with AD. 1,3 Mutations within the APP coding sequence can lead to enhanced formation of -amyloid, 4 which is toxic to neurons; the damage that it produces increases in the presence of reactive free radicals. A decreased level of apolipoprotein E has been reported in patients with AD, and that decrease is greater in patients with the apolipoprotein E type 4 allele. 1 The decrease in the concentration of ACh that is associated with AD has been the main focus of new pharmacotherapies.1 Currently, the only therapies approved for the treatment of AD are those that increase the level of ACh in the brain by inhibiting centrally active acetylcholinesterase (AChE), which is the enzyme that hydrolyzes ACh.
ALZHEIMERS DISEASE
Jennifer Osburn, PharmD (Candidate) University of Houston College of Pharmacy, Houston, Texas
Decreased Accumulation of -Amyloid

Ovariectomized rodent models that demonstrate long-term estrogen deprivation exhibit an increase in the level of -amyloid in the brain, which causes impaired memory. 13-16 Research indicates that estrogen blocks -amyloidinduced neuronal cell death via estrogen receptor- (ER- )dependent pathways.17 Estrogen has been shown to enhance the antiapoptotic protein Bcl-xL, which reduces -amyloidinduced apoptosis; this suggests a novel mechanism of estrogen-induced neuroprotection.18 Estrogen also appears to enhance the clearance of -amyloid through microglia, which are key components of the immune system that remove amyloid deposits from the brain. Whether the enhanced clearance of -amyloid is estrogen-receptor- (ER-) dependent or receptor independent is unknown.19 AChE, a protein also found in senile plaques, has recently been found to form complexes with the -amyloid peptide that are more cytotoxic than -amyloid fibrils alone. Both -amyloid and -amyloid-AChE complexes are ameliorated by estradiol therapy, which provides protection against amyloid-induced toxicity at the cellular level. 20 Physiologic doses of estradiol have significantly reduced the production of endogenous -amyloid in primary cortical neurons. 21,22
Increased Synthesis of ACh

Studies indicate that estrogens, which are neuroactive steroid hormones, affect the neuronal function of the basal forebrain. 23 Estrogen receptors (predominantly estrogen receptor- [ER ]) are present on cholinergic neurons in the basal forebrain of rats, and estrogen may directly regulate the activity of cholinergic neurons via those receptors. 24 Low-affinity nerve growth factor (NGF) receptors are located on cholinergic neurons, as is ER- .1 Choline acetyltransferase (ChAT), the ACh-synthesizing enzyme, is directly affected by estrogen.25 The ChAT messenger ribonucleic acid (mRNA) and trkA (NGF receptor) mRNA are decreased after the loss of ovarian function.26-28 Studies indicate that the level of ChAT mRNA may be significantly increased by estrogen25,27-33 and progesterone,28,30,31 but the beneficial effects of replacement therapy may be limited only to women. 29 According to some studies, 30 estrogen and progesterone replacement may enhance spatial memory and reduce the performance deficits that are associated with a decreased level of ACh, but other studies31-34 do not concur. Raloxifene, a selective estrogen receptor modifier, may also exert a beneficial effect on cholinergic
Estrogen-Mediated Actions
The actions of neurosteroids in the prevention and treatment of AD have been the focus of recent investigations.5-12 The following estrogen-mediated actions are relevant to the pathologic mechanism of action of AD: Decreased accumulation of -amyloid Increased synthesis of ACh Enhanced expression of neurotrophins Anti-inflammatory activity of estrogen Cytokine regulation Prevention of cerebral vasculature disruption Antioxidant activity Increased utilization of glucose Regeneration of neurons in the brain Increase in the number of synapses The neuroactive steroid hormone progesterone is also believed to stimulate the production and proliferation of myelin.
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neurotransmission in the brain without producing the undesirable stimulation of breast or uterine tissue that is associated with hormone replacement therapy.35
Prevention of Cerebral Vasculature Disruption

Cerebral blood vessel dysfunction is induced by a chronic inflammatory reaction mediated by -amyloid. In rodent models, conjugated equine estrogens (CEE) prevented endothelial and vessel wall disruption resulting from -amyloid induced inflammatory reactions. Those reactions include plasma leakage, platelet and mast-cell activation, and the adhesion and transmigration of leukocytes. The protective effects of estrogen against -amyloidinduced cytotoxicity were lost when CEE therapy was discontinued. 45,46 In separate studies, 47,48 Wise and Dubal used a model of cerebral artery occlusion and physiologic levels of estradiol replacement therapy to demonstrate the profound protective effects of estradiol against ischemic brain injury. Improved blood flow protects the brain from metabolic injury caused by hypoxia. Estrogen replacement therapy can prevent cognitive dysfunction and decrease the risk of neurodegenerative conditions such as AD and stroke.
Enhanced Expression of Neurotrophins

Cholinergic neurons require neurotrophic growth factors (neurotrophins such as NGF and brain-derived nerve factor [BDNF]) for their survival. Estrogen enhances the expression of neurotrophins, which, acting through their respective receptors, activate cholinergic neurons. 36 Long-term loss of ovarian function leads to a decline in the production of high-affinity NGF receptors and in a decrease in the responsiveness of cholinergic neurons to endogenous NGF. Basal forebrain cholinergic decline that exceeds the effect of normal aging results. 26,30 Studies also indicate that estrogen deprivation leads to a reduction of both NGF 26,37 and BDNF 37 mRNA levels. Estrogen 28,30,33 and progesterone 30 have been shown to significantly increase the level of trkA mRNA. Estrogen is more effective in maintaining BDNF mRNA in the hippocampus than in the cerebral cortex; this suggests a regional difference in the neurosteroid requirement for BDNF expression. 37
Antioxidant Activity
Oxidative neuronal cytotoxicity is attenuated by estradiol-17 , estradiol-17, and estrone.49 In some studies,49-53 estrogen-receptor antagonists did not reverse the antioxidant effect of estrogen. This suggests that the antioxidant effect of estrogen is not receptor mediated but may instead be due to free-radical scavenging. Other ndings54,55 have suggested that estradiol provides better antioxidant protection than does -tocopherol (vitamin E), but some studies56 indicate that both natural and synthetic vitamin E exerted greater neuroprotective effects than did estradiol.
Anti-Inammatory Activity of -Amyloid

-Amyloid induces an inflammatory reaction in the brain that is an essential component of the pathologic effect of AD. This reaction is characterized by the adhesion and transmigration of leukocytes across the vessel walls, disruption of the endothelium, and platelet activation. 38 It has been suggested by Salem et al 39 that estradiol may inhibit inflammatory responses by suppressing the homing and activation of inflammatory cells as well as the production of tumor necrosis factor- (TNF- ) and interferon- (IFN-). Results of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study 40 suggest that estrogen therapy produces early adverse inflammatory effects on vasculature by increasing the concentration of C-reactive protein, an inflammatory factor, after which a beneficial anti-inflammatory effect occurs from a reduction in the level of soluble E-selectin. Another study by Bruce-Keller et al41 indicates that estrogen may attenuate the progression of neurodegenerative diseases by estrogen-receptordependent activation of mitogen-activated protein (MAP) kinase. MAP kinase is involved in estrogen-mediated pathways in microglial cells. The involvement of estrogen in the anti-inflammatory pathway is yet another mechanism by which estrogen may protect against AD. 40,41
Increased Utilization of Glucose

Disturbances in cerebral energy metabolism and deterioration in memory function in animal models have been decreased by estradiol administration. 57 Some findings58 suggest that the beneficial effects of estrogen on neuronal tissue are produced by the upregulation of glucose transporters and increased insulin-like growth factor 1 (IGF-1) expression. Glucose transporters were impaired when synapses were experimentally exposed to -amyloid and ferrous sulfate. When the synapses were pretreated with estradiol, the glucose transport impairment was prevented.59 The effect of estrogen on regional cerebral glucose metabolism was evaluated by means of positron-emission tomography, and the study results suggested that brain metabolic activity was affected by estrogen depletion. 60 ChAT converts choline into ACh via the acetylation of acetyl-coenzyme A, the synthesis of which is decreased in the presence of low glucose turnover in the demented brain. 61
Cytokine Regulation
The neurodegenerative -amyloid plaques seen in patients with AD cause an upregulation of the proinflammatory cytokines interleukin-1 (IL-1) and interleukin-6 (IL-6). 42 Nitric oxide (NO) exerts a protective anti-inflammatory effect on the endothelium by decreasing the level of IL-6 in the brain. Estrogen, which affects specific receptors on brain cells, can block IL-6 production by promoting vascular NO synthesis.43 NO synthesis is rapid after estrogen administration and does not decline after repeated administration.44 IL-1 activity may be potentially decreased by means of estrogen-receptormediated action as well. 43
Regeneration of Neurons in the Brain

The formation of axodendritic and spinal synapses is facilitated by estrogen.62,63 Apolipoprotein E has an important role in regenerating synaptic circuitry after neural injury. The combined effect of apolipoprotein E and estrogen modulates the neurologic effects of AD. 64
Increase in the Number of Synapses

Estrogen has been shown to increase the density of dendritic
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spines on CA1 pyramidal cell dendrites and to increase the number of spinal synapses.65 The findings of Yankova et al 65 also suggest that estrogen facilitates the formation of new synaptic connections between previously unconnected hippocampal neurons. Studies 66 show that estradiol may increase spine density and enhance N-methyl-D-aspartate (NMDA)-dependent calcium signals in spines and dendrites; this could reduce the threshold for the induction of NMDA-dependent synaptic plasticity. In rodent models, an elevated estradiol level is associated with an increased density of dendritic spine synapses on CA1 pyramidal cells, which increases hippocampal excitability as well as the potential for synaptic plasticity. 67,68 IGF-1 is believed to be involved in estrogen-induced synaptic plasticity, which may depend on the activation of both the estrogen receptor and the IGF-1 receptor.69
Clinical Trials
Observational studies and randomized clinical trials 5 of estrogen replacement therapy with or without progestin therapy have suggested that estrogen protects against age-associated decreases in cognition (particularly memory) in postmenopausal women. The results of the Womens Health Initiative, a 15-year study conducted by the National Institutes of Health, are expected in 2005. That trial is the first long-range study in which the effects of hormone replacement in older women are studied. Estrogens appear to prevent -amyloidinduced cell death and to protect remaining neurons from further cytotoxic effects. Results from that study could provide insight about the effects of estrogen replacement therapy on cognitive function and AD. 6 In general, most studies to date have confirmed that estrogen replacement therapy enhances memory and various other cognitive functions. Those results 7-12 provide support for the hypothesis that estrogen helps maintain aspects of short-term and long-term verbal memory in women but has no effect or exerts a negative influence on visual spatial memory. Flaws in studies still remain: small sample sizes, variances in the cognitive examinations used, study durations, the type of estrogen replacement therapy administered, and whether all appropriate hormone levels were monitored throughout the study period. A few
Facilitating Myelin Production and Proliferation

Neurosteroids, which are synthesized primarily by glial cells, regulate the synthesis of myelin proteins. Neurosteroids demonstrate an important role in myelin repair. Schwann cells synthesize progesterone and its direct precursor pregnenolone. Blockage of the local synthesis or action of progesterone impairs remyelination. The formation of new myelin sheaths is enhanced by progesterone administration.70
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studies 71-73 have failed to demonstrate a positive association between estrogen replacement therapy and enhanced cognitive function and memory, but those studies were limited by a small sample size and a short duration of therapy.
Components of Hormone Replacement Therapy

Studies 74,75 indicated that decreases in estradiol were associated with AD in postmenopausal women but that significant variances in estrone levels were not. At the time of this writing, many studies 5-12, 71-73 of the effects of estradiol and CEE (but not bioidentical hormones) on AD in women have been conducted. Human estrogen consists of 10% to 20% estrone, 10% to 20% estradiol, and 60% to 80% estriol. In contrast, CEE consists of 75% to 80% estrone, 5% equilin, 5% to 19% estradiol, and other estrogens. 76 Because of findings that postmenopausal women with AD have
a decreased level of estradiol,74,75 hormone replacement should include estradiol as a major component. Supplementation with bioidentical hormones supplies physiologic amounts of estradiol and replaces estrone and estriol. The use of bioidentical hormones 77-79 also prevents side effects that may be caused by the use of CEE, which contains equine hormones and metabolites80-82 foreign to the human body in addition to estradiol and estrone.
Conclusion
Many exciting prospects lie ahead in the quest for a cure for AD. Studies of the beneficial effects of estrogen replacement therapy may include evaluating the effect of estrogen on decreasing -amyloid accumulation, increasing ACh synthesis, reducing inflammation, protecting the vasculature of the central nervous system, and increasing antioxidant protection against free radicals. Less is known about the effects of enhancing the expression of neu-
rotrophins, regulating cytokines, increasing glucose utilization, enabling neuron regeneration, increasing synaptic numbers, and facilitating myelin production and proliferation, but plausible mechanisms by which neurosteroids may protect against AD have been identified. AD remains a complex multifactorial challenge for clinicians. Collaborative interdisciplinary efforts may lead to further advancements in the prevention and understanding of AD and in the treatment of those whom it afflicts. Randomized, placebo-controlled studies of large sample sizes over extended periods of time are needed before the benefits of estrogen replacement therapy for patients with AD can be fully explained.
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81.
82.
get sites for estrogen action in the dorsal hippocampus: An examination of synaptic proteins. Endocrinology 2001;142:1284-1289. Cardona-Gomez GP, Trejo JL, Fernandez AM, et al. Estrogen receptors and insulin-like growth factor-I receptors mediate estrogen-dependent synaptic plasticity . Neuroreport 2000;11:17351738. Schumacher M, Baulieu EE. Neurosteroids: Synthesis and functions in the central and peripheral nervous systems . Ciba Found Symp 1995; 191:90-106; discussion 106-112. Binder EF, Schechtman KB, Birge SJ, et al. Effects of HRT on cognitive performance in elderly women. Maturitas 2001;38:137-146. Polo-Kantola P, Portin R, Polo O, et al. The effect of short-term estrogen replacement therapy on cognition: A randomized, doubleblind cross-over trial in postmenopausal women. Obstet Gynecol 1998;91:459-466. Barrett-Connor E, Kritz-Silverstein D. Estrogen replacement therapy and cognitive function in older women . JAMA 1993;269:2637-2641. Manly JJ, Merchant CA, Jacobs DM, et al. Endogenous estrogen levels and Alzheimers disease among postmenopausal women. Neurology 2000;54:833-837. Cunningham CJ, Sinnott M, Denihan A, et al. Endogenous sex hormone levels in postmenopausal women with Alzheimers disease. J Clin Endocrinol Metab 2001;86:1099-1103. Wright JV, Schliesman B, Robinson L. Comparative measurements of serum estriol, estradiol, and estrone in non-pregnant, premenopausal women: A preliminary investigation. Altern Med Rev 1999;4:266-270. Taylor M. Alternatives to conventional hormone replacement therapy. Compr Ther 1997;23:514-532. Hargrove JT, Maxson WS, Wentz AC, et al. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstet Gynecol 1989;73:606-612. de Lignieres B, MacGregor EA. Risks and benefits of hormone replacement therapy . Cephalalgia 2000;20:164-169. Shen L, Qiu S, Chen Y, et al. Alkylation of 2'-deoxynucleosides and DNA by the Premarin metabolite 4-hydroxyequilenin semiquinone radical. Chem Res Toxicol 1998;11:94-101. Chen Y, Shen L, Zhang F, et al. The equine estrogen metabolite 4-hydroxyequilenin causes DNA single-strand breaks and oxidation of DNA bases in vitro. Chem Res Toxicol 1998;11:1105-1011. Chen Y, Liu X, Pisha E, et al. A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines. Chem Res Toxicol 2000;13:342-350.
Address correspondence to: Jennifer Osburn, 21731 Tara Park Drive, Hempstead, TX 77445. E-mail: jennifer_osburn@hotmail.com.
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LOLLIPOPS:
The Evolution of a Dosage Form
Dave Mason, DPh, FIACP Shannon Fields, PhTech Innovative Pharmacy, Edmond, Oklahoma of the huge pain category. Not long afterwards, I responded to a post on Pitcher Mountain (the electronic bulletin board of George Roentsch, RPh) from Phil Pylant of Village Pharmacy in Houston, Texas. He was facing the same frustrations with lollipop making that I had encountered. I faxed him a copy of the candy label I used and some of my auxiliary patient handouts. The next thing I knew, he was successfully making high-dose analgesic lollipops for his ear, nose, and throat (ENT) specialists to prescribe for their patients. Joe Wise (Wise Pharmacy, Littleton, Colorado) became the next person to carry the torch. He and Randy Carr (Carr Drug, New Orleans, Louisiana) had been collaborating on their lollipop making. They used the hard-candy methods and had been fighting the sugar-candyhard-ball mold battle for some time. However, they persevered and have had success with lollipops as a dosage form because Randy perfected his method of making them. Unfortunately, that technique could not easily be re-created in the pharmacy setting. The usual compounding laboratory equipment cannot provide the high temperature and extended heating that making lollipops requires. Randy would measure the ingredients, take them home, and use an old Sears Crock Pot that was perfect for the purpose. The dosage form was of the desired quality, but the technique was by no means efficient. Joe and Randy had tried a few different molds as part of the usual trial-and-error method that is essential to innovation. Often, the molds would come apart or warp as a result of the heat. The process required creativity: The mold was once sealed with several forks from the restaurant next door.
Several years ago, I decided to try my hand at making lollipops. I purchased a 12-cavity lollipop mold, a dozen bulldog clips, a candy thermometer, and a couple of pounds of sugar, and I was ready to go! A little research into candy making left me somewhat less enthusiastic: hard-ball stage, hard-crack stage, soft-ball stage, etc. Then, after sweating in the lab with the hot plate on high as the syrup boiled for hours only to reach the next texture stage, I was even more disheartened. After realizing that this procedure had to be performed almost every time lollipops are made, I uttered the words bequeathed to me by my late father, To hell with that noise.
The Benets of Networking

While at a seminar to present a talk on the success of his lollipop dosage form, Joe explained that he had made some placebo lollipops, which had been distributed to all of his professional contacts in his business community. Almost everyone who received a lollipop was either fascinated or perplexed. During or shortly after Joes presentation, Phil Pylant presented a talk on the method in which sorbitol is heated to create a liquid candy for use in formulations; he stressed how easy that is when compared with other current methods. Joe decided to try the sorbitol method and was pleasantly surprised. His lollipop business exploded. He contacted a candy company, established communications, and enabled other pharmacists to buy the candies in bulk and without wrappers. A number of pharmacists were not too excited about the lollipop mold that was available at that time. It was awkward and messy to use, and it did not produce the desired elegant dosage form that patients and prescribers expected from their pharmacists. Dan Crouch, the sourcing manager at Professional Compounding Centers of America, Inc (PCCA), heard what he called a chorus of voices: a series of complaints that served as his call to action. He used those demands for change as an opportunity to fill a particular need for his clients. He was sure that he could
If At First You Dont Succeed. . .

Accustomed to thinking outside the box, I eyed some sorbitol candies that hung on a rack at the front of our store. After we had zapped them a few times in the microwave voila! liquid candy that was ready to mix with medication and be poured into lollipop or troche molds. After a few painful episodes (physically and emotionally), I learned that if I didnt heat the candy too much, it would cool and harden in 6 to 8 hours. If the mix was superheated, it might take overnight to set. I wasnt making a lot of lollipops at the time, but I was satisfied that I had solved a problem and now had a new tool in my arsenal of dosage forms. For me, formulating lollipops was now out
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design a better mold that would result in a higher quality dosage form, and he approached the company management with his ideas for improvement. They approved Dans concept and commissioned the project. Dan quickly drew a sketch of a prototype model. The only major stumbling block was determining how to prevent the lollipop sticks from bottoming out in the mold. However, after measuring scores of sticks, he thought about using a tapered-hole design. The entire redesign process, from budding concept to fruition, took only 6 months. Dans greatest satisfaction came from not only solving a problem for the pharmacists with whom he worked but also from having helped a close friend and family member. The applications of lollipops as dosage forms soon became apparent to Eric Holgate (Custom Prescription Shoppe, Augusta, Georgia). Shortly after having seen the new lollipop mold, he heard a talk-radio hosts comments on legislation pertaining to nicotine and tobacco company lawsuits. He then thought of using lollipops to aid smoking cessation, because that dosage form provides the hand-to-mouth action that is one of the most persistent obstacles to quitting smoking. He began preparing nicotine lollipops for that purpose for his patients and prescribers. The success of that formulation enabled Eric to build a virtual franchise on techniques for quitting smoking. He now offers his clients a basic protocol for smoking cessation that includes food recipes, coun-
seling materials, and even an audiotape. A pharmacist working in my pharmacy heard Erics presentation on smoking cessation at a seminar and brought the idea home to me. I followed his lead and developed the same program that he had presented. Our nicotine lollipops became very popular at our pharmacy and at other pharmacies in our metro area after they were featured in a human interest story by a local news station. The formulation works quite well.
What Goes Around Comes Around: The Path to Success

As I was making a batch of nicotine lollipops one morning, it occurred to me how this venture has come full circle. My miniscule contribution several years ago has been adopted, nurtured, and improved by several people. Each imparted his or her particular skill, talent, or flair, and the success of that dosage form has grown exponentially. My small contribution has returned many dividends, all of which resulted from the spirit of giving, sharing, networking, and collaborating to produce the best possible answer to a need. Address correspondence to: Dave Mason, DPh, FIACP, 1716 S. Kelly, Edmond, OK 73013. E-mail: rxdave@aol.com.
W E L L N E S S
BOOK REVIEWS:
WELLNESS, NUTRITION, and GERIATRICS

Natural Approaches Index to Drug Interactions, Depletions, and Complements
Baylor Rice, RPh, and Jennifer Edelblute ACHS, LLC, Midlothian,Virginia; 2002. $130 na@customdrugs.com, 888-879-7713 An excellent resource on nutrient depletion This index was written by a pharmacist for the pharmacist. It is a reference guide designed to save time required to locate information on drug interactions, depletions, and complements. It is well-referenced and is a compilation of the best information from references such as the following: German Commission E monograph system for phytomedicines: A model for regulatory reform in the United States. In: Phytomedicines of Europe: Chemistry and Biological Activity (American Chemical Society, Distributed by Oxford University Press, Washington, DC; 1998) Review of Natural Products, 2001 (Facts & Comparisons, St. Louis, MO; 1998) PDR for Herbal Medicines 1999. 2nd ed. (Medical Economics, Montvale, NJ; 1999) Drug-Induced Nutrient Depletion Handbook (Lexi-Comp, Inc, Hudson, OH; 1999) Encyclopedia of Nutritional Supplements: The Essential Guide for Improving Your Health Naturally (Prima Publishing, Rocklin, CA; 1996) The Healing Power of Herbs (Prima Communications, Inc, Rocklin, CA; 1995) Information in this text is presented in a three-ring binder and is updated annually. It is indexed by drug, drug category, and natural ingredient (herb or nutrient) and contains more than 60 drug or drug categories and natural ingredients. The effects of the natural ingredients (depletions, complements, or interactions) are also listed. Mechanisms of action and references are also provided. This reference is easy to use, and finding information takes only a few minutes. Unlike other similar references, it contains only documented information about depletions, complements, and drug interactions. It is exactly what the pharmacist needs to recommend a natural product. Other reference texts contain extensive information on chemical compositions, dosage forms, and pharmacology. Although those topics are very valuable, locating information specifically on drug depletions is very time-consuming. This book is considerably more expensive than the Drug-Induced Nutrient Depletion Handbook, but it is much easier and faster to use, much more concise, and contains only relevant information, so it is worth the extra expense. For an additional cost, you can obtain customized natural medicine monographs, patient evaluation forms, and disease-state condition protocols for use in your pharmacy, as well as technical support and assistance.
Dana Reed-Kane, PharmD, FIACP, FACA Reeds Compounding Pharmacy Tucson, Arizona Lisa D. Ashworth, RPh Coppell, Texas
Drug-Induced Nutrient Depletion Handbook, 2nd ed

Ross Pelton, RPh, PhD, CCN; James B. LaValle, RPh, DHM, NMD, CCN; Ernest B. Hawkins, RPh, MS; and Daniel L. Krinsky, RPh, MS Lexi-Comp, Inc, Hudson, Ohio; and Natural Health Resources, Inc, Cincinnati, Ohio; 2001. $29.95 www.lexi.com, 800-837-LEXI An inexpensive reference on nutrient depletion
This well-referenced, 591-page pocket handbook is packed with facts about nutrient depletion, as well as other drug information. It lists drugs by US and Canadian brand and generic names and contains hundreds of entries. Drugs are listed with and without depletions, which accounts for the number of entries, and the book is indexed by drug and by nutrient. However, it does not contain information on drug-nutrient interactions, as did the rst edition, nor is information on herbs or complementary therapy included. Although this reference contains extensive information about the subjects mentioned above, it includes no more facts on nutrient depletion than do similar references half its size. It is difficult and time-consuming to use, and the reader is referred to several different pages and sections throughout the book when monographs on nutrients or information about drug depletion, studies, and abstracts are sought. This reference is a great resource for answering an occasional drug-information question because it is inexpensive and contains pertinent and essential information on nutrient depletion. However, for the pharmacist who wants to use that type of information daily to assist in making recommendations about nutrients, the Natural Approaches Index to Drug Interactions, Depletions, and Complements is much more complete, user-friendly, and concise.
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Recipes & Remedies: Prescription for Healthy Living

California Pharmacists Association, Sacramento, California; or Favorite Recipes Press, Nashville, Tennessee; 2000. $19.95 www.cpha.com 800-444-3851, ext. 321 Gift idea! This beautifully illustrated, elaborate, award-winning gourmet cookbook is a collection of 125 recipes compiled by the California Pharmacists Association. It contains amazing full-color pictures of and recipes for appetizers, entrees, desserts, and more. This cookbook includes tips for healthful living and information about disease awareness and prevention, proper medication use and storage, and common herb and food interactions. It also offers tips on how to modify recipes to make them heart healthful, low salt, or vegetarian. However, the recipes are complex and may require some ingredients, utensils, and cooking equipment that are not always household staples. Dana Reed-Kane, PharmD, FIACP, FACA
accurate information about medications used to treat geriatric patients (those older than 65 years of age). Any pharmacist who provides services to that population should have the Geriatric Dosage Handbook readily available. Medications are listed alphabetically by generic and brand names, and description fields are featured in boldface. Special Geriatric Considerations, a description field exclusive to this publication, provides useful information about medications associated with an increased risk of adverse events and the adjustment of a dose or dosage to decrease the incidence of adverse events in geriatric patients. The charts in this text, which are concise, accurate, and easy to access, include topics on drug therapy for the treatment of glaucoma; the management of hyperlipidemia, osteoporosis, Parkinsons disease, constipation, and heart failure; and a list of tablets that cannot be crushed or altered. The well-organized guidelines from the Health Care Financing Administration (HCFA) on the use of medications (especially the
unnecessary use of anxiolytic or hypnotic drugs in long-term healthcare facilities) are of particular interest to the consultant pharmacist. Some elderly patients travel to Mexico or Canada to purchase prescription medications at prices much lower than those charged in the United States. The description field titled Canadian Brand Names provides useful information, and the 216-page index of international brand names (which includes the trade names of medications from 21 countries and the United States) can also be used by older adults who travel worldwide. Who knows when a patient visiting a foreign country might lose his or her medication? Although the Geriatric Dosage Handbook contains extensive information on its subject, its size enables the reader to carry it in a lab coat pocket or luggage. However, older readers with poor eyesight might prefer to use a magnifying lens to read this text, which is set in small type. Lisa D. Ashworth, RPh
Geriatric Dosage Handbook, 7th ed

Todd P. Semla, PharmD, BCPS, FCCP; Judith L. Beizer, PharmD, FASCP; and Martin D. Higbee, PharmD, CGP Lexi-Comp, Inc, Hudson, Ohio; 2002. $39.95 www.lexi.com A very useful reference The authors of this book have written an outstanding text that contains current,
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Compounding in History:
THE ROAD TO WELLVILLE

Dennis B. Worthen, PhD Lloyd Library and Museum Cincinnati, Ohio
Suggestions on the mode of preserving health and attaining old age: Perfect nutrition is essential. The process of digestion must be completely and perfectly accomplished. Great attention must be paid to the habitual condition of the organs of excretionparticularly the bowels and the skin.1
health and wellness, which were then known as hygiene. Health fads of the time included phrenology and palmistry. Practitioners of those pseudosciences claimed that they could understand a patients disease and personality by studying the shape of his or her head or the length of the heart line. It was the period during which cures and restorative powers were attributed to electrotherapy, mechanotherapy, hydrotherapy, and a host of other therapies. Food was seen as both the cause and the cure for the ills of the day.
Healthful Habits and Remedies from a Century Ago

The latter part of the 19th century marked the beginning of an industry devoted to popular how-to health manuals and health fads that continued well into the next century and into the present. From the publics perspective, such printed materials and ideas were welcome. The causes of many diseases were poorly understood, and the health system offered little to combat or explain debility and chronic disease. Infectious illnesses such as tuberculosis, pneumonia, and venereal diseases continued to be major causes of death. Even many of those in the increasing middle class could not afford a doctor and his treatments. In the late 1800s, there was great interest in the general subjects of An old postcard showing the Battle Creek Sanitarium.
Leaders of the Wellness Movement

The names of three individuals involved with the dietary movement (Samuel Graham, John Harvey Kellogg, MD, and C.W. Post) were memorialized and became part of the vernacular. Samuel Graham (1794 1851) was a minister, reformer, and avid vegetarian who took on causes ranging from the dangers of feather beds and corsets to white bread and pork. He was most renowned, however, for his theories on the association of diet and masturbation and advanced the theory that diet influenced sexuality. He championed the use of coarsely ground wheat flour (quickly named graham flour), which became the basic ingredient in graham crackers. John Harvey Kellogg, MD, (1852 1943) was a physician and vegetarian who transformed a struggling Seventh Day Adventists home in Battle Creek, Michigan, into the major sanitarium* of the day. J. H. Kellogg was also an inventor: He is said to have developed the electric blanket. In addition, he devised cold cereals as breakfast food for his patients at the Battle Creek Sanitarium. His brother, William, commercialized one flaked cold cereal as Kelloggs Corn Flakes. Charles William Post (1854 1914), an inventor and businessman, was a patient at the Kellogg sanitarium. He viewed cereals and coffee substitutes as health products and promoted them via consumer advertising. He developed the dried cere-
al Grape Nuts which he claimed was a brain food that could also cure tuberculosis. He was also the developer of Postum, a cereal-based coffee substitute. Each of those men believed that health could be achieved and maintained only through the proper use of food and the equally important issue of elimination. Kellogg was particularly given to the use of enemas to cleanse the bowels. He cautioned against the habitual use of laxatives and believed that laxative abuse increased constipation instead of curing it. As a remedy for dry, hard stool, he An early recommended the Kelloggs advertising use of Neptunes trade card. girdle, or wet abdomen. That process included the bedtime routine of placing, on the patients abdomen, a towel that had been soaked in cold water, wrung out, and covered with dry flannel. The patient was then wrapped in the flannel-covered towel, which provided warmth overnight. The towel was removed the next morning, and the patient was instructed to dip the hand in cold water and percuss the bowels very thoroughly for five minutes. Go to stool within a half hour after breakfast. Have a regular time.2 In T.C. Boyles novel The Road to Wellville, one of the characters is introduced to the Battle Creek Sanitarium,* where bowel health and hygiene are emphasized. Were going to start you out for the first three days on psyllium seeds and hijiki. The psyllium is hygroscopic, it absorbs water and will expand in your stomach, scouring you out as it passes through you just as surely as if a tiny army of janitors were down there equipped with tiny scrub brushes. The same with the hijikiperfectly indigestible. Like eating a broombut that broom will sweep you clean. 3 Other physicians used a broad range of
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Formula 1. Mild Laxative.

Rx Coarse balmony Chelone glabra Butternut bark Inner bark and unripe fruit of butternut or white walnut ( Juglans cinerea ) Senna Leaves of Cassia acutifolia Bicarbonate of soda Essence of peppermint Sugar For 3 pints 4 oz 4 oz
Formula 2. Liver Pills for All Obstructions of the Liver, Gall Ducts, and Bowel.
Rx Leptandrin A resinoid prepared from Leptandra virginica Apocynin A tincture prepared from Indian hemp (Apocynum cannabinum) Shavings of white Castile soap Essence of peppermint 3 drachms
4 oz 1/2 oz 1/2 oz 2 lbs
1 drachm
Directions: Simmer the rst 3 ingredients in 5 pints of water for 2 hours, strain, and add the sugar to the water. Then slowly evaporate to 3 pints. Add the soda and peppermint. Dose: One tablespoon every 3 hours. medicines to cause evacuation of the bowels. Those remedies were divided into five groups according to the action and thoroughness desired. Laxatives provided the gentlest action (Formula 1).4 Mild cathartics were used for thorough bowel cleansing without irritation. Cholagogue cathartics acted on the liver by increasing bile secretion (Formula 2).4 Hydragogue cathartics produced large volumes of watery discharge, and irritant cathartics produced a vigorous evacuation of the bowel. 5
2 drachms qs
Directions: Soften the soap with a small amount of the essence of peppermint and mix the powders into a pill mass. Dose: Two pills at bedtime.
4. Cook WH. Womans Book of Health: A Guide for the Wife, Mother, and the Nurse. 8th ed. Cincinnati:W Wesley Cook Publisher; 1884:399-400. 5. Scudder JM. Domestic Medicine or Home Book on Health, A Popular Treatise on Anatomy, Physiology, Hygiene, Materia Medica, Surgery, Practice of Medicine and Nursing. Cincinnati, OH:J Hawley & Co; 1865:198. 6. Lorand A. Old Age Deferred: The Causes of Old Age and Its Postponement by Hygienic and Therapeutic Measures. 3rd ed. Philadelphia, PA:FA Davis; 1912:423.
Illness and the Intellect

Not all the theories regarding health and wellness focused exclusively on the digestive tract. Arnold Lorand explored geriatrics, including the possible postponement of aging by practicing hygienic measures. In his book, Old Age Deferred , he offered advice to brainworkers (something of particular interest to pharmacists, teachers, and writers). He commented on the physical appearance of those who earned their living
by intellectual pursuits. They, he theorized, were subject to chronic constipation and nervous and intestinal disorders because blood was diverted from the digestive tract to the brain during intellectual activities. His solution was that: Intellectual activity should, if possible, be suspended a full hour before and after meals. Congestion of the brain likewise interferes with proper sleep, which, as a rule, can only become truly deep when the brain is bloodless. Intellectual efforts should therefore be avoided for a period of one to two hours before going to bed, and especially one should not read in bed. 6
References
1. Fitch SS. A Treatise on Health, Its Aids and Hindrances Containing an Exposition of the Causes and Cures of Disease and the Laws of Life. NY:Pudney and Russell; 1857:505-506. 2. Kellogg JH. Man the Masterpiece of Plain Truths Plainly Told About Boyhood, Youth, and Manhood. Des Moines:WD Conduit; 1889:588-589. 3. Boyle TC. The Road to Wellville . NY;Viking; 1992:117.
Address correspondence to: Dennis B. Worthen, PhD, The Lloyd Library and Museum, 917 Plum Street, Cincinnati, OH 45202. E-mail: dbworthen@fuse.net *According to Dorlands Illustrated Medical Dictionary (26th ed, Philadelphia:WB Saunders Co; 1985), the term sanitarium was coined to refer to the Seventh Day Adventist institution in Battle Creek, Michigan, to distinguish it from institutions called sanitoriums providing care for patients with psychiatric disorders or tuberculosis.
The Pharmacists Toast

May his occupation never become a drug in the market, as long as he sticks like his own plasters, to business! May he never be bruised in the mortar of adversity by the pestle of misfortune, and may his rise in his profession be as accurately marked as his graduated measure. May his career be as unsullied as distilled water and as smooth and pleasant as pure Narbonne honey! May his success never be alloyed
by a mixture of ill-luck or a tincture of regret! May his counter prove the crucible whereby he transmutes human ailments into precious metal and precipitates the golden deposit into his own pocket! May he never be called upon to swallow the bitter pill of disappointment or be macerated in the bitter spirit of enmity! Should fickle Fortune ever refuse him her smiles, may he find an antidote in the soothing opiate of womans love, be strengthened by the tonic of experience and purified by
the sudorific of patience! Thus, his best days being evaporated and the lamp of existence past trimming, when Dr. Death sends to his shop the dreadful prescription endorsed To be taken at bedtime and labeled and directed for heaven. The Apothecary March 1943 Editors note: Dr. Dennis Worthen discovered this article while scanning journals for material on World War II. It is reprinted from The Apothecary, a regional journal for northeastern America that is no longer in print.
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How To Perform a Study in Your Pharmacy with Little or No Effort

Dana Reed-Kane, PharmD, FIACP, FACA Reeds Compounding Pharmacy Tucson, Arizona
Sources of Assistance in Performing a Study

Most pharmacy programs today require their students to complete a senior project before graduation, and compounding pharmacies are an excellent source of interesting and pertinent subjects. If you have a unique program, service, or formulation, then you have good material for a study. Students are eager to publish an article on work in which they have participated and thus distinguish themselves from their colleagues. The International Journal of Pharmaceutical Compounding is an excellent journal in which to publish studies pertaining to compounding. In this age of criticism from the medical and legal communities, compounding pharmacists must prove the worth of their products and services. It is important to validate our work as compounders. Conducting and publishing studies lend validity to our mission and our professional objectives. Students are excellent at performing pharmacy-based studies. They are taught research methods and techniques in school and can aid community practitioners with their knowledge. The world of drug information is constantly changing, and pharmacy students have kept abreast of recent information, up-to-date techniques, and various methods of data collection. They can help community pharmacists to be up-to-date as well. We provide such unique services and create a wide variety of products for patients! It is a shame not to network with our colleagues to share information of interest. This sharing helps our profession and benefits patients as well. Reach out to pharmacy students. You may be able to secure help in conducting a study that provides valid information for a professional audience as you introduce a student to the wonderful opportunities available in compounding pharmacy.
Have you ever created a magnificent compound? Has that compound ever been rejected by a provider because you did not have a study to prove its safety and effectiveness? If so, you may consider performing a study in your pharmacy to do just that. You might be concerned about whether you have the time or expertise, but performing a study can be as easy as calling the nearest college of pharmacy.
How To Find Your Intern or Resident

Here are suggestions for finding and working with a student in your pharmacy: Contact a local college or school of pharmacy about your interest in having a student perform a study in your pharmacy. Send a list of possible topics to be studied. Collaborate with a professor (perhaps from the disciplines of pharmacy practice, ambulatory practice, or pharmaceutics) in the college of pharmacy.
Hire a student to work in your pharmacy as an intern full-time, part-time, or during the summer.
Contact a local college or school of pharmacy about methods of advertising opportunities for interns in your pharmacy. Students can be a great asset to your business. They take great pride in their work and are constantly seeking knowledge. They can also perform more tasks than a technician can; this will make your job much easier. After a student has worked in the pharmacy, he or she can identify ideas for projects and studies to conduct. Pharmacy students are pharmacists in training, and the experience of working on scholarly research and publishing a related article can benefit you and your intern.
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Become a preceptor for students at a local college or school of pharmacy.

Contact colleges of pharmacy about your interest in becoming a preceptor. Each school usually has a clerkship coordinator. Some programs pay preceptors for their time and expertise. If a college of pharmacy is not nearby, you can become a preceptor at a school of pharmacy. Some may require that you offer housing for the student, but this is not always a prerequisite. Most schools of pharmacy require students to complete 4- to 6-week internships or rotations through various practice sites. Pharmacy students are not paid during their rotations with preceptors, so this may offset the costs of training, housing, etc. Students often have more to offer you than you have to offer them. Contact your student before he or she accepts the assignment in your pharmacy to discuss conducting a study.
Develop a residency program in your pharmacy.

Residents are pharmacists who have just graduated from pharmacy school. Students often undertake a residency to gain more knowledge in certain specialty areas of pharmacy practice before they enter the work force. Residents salaries usually amount to about half that of a staff pharmacists wages. In return for the reduced pay, residents
expect a valuable learning experience. A resident is usually expected to work on special projects, perform studies, develop programs, and serve as a member of the pharmacy staff. If you are interested in developing a disease management program on diabetes, osteoporosis, asthma, anticoagulation, heart disease, womens health, or mens health or in creating a new service such as compounding, a resident could help develop, manage, market, study, and facilitate your program of interest. For the pharmacist, residents are even more valuable than interns. Hiring a resident is a great way in which to train a new pharmacist to work for you. Many organizations sponsor and accredit residency programs. For more information on how to establish a residency program in your pharmacy, contact the American Society of HealthSystem Pharmacists (ASHP), the American Pharmaceutical Association (APhA), the National Community Pharmacists Association (NCPA), or the International Academy of Compounding Pharmacists (IACP). Assistance in developing a residency program can be obtained from a college of pharmacy. Address correspondence to: Dana Reed-Kane, PharmD, FIACP, FACA, Reeds Compounding Pharmacy, 2729 E. Speedway, Tucson, AZ 85716.
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TECHNOLOGY SPOTLIGHT:
ELECTRIC MIXING
MACHINES
Gary Schneider, RPh Gallipot, Inc, St. Paul, Minnesota
pound remains in its Unguator jar, which is then used for both dispensing and storage. This ensures maximum shelf life for the product. Each jar is equipped with a sliding, push-up bottom that facilitates the expulsion of air before and after the ingredients are mixed. Each jar lid accepts a special tip designed to accommodate the flow of preparations of various viscosities. The jar tips provide the benefits of ointment tubes without the hassles of filling and sealing. Instead of unscrewing the container and removing product with a contaminated finger or implement, the patient can withdraw a small amount of the formulation from the jar tip.
EMP Models and Accessories Electronic Mixing Machines: The Benets

Compounding pharmacists are always looking for ways to improve compounding procedures, provide pharmaceutically elegant preparations, and reduce nonproductive time. In Germany, where acquiring an ointment mill is a prerequisite to obtaining a pharmacy license, the Electro Mortar and Pestle (EMP) is considered an approved alternative. In 1994, the German-made Unguator Mixing System, a mechanical mixing unit, was designed to facilitate the preparation and compounding of ointments, creams, and a wide range of other pharmaceutical formulations. Various products of high or low viscosity (emulsions, suspensions, lotions, gels, creams, pastes, ointments) can be prepared hygienically and easily with the Unguator. Ingredients can be weighed and added to one of several Unguator jars before being mixed; wetting agents and premixing are unnecessary. Homogeneous formulations are prepared quickly and precisely in each jar, and the closed, air-tight system prevents microbiologic contamination. The product quality is excellent, and the clean-up is minimal. The finished comTwo models of the EMP are available. The Cito-Unguator-e is fully automatic. It mixes quantities between 15 and 500 mL. Mixing time and speed are set before the jar is attached. During the use of Cito-Unguator-e, the mixing blade and arm move the jar up and down automatically; this ensures that the ingredients inside the jar are homogeneous after being mixed. After the pharmacist has compounded a particular formulation a few times, routine settings can be documented for that preparation, which can then be mixed in the same manner whenever it is prepared and regardless of the operator. Although it has electronic features of operation, the Cito-Unguator-B requires some manual operation (the ingredients in the jar must be mixed manually with an up-and-down motion). The Cito-Unguator-B is designed to mix quantities up to 200 mL. Two types of mixing blades are included with either model. Each standard mixing blade consists of a titanium hardened metal shaft with a uniquely shaped polyoximethylene blade. Several sizes of blades matched to the corresponding Unguator jar are available. This optimizes mixing results. The blades work nicely for blending powders. Disposable mixing blades are also available. After the ingredients have been mixed, the blade remains in the jar to preserve the closed system, prevent contamination of the nal preparation, and reduce clean-up time. Several accessories are also available. Unguator jar coupling or transfer adapters connect jar tips so that the pharmacist can mix ingredients in larger volumes and transfer the mixture into small jars for dispensing. Several applicator tip sizes that direct the medication to a precise area can be obtained. Some imaginative pharmacists use those tips to fill oral dosing syringes and for other unique and innovative purposes.
Special Features of Unguator EMPs

Quick, precise, homogeneous preparation of formulations in a dual-purpose jar. A closed-air system minimizes microbiologic contamination. Excellent product quality, minimal cleanup. Ensured reproducibility of formulations.
For more information, contact:

Gary Schneider, Martin Erickson III, or Clark Zander, Gallipot, Inc, 2020 Silver Bell Road, St. Paul, MN 55122, 800-4236967 The Electro mortar and pestle is also supplied by Professional Compounding Centers of America (PCCA), 800-3312498; and Spectrum Pharmacy Products, 800-791-3210, ext. 301.
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TREATMENT OF PAIN WITH A TOPICALLY APPLIED COMBINATION OF

Abstract
We evaluated 30 patient charts to determine the effectiveness of a topically applied combination of indomethacin and piroxicam in the treatment of osteopathologic pain of various intensities in hospice patients. The study was designed as a retrospective follow-up to determine whether that combination of drugs resulted in pain reduction. The level of pain experienced by each subject was noted at three intervals after the administration of the topical indomethacin and piroxicam combination in gel form. Patients pain scores were reduced by a median of 2 points on a 10-point scale; those results
IN D O M E T H A C I N AND P I R O X I C A M
Eric R. Vetter, RPh, PharmD (Candidate) Ferris State University Big Rapids, Michigan did not reach statistical significance. Twenty-one of the 30 subjects treated with the combination of topically applied indomethacin and piroxicam noted an improvement in their pain score. Lawrence Curtis, RPh Portage Pharmacy Portage, Michigan priate therapy for hospice patients and in improving the outcome of treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been recognized as a valuable analgesic option for patients with many different types of pain. In fact, NSAIDs are considered first-line drugs of choice in the treatment of osteopathologic pain, which is an ailment that afflicts many hospice patients. 1-6 NSAIDs are often used to treat other types of pain (muscle ache, arthritis) as well. 3,7
Introduction
In the hospice setting, it is important to remember that the best therapy may be one for which the traditional dosing route is ineffective. The compounding pharmacist can play a crucial role in designing appro-
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NSAIDs are cost-effective as primary or adjuvant therapy for controlling pain in hospice patients and should therefore be used whenever clinically appropriate.1,8 Selecting effective treatment for patients unable to take oral medication is a challenge for the hospice team. No topically applied NSAIDs have been approved by the Food and Drug Administration and are therefore unavailable in the United States, and only indomethacin and aspirin are commercially available in suppository form. 9 A number of NSAIDs such as flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, and piroxicam are systemically absorbed when applied topically, and most NSAIDs have been effective in treating osteopathologic pain in controlled trials. 10 Topical use of NSAIDs may also be associated with a decrease in side effects, although that claim requires further investigation. 11
Materials and Methods

We conducted a retrospective followup study of 30 patients with various primary or metastatic malignancies. Although pain ratings varied among the patients studied, all required analgesia. The goal of our study was to determine the level of analgesia provided by applying a combination of indomethacin and piroxicam in gel form to the inner wrist. We have been using that preparation since
Table 1. Demographics of Patients Treated with Indomethacin and Piroxicam Gel for Pain.*
Variable Age (mean) Age range Race Caucasian Black Asian Opioid use at initiation of treatment Ability to walk Yes No Not noted
* n = 30.
No. Patients 77 yrs 38 - 94 yrs 28 1 1 26 16 9 5
1997 to treat osteopathologic pain in hospice patients. Indomethacin and piroxicam were selected as the active components because both of those products produce analgesia when applied topically. 10,12 In addition, it was felt that the pharmacokinetic profile of each agent improved the effectiveness of that combination of drugs, because indomethacin is usually considered to be the more effective of the two and piroxicam has a longer duration of action.3,13-14 Therefore, the combination of indomethacin and piroxicam maximizes the effectiveness of the medication and its duration of effect. We usually prepare indomethacin-piroxicam gel (IPG) in a concentration of indomethacin 50 milligrams and piroxicam 10 milligrams per milliliter in a Pluronic lecithin organogel (PLO) base. We have also compounded IPG in concentrations of 100/20 mg/mL, 100/10 mg/mL, and 25/5 mg/mL for various patients. Our physicians usually order the 50/10 formulation. In our study, only one patient used a different concentration. The subjects in our study were identified by means of a drug utilization program installed in our pharmacy computer. We searched all compounded drugs containing indomethacin and piroxicam that were dispensed by our pharmacy between January 1, 1998, and September 1, 2000, and the search results produced our patient population. We limited the search to one hospice group, although our pharmacy provides services for several. Sixty-five men and women (age range, 38 to 94 years) were identified via the computer program. All had documented symptoms of osteopathologic pain that ranged in duration from 3 days to 4 weeks and required treatment.
Patients were included in the study if they were undergoing treatment with IPG (50/10 mg/mL, 100/10 mg/mL, 100/20 mg/mL, or 25/5 mg/mL) as verified by the chart review. A visual analog scale (VAS) was used by the primary hospice nurse to evaluate and record the pain level of each patient. Our VAS had a rangeof-pain rating from 0 to 10, where 0 represented no pain and 10 represented the worst pain possible. Subjects selected for the study must have had a VAS pain rating of greater than or equal to 1 and a median pain rating of less than or equal to 9 at the initiation of treatment with IPG. A VAS rating must have been recorded for patients with new-onset pain within 24 hours of the initiation of treatment with IPG. For patients with chronic pain, a VAS recorded within 3 days of the initiation of treatment with IPG was acceptable. All patients must have had a VAS recorded no more than 3 days after the initiation of treatment with the gel to be included in the study. The only patients excluded as participants were those treated for neuropathic pain. Hospice medical records were available for 60 (92%) of the 65 patients identified. The date on which treatment with IPG was initiated was identified via chart review. We collected data on each patients age, gender, race, use of opioids, and whether or not he or she was ambulatory at initiation of therapy. The dose and directions for application, including application site, were noted when that information was available. We recorded and used the five most recent VAS results for each patient; if five results were unavailable, we used all available ratings. For patients who experienced chronic pain, we recorded the five most recent VAS ratings obtained before
Table 2. Visual Analog Scale Results of Patients Treated with Indomethacin and Piroxicam Gel for Pain.
Baseline VAS Pain relieved after treatment (n = 21) Pain maintained after treatment (n = 5) No improvement in pain treatment (n = 4)
VAS = Visual analog scale.
First VAS (median) Patients (median) 3 4 2.75 0 4 7
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the initiation of treatment with IPG. For patients with new-onset pain, only the five VAS ratings recorded after new pain had begun were used. Patient demographic data are listed in Table 1. Of the 60 patients reviewed, 8 were excluded because no VAS rating had been recorded before the rst use of IPG, 12 were excluded because no rating had been assigned within the mandatory 3 days after the initiation of therapy, 5 patients had neither a before nor after VAS rating, 2 had a VAS rating of 0 at the initiation of treatment with IPG, 2 more were excluded because their chart contained no record of IPG use, and 1 patient was excluded because she was being treated for neuropathic pain.
Results
Thirty patients were included in the final evaluation of the effectiveness of topically applied IPG in treating pain. Pain score data were evaluated for each patient by taking a patients median pain rating before the administration of IPG and comparing it with the rating at three points in time: the first available rating (n = 30), the rating 1 week after the initiation of therapy with topical IPG (n = 25), and the rating 2 weeks after the initiation of therapy with topical IPG (n = 17). The median pain rating before the administration of
IPG was 3 (range, 2 to 6). Twenty-one of a total of 30 patients reported an improvement in pain indicated by a reduction in the VAS rating within 3 days after treatment with IPG. Five patients noted no change in their pain after treatment with IPG, and the remaining four patients noted greater pain after treatment (Table 2). Figure 1 features a graph of the pain ratings of the 30 subjects before and after treatment with IPG was initiated. The points on the line in the center of the graph represent patients who experienced no change in their level of pain. Any point below the line represents an improvement in pain relief, and any point above the line represents no improvement. Thirteen of the 21 patients who experienced pain relief reported having no pain at all (VAS = 0) on their first evaluation after treatment with IPG was initiated. Figure 2 shows the trend toward an improvement in the level of pain after treatment with IPG. A Wilcoxon signed rank confidence interval and test for the median were conducted to evaluate the data. At the rst evaluation point, there was a median decrease of 2 points on the VAS (95% CI, 0.5 - 2). That decrease approached but did not reach statistical significance ( P = 0.089). One week after the initiation of treatment, the median decrease was 2 points (95% CI, 0 - 2). That decrease was not statistically
signicant (P = 0.125). The median decrease at the 2-week interval was again an absolute value of 2 points (95% CI, 0.5 - 3), but again, that was not statistically significant ( P = 0.638). Patients were also evaluated to determine whether pain relief varied according to gender. Pain scores were evaluated when the first VAS rating was obtained ( P = 0.676), 1 week after the initiation of therapy (P = 0.157), and 2 weeks after the initiation of therapy (P = 0.564), but no differences in the level of pain according to gender were found. A chi-square test of independence was conducted to determine whether opioid use or ambulatory status and a change in the VAS were related, but those relationships were not significant. Because many charts did not contain an objective VAS rating, the patients subjective statements of effect, regardless of their VAS scores, were also evaluated. Fifty-seven charts were reviewed; patients without verification of IPG use and the patient with neuropathic pain were excluded. No subjective statements about the degree of pain relief resulting from treatment with IPG were noted in 31 (54%) of the 57 charts evaluated. Twenty-three of the remaining 26 charts contained positive statements about treatment-related pain relief, and only 3 listed IPG as ineffective.
Figure 1. Visual Analog Scale Pain Ratings of Patients Treated with Indomethacin-Piroxicam Gel (IPG).
Patient Pain Ratings
10 9 Rating after treatment with IPG 8 7 6 5 4 3 2 1 0 0 1 2 3 4 5 Rating before treatment with IPG 6 7 8 9 10
Figure 2. Effect of Treatment with Indomethacin-Piroxicam Gel (IPG).

Patient Pain Ratings
10 9 Rating after treatment with IPG 8 7 6 5 4 3 2 1 0 0 1 2 3 4 5 Rating before treatment with IPG 6 7 8 9 10 y = 0.6312x
No improvement (n = 4) Improvement (n = 21)
No improvement (n = 4) Improvement (n = 21)
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Discussion
Analyses of these results suggest that IPG is a valid primary or adjuvant agent in the treatment of pain, especially osteopathologic or arthritic pain. We would have preferred that a decrease occurred in the amount of opioid analgesics used by our patients. Unfortunately, many patients receive opioids as needed for pain control, and we were unable to determine from our chart review whether the use of opioids changed in our subjects after treatment with IPG was initiated. Most patients with cancer-related pain require a combination of opioid and nonopioid medications. Although the trend and overall effectiveness of IPG was good, the benefit of treatment did not reach statistical significance. We believe this is due primarily to the small sample size of our study. Seventy percent of our patients treated with IPG noted a reduction in their pain. In most patients, pain relief was noted within the first 24 hours of the initiation of treatment with IPG, although more time was required in some cases. The benefit of that topically applied NSAID was maintained during the 2-week review period. Patients who report that the effect of the medication diminishes over time can be treated with IPG every 6 or 8 hours, but most of our patients indicated that a 12-hour dosing schedule was sufficient to maintain a reduced level of pain.
Conclusion
Hospice patients often require many different forms of therapy to control pain. Controlling that pain while the patient is undergoing significant changes in his or her disease state is often a challenge for the hospice team. This is especially true when oral medications can no longer be administered. NSAIDs, which are effective and do not cause central nervous system or respiratory depression, remain a favorite treatment for pain in those patients. The role of the compounding pharmacist in preparing topical NSAIDs should not be ignored. We believe that this retrospective analysis paves the way for a well-designed, randomized, controlled trial that will prove the benefit of topical NSAID combinations in the treatment of chronic pain.
Acknowledgments
We thank our statistician, Diana Cucos, for reviewing the results of this study, and the staff of the Hospice of Holland in Holland, Michigan, for allowing us to evaluate the effectiveness of IPG in their patients.
References
1. 2. 3. 4. Thurlimann B, de Stoutz ND. Causes and treatment of bone pain of malignant origin. Drugs 1996;51:383-398. Payne R. Mechanisms and management of bone pain. Cancer 1997;80 (suppl):1608-1613. Bushnell TG, Justins DM. Choosing the right analgesic. A guide to selection. Drugs 1993;46:394-408. Gordon RL. Prolonged central intravenous ketorolac continuous infusion in a cancer patient with intractable bone pain. Ann Pharmacother 1998;32:193-196. Levick S, Jacobs C, Loukas DF, et al. Naproxen sodium in treatment of bone pain due to metastatic cancer. Pain 1988;35:253-258. Lomen PL, Samal BA, Lamborn KR, et al. Flurbiprofen for the treatment of bone pain in patients with metastatic breast cancer. Am J Med 1986; 80:83-87. Gotzsche P. Non-steroidal anti-inflammatory drugs. BMJ 2000;320: 1058-1061. Bailes J. Cost aspects of palliative cancer care. Semin Oncol 1995;22 (suppl 3):64-66. [No author listed.] Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000. Moore RA, Tramer MR, Carroll D, et al. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ 1998;316: 333-338. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal conditions. A review of the literature. Drugs 1998;56:783-799. El-Faham TH, Safwat SM. Comparative study of the release and anti-inflammatory activity of indomethacin from topical formulations. Pharm Ind 1992;54:82-86. Indocin [package insert].West Point, PA: Merck; 1998. Feldene [package insert]. Memphis, TN: Pfizer; 1999.
5. 6.
7. 8. 9. 10.
11. 12.
13. 14.
Address correspondence to: Lawrence Curtis, RPh, Portage Pharmacy, 1256 East Centre Street, Portage, MI 49002. E-mail: ips@net-link.net.
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MEDICATIONS DISCONTINUED IN THE UNITED STATES

Ergotamine is an alkaloid derived from ergot, the sclerotium of the fungus Claviceps purpurea , which develops in the ovary of rye (Secale cereale). Ergot has powerful vasoconstricting and oxytocic actions.1 Ergotamine is slowly and incompletely absorbed from the gastrointestinal tract. 2 Lisa D. Ashworth, RPh, Coppell, Texas portional to the promptness with which ergotamine tartrate tablets are administered after the onset of headache. When treatment is administered early in the course of a headache, the required dosage needed may be decreased considerably. If the headache has reached its peak, more medication is required to relieve symptoms, and the incidence of drug-related side effects increases.
Ergotamine Tartrate Tablets

(Ergostat, Ergomar, Gynergen, others)2 This medication has been available since 1951, as manufactured by Lilly.3 At one time, ergotamine tartrate tablets were manufactured by Parke-Davis. While on the market, ergotamine tartrate was available in 1-mg (oral) and 2-mg (sublingual) tablets. When discontinued from the market in 1996, it was available in a 2-mg sublingual tablet.4 Indications. Treatment for migraines or cluster headaches. A dose of 2 mg is to be taken or given at the onset of headache, and 2 mg can be taken every 30 minutes thereafter as needed up to a maximum dose of 6 mg during one headache or migraine episode.2 A patient should not ingest more than 10 mg per week.2 Overdosage is the primary cause of adverse effects produced by ergotamine; the smallest amount needed to relieve headache should be administered. The extent and rapidity of pain relief are directly pro-
References
1. 2. 3. 4. Partt K, ed. MARTINDALE: The Complete Drug Reference. 32nd ed. London:The Pharmaceutical Press; 1999:1576. Gilman AG, Goodman LS, Gilman A. Goodman and Gilmans: The Pharmacological Basis of Therapeutics. 6th ed. New York:Macmillan; 1980:946. Kastrup EK. Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 1951. Drake E, Drake R. Saunders Pharmaceutical Word Book 2001. Philadelphia:PA:WB Saunders Company; 2001.
Address correspondence to: Lisa D. Ashworth, RPh, 638 Havencrest Lane, Coppell, TX 75019-5722.
Dont miss the related formulas featured on the IJPC Website at www.ijpc.com.
G E N E R A L
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BASICS OF COMPOUNDING
Loyd V. Allen, Jr, PhD, RPh corneum according to the basic electrical principle that like charges repel each other and opposite charges attract. In practice, a solution of the drug in a pad or a gel is placed on the skin. An active electrode is placed on this pad or gel, and the return electrode is placed elsewhere on the body. A small electrical current (usually less than 1 mA) is applied for a period of time (usually 15 to 20 minutes). The drug travels through the tissue and can thus exert its local effect or is carried by the microcirculation to produce an eventual systemic effect.
IONTOPHORESIS
Introduction
The transdermal administration of drugs has an important role in modern drug therapy. The transdermal route is now used primarily to administer nonionized drugs that are required in a relatively small dosage. In that method of treatment, the laws of passive diffusion transport the nonionized drug through the rate-limiting dermal
PART 1
membrane (the stratum corneum). Ionized drugs, however, do not easily penetrate the stratum corneum and are thus unsuitable in routine transdermal dosage forms unless an external source of energy enables the drug to penetrate that barrier. In iontophoresis (IP), that external source of energy takes the form of an applied direct electrical current. Electrical energy assists the movement of ions across the stratum
Table 1. Drugs and Chemicals First Investigated for Use in Iontophoresis.

Year 1937 1941 1942 1950 1954 1955 1964 1965 1967 1969 1973 1974 1975 1977 1978 Drug Name Histamine Cl Ragweed pollen extract Sulfa drugs, grasses Sodium iodide Citrate Phosphorus, hyaluronidase Lidocaine HCl Iodine, penicillin Hydrocortisone phosphate, pilocarpine, zinc, esteried glucocorticoids Sodium salicylate Lidocaine HCl, phenylbutazone Methylene blue, potassium iodide Calcium, insulin Vidarabine monophosphate, idoxuridine, acetic acid, triamcinolone Procaine HCl, cocaine HCl, bupivacaine HCl, mepivacaine HCl, prilocaine HCl, epinephrine bitartrate, levarterenol bitartrate, phenylephrine HCl, methylprednisolone sodium succinate, hydrocortisone sodium succinate, methotrexate, cyclophosphamide, bleomycin, doxorubicin, adenosine salts (var), uridine salts (var), thymidine salts, thymine arabinoside Dexamethasone sodium phosphate Zinc oxide Copper, vasopressin, alkaloids, papaverine, nicotinic acid, lidocaine HCl with epinephrine HCl Sodium uoride, 6-hydroxydopamine Gentamicin sulfate, N-acetylcysteine, sodium cefoxitin, benzydamine, uorescein Metoprolol, uorescein, cefazolin sodium, ticarcillin, cortisone, sodium benzoate, thyrotropin-releasing hormone, sulfadiazine, sulfapyridine, sulfathiazole, sulfacetamide Diphenhydramine HCl, catecholamines, oxycodone
History of IP
IP (cataphoresis, ionic treatment, electrolytic treatment, ion transfer, electrophoresis) was invented early in this century when, in 1908, Le Duc demonstrated that ions could be driven across the skin by means of an electric current. 1,2 From that time until 1924, many studies of ophthalmologic IP were conducted, but the results were not always successful. Adverse sequelae included corneal scarring, burned tissue, and (occasionally) the induction of electrical shock. In 1911, Albrecht3 studied the successful use of IP in which a combination of cocaine and epinephrine was used to anesthetize the tympanic membrane. However, only limited anesthesia to the external auditory meatus was achieved with that technique. Those and other major technical problems were associated with the early use of IP, which was virtually disContinuing Education Goal: To provide pharmacists, pharmacy students, and pharmacy technicians with supportive information on the basics of compounding solutions for iontophoretic administration Objectives: After reading and studying the article, the reader will be able to: 1. Discuss the history of iontophoresis 2. Discuss the applications of iontophoresis 2. Discuss the general process of iontophoresis 3. Describe the variables that affect iontophoresis 4. List at least five drugs that are administered iontophoretically
1980 1981 1982 1983 1984 1986
1987
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carded until the early 1940s. At that time, it was again used in the experimental (and successful) transfer of penicillin and sulfadiazine into the infected eyes of animals.1,2 Over the years, studies have chronicled the iontophoretic administration of various medications in the treatment of widely varying disorders: glycopyrronium bromide for hyperhidrosis, sodium salicylate
for palmar and plantar warts, steroids for Peyronies disease, acetic acid for calcium deposits in muscle and joint disorders, and -chymotrypsin for inflammatory reactions involving joints and soft tissues. Some studies 1 have included the iontophoretic administration of local anesthetics combined with steroids to treat muscle and tendon injuries.
IP of penicillin into burn eschars has been used to decrease the risk of severe infection in patients who have sustained burns, and histamine has been administered iontophoretically to induce local capillary dilatation, which enables the accurate determination of blood gases. It has also been used to promoted the healing of chronic sclerotic ulcers. IP of local anesthetic
Table 2. Drugs Used for Iontophoresis.

Drug Solution Acetic acid Atropine sulfate Calcium chloride Sodium chloride Potassium citrate Copper sulfate Dexamethasone sodium phosphate Estriol Fentanyl citrate Fluoride sodium Gentamicin sulfate Glycopyrronium bromide Hyaluronidase Idoxuridine Iodine ointment Iron oxide or titanium oxide Lidocaine hydrochloride with or without epinephrine (1:50,000 1:100,000) Lithium chloride Magnesium sulfate Metholoyl chloride Meladinine sodium Methylphenidate hydrochloride Morphine sulfate Pilocarpine hydrochloride Poldine methyl sulfate Potassium iodide Sodium salicylate Tretinoin Water Zinc oxide suspension Percent Concentration 2-5 0.001 - 0.01 2 2 2 2 0.4 Varies Varies 2 0.8 0.05 150 U/mL solution 0.1 4.7 Varies 4 Use or Indication Calcium deposits, calcified tendonitis Hyperhidrosis Myopathy, myospasm, immobile joints Sclerosant, scar tissue, adhesions, keloids Rheumatoid arthritis Astringent, fungus infection Tendonitis, bursitis, arthritis, tenosynovitis, Peyronies disease Acne scars Analgesia Desensitization of teeth Otochondritis Hyperhidrosis Enhancement of absorption, edema, scleroderma, lymphedema Herpes simplex Sclerosant, antimicrobial, fibrosis, adhesions, scar tissue, trigger finger Skin pigmentation Dermal anesthetic, trigeminal neuralgia Polarity Negative Positive Positive Negative Negative Positive Negative Positive Positive Positive Positive Positive Positive Negative Negative Positive Positive
2 2 0.25 1 Varies 0.2 - 0.4 Varies 0.05 - 0.5 10 2 Varies 100 20
Gouty arthritis Muscle relaxant, vasodilator, myalgias, neuritis, deltoid bursitis, low-back spasm Vasodilator, muscle relaxant, radiculitis, varicose ulcers Vitiligo Attention deficit disorder Analgesia Sweat test for cystic fibrosis Hyperhidrosis Scar tissue Analgesic, sclerosant, plantar warts, scar tissue, myalgias Acne scars Palmar, plantar, or axillary hyperhidrosis Antisepsis, ulcers, dermatitis, wound healing
Positive Positive Positive Negative Positive Positive Positive Negative Negative Negative Positive Positive and negative Positive
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agents has been used during tooth extraction and the treatment of infected tooth root canals, as well as to deposit fluoride into the dentin of teeth. For some years, many practitioners have considered using IP to administer insulin to patients with diabetes. That method of treatment has several advantages. IP is used to administer continuous subcutaneous insulin infusions, and when suitable patient-adjusted current control is permitted it is theoretically feasible to administer insulin in both baseline and bolus dosages. No transcutaneous penetration by needle is necessary, and therefore localized infections, inflammation, and localized fibrosis are prevented, as is crystallization, because insulin does not traverse narrow tubing. Harris 4 concluded that IP is a clinically
effective, painless, and safe mode of delivering ionized anti-inflammatory drugs to inflamed tissues. Also, DeLacerda 5 has demonstrated that IP is more effective than treatment with muscle relaxants, analgesics, or hydrocollator-ultrasonographic modalities in the administration of anti-inflammatory drugs to treat shoulder-girdle myofascial syndrome. Many drugs such as lidocaine, dexamethasone, and sodium fluoride, which have been investigated for their potential use in IP, are used for the treatment of that syndrome today (Table 1).
induces an increased migration of ionic drugs into the skin by electrostatic repulsion at the active electrode: Negative ions are delivered by the cathode and positive ions by the anode. A typical iontophoretic device consists of a battery, a microprocessor controller, a drug reservoir, and electrodes.
Advantages of IP
The advantages of IP include providing a controlled rate of drug delivery (by varying the current density, pulsed voltage, drug concentration, and ionic strength); eliminating the effects of erratic drug absorption, first-pass metabolism, and gastrointestinal incompatibility with some drugs; reducing side effects and minimizing interpatient variability; obviating the risks of infection, inflammation, and fibrosis associated with continuous injection or infusion; and enhancing patient compliance by providing a convenient, noninvasive therapeutic regimen. In addition, IP units are being manufactured in increasingly smaller sizes.
Mechanism of Action of IP
During IP, a potential gradient through the skin tissue is created with an applied electrical current or voltage. That energy
Table 3. Equipment Used for Iontophoresis.

Manufacturer (Location) Empi, Inc (St. Paul, MN) Henley Healthcare (Sugarland, TX) Iomed (Salt Lake City, UT) LifeTech, Inc (Houston, TX) General Medical Co (Los Angeles, CA) Wescor Inc (Logan, UT) Scandipharm (Birmingham, AL)
a
Brand Name Dupela Dynaphor b Phoresor II b Iontophor b Lectro Patch b Sweat-Chek b CF Indicatorb
Disadvantages of IP
Using IP also has disadvantages. Improperly placed electrodes can cause burns. That problem has been minimized, however; newer IP units are powered by a battery pack instead of household current, and the current used is very low. Compliance with a current-time recommendation according to the method used also prevents iontophoretic burns. The formation of undesirable vesicles and bullae in treated skin can be avoided by periodically interrupting a unidirectional treatment current with a relatively short pulse of current of the opposite direction. There is also the minor inconvenience of using an electrical device.
Dual-channel system.
Single-channel system.
Table 4. Drugs Used in Veterinary Iontophoresis.*

Drug Solution Nonsteroidal anti-inflammatory drugs Phenylbutazone Flunixin meglumine Ketoprofen Corticosteroids and other anti-inflammatory agents Dexamethasone sodium phosphate Betamethasone Prednisolone sodium succinate Antibiotics Gentamicin sulfate Amikacin sulfate Ceftiofur sodium Local anesthetic Lidocaine HCI Polarity Used Negative Negative Negative Negative Negative Negative Positive Positive Negative Positive
Drugs Administered via IP

IP is also used to administer pilocarpine to patients with cystic fibrosis, to treat excessive perspiration (hyperhidrosis), to induce local anesthesia with lidocaine, to reduce inflammation by means of dexamethasone, and (as mentioned) to apply uoride to the teeth (Table 2). Drugs such as corticosteroids, nonsteroidal anti-inflammatory agents, and other anesthetics are often delivered via IP. Other medications
*Adapted from: Product information 801419. Revision B. St. Paul, MN:Empi, Inc; 1996.
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undergoing evaluation for that purpose include analgesics, nicotine, drugs used to treat AIDS-related symptoms, insulin, antineoplastic drugs, and proteins. IP is also useful in veterinary medicine. 1
Iontophoretic Devices
During IP, (as described previously), an electric current is transferred from the electrodes through the ionized drug solution as ionic flow. The drug ions are moved to the skin, where ionic repulsion continues and the drug is moved through whichever pathways are available (pores or possibly disrupted stratum corneum). The drug-containing electrode (the active electrode) is placed over the affected site, and the other electrode (the passive electrode) is placed elsewhere on the body. Current densities up to 0.5 mA/cm 2 produce little or no discomfort for the patient. The larger the electrode surface, the greater the current needed to transport the drug.
Early devices used for IP were large and cumbersome. Today, however, the size of such devices ranges between that of a small flashlight to a Walkman-radiosize device. In some newer devices, the need for additional wiring has been eliminated because the electrodes have been incorporated into the unit. In the near future, devices used for IP will be small and flat and will be equipped with selfcontained batteries incorporated into a dosage unit the size of a transdermal patch. Miniaturization of such devices that use smaller, more powerful batteries and electronics is now possible. The next generation of patches used for IP may also provide an electronic record of the date, time, and quantity of each dose delivered, as well as information about patient compliance. Currently, however, IP involves the use of a device (Table 3) attached to electrodes that contain a solution of the drug to be administered.
Veterinary Use of IP
Drugs such as those listed in Table 4 are used for IP in veterinary patients. Various electrodes, drug concentrations, and dosages are required according to the size and anatomic requirements of the animal patient.
References
1. Banga AK. Electrically Assisted Transdermal and Topical Drug Delivery . Bristol PA:Taylor & Francis Group; 1998. Tyle P. In: Proceedings of the Bio-Expo 86. The American Commercial and Industrial Conference and Exposition in Biotechnology . Stoneham, MS:Butterworth; 1986:583-594. Albrecht N. Arch Orhenkeil Kd 1911;85:198212. Harris PR. Iontophoresis: Clinical research in musculoskeletal inflammatory conditions. J Orthopaed Sports Phys Ther 1980;4:109-112. DeLacerda FG. Shoulder girdle myofascial syndrome. A biomechanical analysis.Occup Health Saf 1982;51:45-46.
2.
3. 4.
5.
F O R M U L A T I O N S
Anhydrous Emollient Dry Skin Lotion
Rx
For 100 g Olive oil, light Cocoa butter White petrolatum 20 g 40 g 40 g
METHOD OF PREPARATION
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Melt the cocoa butter and white petrolatum together at a temperature of about 40C. 4. Incorporate the light olive oil, mix well, and cool. 5. Pour into a plastic squeeze bottle that has a dispenser tip. 6. Package and label.
Cocoa butter (Theobroma oil) is a yellowish or white brittle solid that has a slight odor of cocoa. It is derived from natural sources and is composed primarily of the triglycerides of saturated and unsaturated fatty acids. It melts between 31C and 34C, is freely soluble in chloroform and in ether, and is slightly soluble in 95% ethanol. Heating to a temperature greater than 36C lowers the solidification point of cocoa butter because of its polymorphic nature and the formation of a metastable form. Cocoa butter should be stored at temperatures less than 25C. It is used as a suppository base and is also a major ingredient in chocolate. 2 White petrolatum (white petroleum jelly, white soft paraffin) is a white, translucent, soft unctuous mass that is inert, odorless, and tasteless. It is a mixture of semisolid saturated hydrocarbons obtained from petroleum. It is used primarily in the following topical formulations in the concentrations listed: emollient creams (10% to 30%), topical emulsions (4% to 25%), and topical ointments (up to 100%). White petrolatum has a specific gravity of about 0.815 to 0.880 and melts in a temperature range between 38C and 60C. It is practically insoluble in ethanol, in glycerin, and in water but is soluble in chloroform and in most fixed and volatile oils. It is stable, but when exposed to light it may discolor as a result of the oxidation of impurities. That oxidation can be minimized by the addition of a suitable antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, or -tocopherol. Heating white petrolatum to a temperature above its melting range (about 70C) for extended times should be avoided, but it can be sterilized by dry heat. 3
PACKAGING
Package in a tight, light-resistant container.
LABELING
For external use only. Keep out of the reach of children.
STABILITY
A beyond-use date of 6 months can be used for this preparation.1
USE
This thick lotion has been used to treat very dry skin. It has excellent emollient properties and is often applied at bedtime.
REFERENCES
1. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:US Pharmacopeial Convention, Inc; 1999:2487, 2698-2702. 2. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy. 19th ed. Easton PA:Mack Publishing Company; 1995:1400, 1409. 3. Weller PJ. Petrolatum: In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington DC:American Pharmaceutical Association; 1994:331-333.
QUALITY CONTROL
Actual yield compared with theoretical yield, physical observation.
DISCUSSION
Dry skin (especially during the winter in a cold climate) is very common. The low relative humidity indoors during the winter in cold climates causes the loss of moisture from the skin, which becomes dry, cracked, painful, and sometimes infected. A good emollient preparation applied at least once daily and allowed to remain in place facilitates dermal hydration by minimizing the evaporation of water from the skin surface. A thicker or thinner preparation can be easily prepared from this formulation. Olive oil is obtained by carefully crushing and pressing recently collected ripe olives in a mill and a press. When that process does not break the putamen, the highest grade oil (virgin oil, sublime oil, first-expressed oil) is obtained. Olive oil is a pale yellow or light greenish-yellow oily liquid that has a slight characteristic odor and taste. It is slightly soluble in alcohol and has a specific gravity between 0.910 and 0.915. Olive oil is used in making ointments, liniments, emulsions, and various other dosage forms. It is also used as an emollient laxative. 1,2
Antiseptic Protective Ointment
Rx
For 100 g Menthol Phenol Salicylic acid Resorcinol Peruvian balsam Castor oil Juniper tar (cade oil) Benzocaine Bismuth subnitrate Zinc oxide White petrolatum 1 1 3 2 2 2 1 5 10 20 53 g g g g g g mL g g g g
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Mix the menthol and phenol together until the mixture has liquified. Add the resorcinol and then the salicylic acid. 4. Mix the Peruvian balsam with the castor oil; then add the juniper tar and benzocaine and mix. 5. Melt the white petrolatum at 60C and sift into it the previously mixed bismuth subnitrate and zinc oxide. 6. Add the mixture from step #4 and mix well. 7. Allow the mixture to begin cooling. Then blend in the materials from step #3 and mix thoroughly. 8. Package and label.
PACKAGING
LABELING
For external use only. Keep out of the reach of children. Use only as directed.
STABILITY
USE
This ointment has been used to treat minor skin abrasions, insect bites, and other skin irritations.
a white or light pink crystalline mass. It is soluble 1 g in 15 mL of water and is very soluble in each of the following: alcohol, glycerin, chloroform, ether, or fixed and volatile oils. Phenol is used as a caustic, a disinfectant, and a topical anesthetic.2 Salicylic acid (C7H6O3, MW 138.12) occurs as white crystals that usually resemble ne needles or as a uffy, white, crystalline powder.1 Resorcinol (C 6H6O2, resorcin, MW 110.11) occurs as white or almost white needle-shaped crystals or powder with a faint, characteristic odor and a sweetish taste that becomes bitter. It acquires a pink tint when exposed to light and air. It is freely soluble in each of the following: water, alcohol, glycerin, and ether. 1 Peruvian balsam (balsam of Peru) is a balsam that exudes from the trunk of Myroxylon balsamum var. pereirae (Leguminosae). It has been used in the treatment of eczema, pruritus, hemorrhoids, and scabies.3 Castor oil is a fixed oil obtained from the seed of Ricinus communis L. (Euphorbiaceae). It occurs as a pale yellow or almost colorless, transparent, viscid liquid that has a faint, mild odor and a bland taste.4 Juniper tar (cade oil, juniper tar oil) occurs as a dark brown, clear, thick liquid that has a tarry odor and a faintly aromatic bitter taste. Juniper tars and tar oils are used to treat eczema, psoriasis, dandruff, and other skin disorders. 1,3 Benzocaine (C 9H11NO 2, ethyl aminobenzoate, MW 165.19) occurs as small white crystals or as a white, crystalline, odorless powder. It is stable in air and produces local anesthesia when placed on the tongue. It is very slightly soluble in water and is freely soluble in alcohol and in ether. It is a topical anesthetic of the ester type that produces low systemic toxicity.1 Bismuth subnitrate [Bi5O(OH) 9(NO3)4, bismuth hydroxide nitrate oxide, MW 1461.99] occurs as a white slightly hygroscopic powder. It is practically insoluble in water and in alcohol and is readily dissolved by hydrochloric acid or by nitric acid. 1 Zinc oxide (ZnO, MW 81.39) occurs as a very fine, odorless, amorphous, white or yellowish white powder that is free from gritty particles. Zinc oxide is a mild astringent and is applied topically as a soothing and protective treatment for eczema and mild skin disorders. 1,3 White petrolatum (white petroleum jelly, white soft paraffin) is a white, translucent, soft unctuous mass that is inert, odorless, and tasteless.5
References
1. United States Pharmacopeia XXIV/National Formulary 19 . Rockville, MD:US Pharmacopeial Convention, Inc; 1999:2278, 2290, 2367, 2382, 2395, 2403, 2698-2702. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy . 20th ed. Lippincott Williams & Wilkins, Baltimore MD; 2000:1045-1046. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 30th ed. London:The Pharmaceutical Press; 1993:769-772, 1401. Tolman KG. Gastrointestinal and liver drugs. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy . 19th ed. Easton, PA:Mack Publishing Company; 1995:897. Weller PJ. Petrolatum: In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 1994:331-333.
QUALITY CONTROL
Theoretical yield compared with actual yield, physical observation.
2.
DISCUSSION
Menthol (C 10H20O, MW 156.27) occurs as colorless, hexagonal, (usually) needlelike crystals that are found in fused masses or as a crystalline powder. Menthol is slightly soluble in water but is very soluble in alcohol. It is freely soluble in glacial acetic acid, in mineral oil, and in fixed and volatile oils. 1 Phenol (C 6H5OH, carbolic acid, MW 94.11) occurs as colorless to light pink, interlaced or separate, needle-shaped crystals or as
3. 4.
5.
200
Camphor, Menthol, and Eucalyptol Rubefacient Ointment
Rx
For 100 g Camphor Menthol Eucalyptol White wax Cocoa butter White petrolatum 5 5 5 10 10 100 g g g g g g
qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Mix the camphor, menthol, and eucalyptol to form a eutectic liquid. 4. Use a beaker to heat the white wax until it has melted; then remove the melted wax from the heat and add the white petrolatum and cocoa butter and mix well. 5. When the ointment is almost cool, incorporate the eutectic liquids and mix well. 6. Package and label.
PACKAGING
LABELING
For external use only. Keep out of the reach of children.
STABILITY
USE
This ointment has been used to treat sore muscles and joints and to relieve the mild symptoms of arthritis.
QUALITY CONTROL
Theoretical yield compared with actual yield, physical observation.
slightly soluble in water, very soluble in alcohol, and freely soluble in glacial acetic acid, in mineral oil, and in fixed and volatile oils. A soft mass forms when it is triturated with each of the following: camphor, chloral hydrate, and phenol, as well as with many other substances. 1 Eucalyptol (C 10H18O, cajuputol, cineol, MW 154.25) occurs as a colorless liquid with an aromatic, camphoraceous odor. It is obtained from eucalyptus oil, cajuput oil, and other oils. It is soluble 1 in 2 of 70% alcohol. It should be stored in a cool place in an airtight container and protected from light. 2 White wax (white beeswax, cera alba, bleached wax) occurs in thin layers as a yellowish-white solid that is somewhat translucent. It has a faint, characteristic odor and is free from rancidity. White wax is a chemically bleached form of yellow wax and has similar applications. It has a specific gravity of approximately 0.95 to 0.96 and melts at about 61C to 65C. It is insoluble in water, sparingly soluble in cold alcohol, and completely soluble in ether and in fixed and volatile oils. White wax is used as a stiffening agent, an emulsion stabilizer, and a controlled-release vehicle. It is incompatible with oxidizing agents. 1,3 Cocoa butter (Theobroma oil) is a yellowish or white brittle solid with a slight odor of cocoa. It is derived from natural sources and is composed primarily of the triglycerides of saturated and unsaturated fatty acids. It melts at a temperature between 31C and 34C, is freely soluble in chloroform and in ether, and is slightly soluble in 95% ethanol. Heating to a temperature higher than 36C lowers the solidification point of cocoa butter because of its polymorphic nature and the formation of a metastable form. Cocoa butter should be stored at a temperature lower than 25C. It is used as a suppository base and is also a major ingredient in chocolate.4 White petrolatum (white petroleum jelly, white soft paraffin) is a white, translucent, soft unctuous mass that is inert, odorless, and tasteless. It is used primarily in topical pharmaceutical formulations. White petrolatum has a specific gravity of approximately 0.815 to 0.880 and melts in a range between 38C and 60C. It is practically insoluble in ethanol, in glycerin, and in water but is soluble in chloroform and in most fixed and volatile oils. 5
DISCUSSION
Camphor (C10H16O, MW 152.23) occurs as colorless or white crystals, granules, or crystalline masses or as colorless to white, translucent, tough masses. It has a penetrating, characteristic odor and a pungent, aromatic taste. Camphor has a specific gravity of about 0.99 and will slowly volatilize at room temperature. It is slightly soluble in water, very soluble in alcohol, and soluble in fixed oils and volatile oils. Camphor is obtained from Cinnamomum camphora (Lauraceae) and is purified by sublimation, or it may be prepared synthetically. Topically applied camphor is used as a rubefacient and mild analgesic. 1,2 Menthol (C 10H20O, MW 156.27) occurs as a crystalline powder or as colorless hexagonal crystals that are usually needlelike or in fused masses. It has a pleasant, peppermint-like odor. Menthol is
REFERENCES
1. 2. 3. United States Pharmacopeia XXIV/National Formulary 19 . Rockville, MD:US Pharmacopeial Convention, Inc; 1999:2278, 2402, 2698-2702. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 30th ed. London:The Pharmaceutical Press; 1993:1347-1348, 1354. Fazzi AA, Kibbe AH. White wax. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington DC:American Pharmaceutical Association; 2000:595-596. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy . 19th ed. Easton, PA:Mack Publishing Company; 1995:1409. Weller PJ. Petrolatum: In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 1994:331-333.
4.
5.
Carbidopa 2-mg/mL and Levodopa 20-mg/mL Oral Suspension
Rx
For 100 mL Carbidopa Levodopa Propylene glycol Ora-Plus Ora-Sweet or Ora-Sweet SF qs Saccharin Flavor (tangerine or other) Almond oil Aqueous 200 mg 2g 5 mL 50 mL 100 mL qs Nonaqueous 200 mg 2g 100 mg qs 100 mL
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Thoroughly mix the carbidopa and levodopa powders in a mortar with a pestle. Aqueous 4. Add the propylene glycol and mix to form a smooth paste. 5. Slowly add the Ora-Plus with mixing between each addition. 6. Add sufficient Ora-Sweet or Ora-Sweet SF to volume and mix well. 7. Package and label. Nonaqueous 4. Mix the saccharin with the active drug powders. 5. Incorporate the flavor and almond oil and mix well. 6. Package and label.
PACKAGING
Package in a tight, light-resistant container with minimal headspace (oral syringes are best).
LABELING
Shake well before taking. Use only as directed. Keep out of the reach of children. Store in a refrigerator.
STABILITY
When the aqueous preparation is stored in a refrigerator, a beyond-use date of 7 days should be appropriate; the oil-based preparation should be stable for at least 30 days. 1,2
system; as a result, more levodopa is available for transport to the brain. Commercially available combinations of carbidopa and levodopa are in ratios of 1:4 or 1:10 (carbidopa to levodopa).3,4 Levodopa (C9H11NO4, MW 197.19) occurs as a white to off-white odorless crystalline powder. In the presence of moisture, it is rapidly oxidized by atmospheric oxygen and darkens. It is slightly soluble in water, freely soluble in 3 N hydrochloric acid, and insoluble in alcohol. It should be stored in a tight container and protected from light. It is used either alone or in combination with the decarboxylase inhibitor carbidopa in the treatment of parkinsonian syndrome. Because levodopa is unstable, it must be prepared in an acidic vehicle and the resultant preparation must be assigned a brief beyond-use date, or it must be prepared in a nonaqueous vehicle.1,3,4 Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste. 5 Ora-Plus is an oral suspending vehicle with a pH of approximately 4.2 and an osmolality of about 230 mOsm/kg. It contains purified water, microcrystalline cellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, sodium phosphate, and citric acid as buffering agents; simethicone as an antifoaming agent; and potassium sorbate and methylparaben as preservatives. 6 Ora-Sweet syrup is a flavoring vehicle buffered to a pH of approximately 4.2. The osmolality of Ora Sweet is about 3240 mOsm/kg. It contains purified water, sucrose, glycerin, sorbitol (5%), avoring, sodium phosphate, and citric acid as buffering agents and potassium sorbate and methylparaben as preservatives. 6 Ora-Sweet SF is a sugar-free, alcohol-free syrup buffered to a pH of approximately 4.2. The osmolality of Ora-Sweet SF is 2150 mOsm/kg. It contains water, sodium saccharin, xanthan gum, glycerin, sorbitol, citric acid, and sodium citrate as buffers; methylparaben, propylparaben, and potassium sorbate as preservatives; and flavoring. 6 Saccharin (C7H5NO3S, MW 183.18) is an intense sweetening agent. It occurs as odorless white crystals or as a white crystalline powder. Saccharin is soluble to the extent of 1 g in 290 mL of water, 1 g in 50 mL of glycerin, and 1 g in 31 mL of 95% ethanol.7 Almond oil (sweet almond oil) is a clear, pale, straw-colored or colorless, almost odorless, oily liquid with a bland taste. Its specific gravity ranges from 0.910 to 0.915, and it is slightly soluble in alcohol.1
QUALITY CONTROL
Final yield compared with theoretical yield, pH, physical appearance.
References
1. United States Pharmacopeia XXIV/National Formulary 19. Rockville, MD:US Pharmacopeial Convention, Inc; 1999:2369, 2383, 2505-2506, 2698-2702. 2. Trissel LA. Trissels Stability of Compounded Formulations . 2nd ed. Washington DC:American Pharmaceutical Association; 2000:214-215. 3. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American Society of Health-System Pharmacists; 2001:2383-2388. 4. Reynolds JEF. MARTINDALE:The Extra Pharmacopoeia . London:The Pharmaceutical Press; 1993:840-847. 5. Dandiker Y. Propylene glycol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC: American Pharmaceutical Association; 2000:442-444. 6. Ora-Sweet, Ora-Sweet SF, and Ora-Plus [package insert]. Minneapolis, MN: Paddock Laboratories, Inc. 7. Higton FR, Thurgood DM. Saccharin. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC: American Pharmaceutical Association; 2000:454-456.
DISCUSSION
Carbidopa (C10H14N2O4.H20, MW 244.24) occurs as a white to creamy white odorless or practically odorless powder. It is slightly soluble in water, freely soluble in 3 N hydrochloric acid, and practically insoluble in alcohol. Carbidopa should be protected from light. It is a decarboxylase inhibitor; it inhibits the decarboxylation of levodopa to dopamine. Concurrent administration of carbidopa with levodopa inhibits the peripheral decarboxylation of levodopa by the aromatic L-amino acid decarboxylase without affecting the metabolism of levodopa within the central nervous
202
Ergoloid Mesylates 15 mg/mL and Selegiline HCl 6.25 mg/mL in Pluronic Lecithin Organogel
Rx
For 100 mL Ergoloid mesylates Selegiline HCl Propylene glycol Lecithin:isopropyl palmitate (1:1) Pluronic F127 20% gel qs 1.5 g 625 mg 5 mL 22 mL 100 mL
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Mix the ergoloid mesylates and the selegiline HCl in the propylene glycol to form a smooth mixture. 4. Add the lecithin:isopropyl palmitate mixture and mix well. 5. Add sufficient Pluronic F127 20% gel and mix with a shearing action until the gel is well-dispersed. 6. Package and label. Note: The lecithin:isopropyl palmitate solution can be prepared by mixing 0.2 g of sorbic acid, 50 g of soy lecithin, and 50 g of isopropyl palmitate. The Pluronic F127 solution can be prepared by mixing 0.2 g of sorbic acid, 20 g of Pluronic F127, and sufficient purified water to make 100 mL.
PACKAGING
LABELING
For external use only. Keep out of the reach of children. Use only as directed.
STABILITY
A beyond-use date of 14 days can be used for this preparation.1
treat the symptoms of mild-to-moderate impairment of mental function. 1,2 Selegiline HCl (C13H17N.HCl, MW 223.74) occurs as a white, odorless, crystalline powder with a pK a of 7.5. It is freely soluble in water. Selegiline HCl is a stereoselective monoamine oxidase (MAO) inhibitor; it is also the levorotatory isomer of dimethyl propynylphenethylamine and is structurally related to pargyline. It is used in the symptomatic treatment of parkinsonian syndrome. Selegiline is metabolized to methylamphetamine and amphetamine, which are excreted in the urine. 1-3 Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste resembling that of glycerin. It has a specific gravity of 1.038 g/mL and is miscible with each of the following: acetone, chloroform, 95% ethanol, glycerin, and water. It is not miscible with fixed oils or with light mineral oil. It will, however, dissolve some essential oils. Propylene glycol is actually a better solvent than glycerin. It is similar to ethanol as an antiseptic and is also used in cosmetics and in the food industry as a vehicle for flavors and emulsifiers. It is stable and may be mixed with many other solvents. Because propylene glycol is hygroscopic, it should be stored in an airtight container and protected from light. Its incompatibilities include potassium permanganate.4 Lecithin is partially soluble in water but will hydrate to form emulsions. It is used as an emulsifying and solubilizing agent. 5 Isopropyl palmitate is a colorless mobile liquid with a very slight odor. It is soluble in alcohol and is insoluble in water, in glycerin, and in propylene glycol. 6 Pluronic F127 is usually available in powdered form. It is either odorless or has a mild odor. It melts at about 56C and is freely soluble in water, in alcohol, and in isopropyl alcohol. 7 The patient should be advised that as the preparation is rubbed on the skin and warms up, it may become slightly more viscous and resistant to rubbing.
USE
Ergoloid mesylates and selegiline gel are used to treat mild mental impairment.
References
1. 2. 3. 4. United States Pharmacopeia XXIV/National Formulary 19 . Rockville, MD:US Pharmacopeial Convention, Inc; 1999:2396, 2698-2702. Reynolds JEF; ed. MARTINDALE:The Extra Pharmacopoeia . London:The Pharmaceutical Press; 1993:849-850, 1356, 2376. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda, MD:American Society of Health-System Pharmacists; 2001:2391-2396. Dandiker Y. Propylene glycol. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:442-444. Fowler K. Lecithin. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:292-294. Taylor AK. Isopropyl palmitate. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:267-268. Collett JH, Popli H. Poloxamer. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:386-388.
QUALITY CONTROL
Theoretical compared with practical yield, physical observation.
DISCUSSION
Ergoloid mesylates (C31H41N5O5.CH4O3S, dihydroergocornine mesylate, MW 659.79; C 35 H 41 N 5 O 5 .CH 4 O 3 S, dihydroergocristine mesylate, MW 707.84; C32H43N5O5.CH4O3S, dihydro-alpha-ergocryptine mesylate, MW 673.82; C 32 H 43 N 5 O 5 .CH 4 O 3 S, dihydro- -ergocryptine mesylate, MW 673.82) occur as a white to off-white microcrystalline or amorphous practically odorless powder. They are slightly soluble in water (1:50) and are soluble in alcohol (1:30). A 0.5% solution in water has a pH of 4.2 to 5.2. Ergoloid mesylates should be protected from light and stored at a temperature that does not exceed 25C.1 They are used as an adjunct to the treatment of mild-to-moderate dementia in the elderly, especially (in an oral dosage of 3 or 4.5 mg daily) to
5.
6.
7.
Misoprostol 0.0024%, Metronidazole 2%, and Pentoxifylline 5% Decubitus Ulcer Cream
Rx
For 100 g Misoprostol 200-g tablets Metronidazole Pentoxifylline Propylene glycol Hydrophilic ointment 12 2 5 qs 100 tablets g g g
qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Pulverize the misoprostol tablets to a fine powder. 4. Incorporate the metronidazole and pentoxifylline powders and mix well. 5. Add propylene glycol to form a smooth, uniform paste. 6. Geometrically incorporate the paste into the hydrophilic ointment (Dermabase, Vanicream) and mix well. 7. Package and label.
PACKAGING
LABELING
For external use only. Use only as directed. Keep out of the reach of children.
STABILITY
When this preparation is stored in a refrigerator, a beyond-use date of 2 weeks can be used. 1
USE
This preparation has been used to treat recalcitrant decubitus ulcers.
yellow, odorless crystals or crystalline powder. It is stable in air but darkens when exposed to light. It is sparingly soluble in water and in alcohol but is only slightly soluble in ether and in chloroform.1 Pentoxifylline (C 13H18N4O3, oxpentifylline, MW 278.31) is a synthetic trisubstituted xanthine derivative that is structurally related to caffeine, theobromine, and theophylline. It occurs as a white, odorless, crystalline powder that has a bitter taste. It is soluble to the extent of about 77 mg/mL in water and 63 mg/mL in alcohol. Pentoxifylline and its metabolites reduce blood viscosity and are reported to increase blood flow to ischemic tissues and to improve tissue oxygenation in patients with peripheral vascular disease. 3-4 Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste resembling that of glycerin. It has a specific gravity of 1.038 g/mL and is miscible with each of the following: acetone, chloroform, 95% ethanol, glycerin, and water. Because propylene glycol is hygroscopic, it should be stored in an airtight container and protected from light. 5 Hydrophilic ointment is a water-washable oil-in-water emulsion base containing methylparaben, propylparaben, sodium lauryl sulfate, propylene glycol, stearyl alcohol, white petrolatum, and purified water. 6,7 Dermabase cream is an unscented, washable, oil-in-water emulsion cream base. It contains purified water (about 45%), mineral oil, petrolatum, cetostearyl alcohol, propylene glycol, sodium lauryl sulfate, isopropyl palmitate, imidazolidinyl urea, methylparaben, and propylparaben. It is a smooth, white, water-washable cream that has a slight, pleasant odor. It is preserved and is compatible with a wide variety of agents. 8 Vanicream is an oil-in-water emulsion base containing white petrolatum, cetearyl alcohol, ceteareth-20, sorbitol, propylene glycol, simethicone, glyceryl monostearate, polyethylene glycol monostearate, and sorbic acid. It is free of dyes, perfume, lanolin, parabens, and formaldehyde and is a stable and widely compatible cream. 9
QUALITY CONTROL
Final yield compared with theoretical yield, physical observation, viscosity.
References
1. 2. 3. 4. 5. United States Pharmacopeia XXIV/National Formulary 19 . Rockville, MD:US Pharmacopeial Convention, Inc; 1999:2279, 2698-2702. [No author listed.] Physicians Desk Reference. 56th ed. Montvale NJ:Medical Economics Company; 2002:3202-3203. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda, MD:American Society of Health-System Pharmacists; 2001:1473-1477, 2837-2842. Reynolds JEF, ed. MARTINDALE:The Extra Pharmacopoeia . London:The Pharmaceutical Press; 1993:1311-1312. Dandiker Y. Propylene glycol. In: Kibbe A, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:442-444. Reilly WJ Jr. Pharmaceutical necessities. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy. 19th ed. Easton, PA:Mack Publishing Company; 1995:1402. Block LH. Medicated applications. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy . 19th ed. Easton, PA:Mack Publishing Company; 1995:1586. Dermabase cream [package insert]. Minneapolis, MN:Paddock Laboratories, Inc. Vanicream [package insert]. Rochester, MN:Pharmaceutical Specialties, Inc.
DISCUSSION
Decubitus ulcers are a very common and very real problem in bedfast geriatric patients. These skin ulcers become very difficult to treat and can cause generalized sepsis. The preparation described here has been observed to increase blood flow in treated areas, and the combined effects of misoprostol (a protectant) and metronidazole (an anti-infective agent) tend to increase the rate of healing of decubitus ulcers. Misoprostol (C 22H38O5, Cytotec, MW 382.53) is a synthetic analog of prostaglandin E 1 (alprostadil). It occurs as a water soluble viscous liquid. It is a gastric antisecretory and antiulcerative agent that exerts a protective effect on the gastroduodenal mucosa. Cytotec tablets contain either 100 g or 200 g of misoprostol, as well as hydrogenated castor oil, hydroxypropyl methylcellulose, microcrystalline cellulose, and sodium starch glycolate. 2,3 Metronidazole (C 6H9N3O3, MW 171.15) occurs as white to pale
6.
7.
8. 9.
204
Nicotine 2-mg Lollipops
Rx
For 100 Lollipops Nicotine polacrilex 1.1 g (equiv to 200 mg nicotine) Alcohol 95% 17 mL Stevia powder extract 1.25 g Flavor qs Sorbitol candies qs or Sucrose lollipop base qs Note: The size of the lollipop mold must be determined before the nal weight of the base that will be used is selected.
DISCUSSION
Novel dosage forms (chewing gum, transdermal patches, lollipops), which are often used as part of a smoking-cessation program, can contribute to participants success and are increasing in popularity. Nicotine polacrilex [(C 4H6O2)x (C 10H10)y] (C 10H14N2) is a complex of nicotine with a methacrylic acid polymer. Nicotine can be absorbed from the gastrointestinal or respiratory tract and through intact skin. Absorption of the nicotine base is more rapid than that of the polacrilex form. Note: Prior to compounding, check the nicotine equivalent of the polacrilex actually used. 2,3 Alcohol (ethyl alcohol, ethanol, grain alcohol) is a clear, colorless, mobile, volatile liquid that has a slight, characteristic odor and a burning taste. 4 Stevia (honey leaf, yerba dulce) in powder form is a relatively new sweetening agent from the leaves of the Stevia rebaudiana (Bertoni) plant. It is natural, nontoxic, and safe and occurs as a white, crystalline, hygroscopic powder. 5 Sorbitol candies are commercially available in different flavors. Different brands can be tried to determine patients preferences. Sucrose occurs in the following forms: colorless crystals, crystalline masses, or blocks or as a white crystalline powder that is odorless and has a sweet taste. It has a melting range of 160C to 186C and exhibits some decomposition when melted. Sucrose is soluble in water 1:0.5, in alcohol 1:400, and in 95% ethanol 1:170. When heated, it caramelizes at temperatures higher than 160C. When sucrose is used in candy-based products, some inversion of sucrose to dextrose and fructose occurs at temperatures ranging from 110C to 145C. Fructose may cause stickiness but inhibits cloudiness and/or graininess. This inversion process is enhanced in the presence of acids and at temperatures higher than 130C.6 Corn syrup, which is used to prepare the lollipop base in this formulation, is made by the enzymatic breakdown of cornstarch. It is very widely used in commercial products today. Karo, the most popular brand of corn syrup, also contains natural vanilla flavor.
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Disperse the nicotine polacrilex in the alcohol. 4. Melt the sorbitol candies at a temperature that is not higher than 70C. 5. Add the nicotine dispersion and mix well. 6. Add the stevia and mix well; then add the flavor. 7. Cool the mixture slightly and pour it into lollipop molds while the mixture is still fluid. 8. Allow the mixture to cool, and remove it from the molds. The lollipops can be dusted with powdered sugar if they are sticky. 9. Package and label. For unique packaging, drill a hole in the cap of a plastic vial for tablets or capsules and insert a lollipop into the cap from the underside before securing the cap. Note: The sucrose lollipop base can be prepared with powdered sugar (42 g), light corn syrup (16 mL), and purified water (24 mL). Combine those three ingredients in a beaker and stir until they are wellmixed. Cover the mixture and heat it on a hot plate at a high setting until the mixture boils. Continue boiling for 2 minutes. Uncover the mixture, remove it from the heat, and allow it to set for a few minutes. Then add the nicotine salicylate solution and mix thoroughly. Add the stevia and flavor, mix well, and pour the mixture into molds.
PACKAGING
References
1. 2. 3. 4. 5. 6. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:US Pharmacopeial Convention, Inc; 1999:2698-2702. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American Society of Health-System Pharmacists; 2001:1335-1352. Budavari S, ed. The Merck Index . 12th ed. Whitehouse Station, NJ:Merck & Co, Inc; 1996:1119-1120. Weller PJ. Alcohol. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients. 3rd ed. Washington DC:American Pharmaceutical Association; 2000:7-9. Reynolds JEF, ed. MARTINDALE: The Extra Pharmacopoeia . 30th ed. London:The Pharmaceutical Press; 1993:1049. Hamlow EE, Armstrong NA, Pickard A. Sucrose. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington DC:American Pharmaceutical Association; 2000:539-543.
LABELING
Use only as directed. Keep out of the reach of children.
STABILITY
USE
This preparation has been used as a smoking-cessation aid.
QUALITY CONTROL
Theoretical yield compared with actual yield, physical observation, weight.
Nicotine Medication Stick
Rx
For twenty 5-g sticks Nicotine polacrilex Polyethylene glycol (PEG) 3350 Polyethylene glycol (PEG) 300 3.3 g 31.4 g 68 g
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Melt the PEG 3350 and the PEG 300 to about 60C and mix well. 4. Cool slightly and add the nicotine polacrilex while the mixture is still fluid. 5. Pour the mixture into medication stick tubes and allow it to cool. 6. Package and label.
PACKAGING
LABELING
Use only as directed. Keep out of the reach of children. Store in a cool place.
STABILITY
A beyond-use date of 6 months can be used for this preparaton.1
USE
This preparation has been applied to the skin to aid in smoking cessation.
QUALITY CONTROL
Theoretical yield compared with actual yield, physical observation, weight.
DISCUSSION
Many methods and techniques are used in smoking-cessation programs, which are quite popular. Reducing addiction to nicotine has been accomplished in many dosage forms, including chewing gum and (because nicotine is well-absorbed through the skin) transdermal patches. Nicotine polacrilex [(C 4H6O2)x (C 10H10)y] (C 10H14N2) is a complex of nicotine with a methacrylic acid polymer. Nicotine can be absorbed from the gastrointestinal or respiratory tract and through intact skin. Absorption of the nicotine base is more rapid than that of the polacrilex form. The base nicotine, a pyridine alkaloid, is a naturally occurring autonomic drug. Nicotine is a highly purified extract obtained from the dried leaves of the tobacco plant (Nicotiana tabacum [Solanaceae]). Nicotine occurs as a basic, colorless to pale yellow, very hygroscopic, oily, volatile liquid that
has an unpleasant, pungent odor and a sharp, burning, persistent taste. It is soluble in water and in alcohol. Nicotine can be absorbed from the gastrointestinal or respiratory tract and through intact skin. Absorption of the nicotine base is more rapid than that of the acid salts. Note: Prior to compounding, check the nicotine equivalent of the polacrilex actually used. 2,3 Polyethylene glycol (Carbowax, polyoxyethylene glycol, PEG) is an addition polymer of ethylene oxide and water. At room temperature, PEGs with a molecular weight of 200 to 600 are liquid, and those with a molecular weight higher than 1000 are solid. The liquid PEGs are clear, colorless or slightly yellow, viscous liquids with a slight but characteristic odor and a bitter, slightly burning taste. The density of the liquid PEGs ranges 1.11 to 1.14 g/mL. The freezing point for PEG 300 is -15C to -8C. Solid PEGs are white or off-white pastes or waxy flakes. Those with a molecular weight higher than 6000 are available as free-flowing powders. The density of the solid PEGs is in the range of 1.15 g/mL to 1.21 g/mL. The melting point for PEG 3350 is in the range of 48C to 54C. The PEGs are soluble in water and miscible in all ratios with other PEGs. The liquid PEGs are soluble in each of the following: acetone, alcohols, glycerin, and glycols. The solid PEGs are soluble in each of the following: acetone, dichloromethane, ethanol, and methanol and are slightly soluble in aliphatic hydrocarbons and in ether. The solid PEGs are, however, insoluble in fats, in fixed oils, and in mineral oil. The PEGs are chemically stable, do not support microbial growth, and do not become rancid. They can be sterilized by autoclaving, filtration, or gamma irradiation. Listed incompatibilities include some colors (dyes) and possible discoloration in the presence of iron. When mixed with a PEG, penicillin and bacitracin may be less bactericidal, and the parabens may lose some preservative efficacy. PEG bases may soften when mixed with phenol, with tannic acid, or with salicylic acid. When mixed with a PEG, sulfonamides or dithranol may discolor and sorbitol may precipitate. Polyethylene, polyvinyl chloride, and cellulose-ester membranes (filters) may soften or be dissolved by the PEGs. When applied topically, especially to mucous membranes, the PEGs may cause irritation or stinging. In parenteral products, up to a maximum concentration of PEG 300 of 30% can be used. 4
References
1. 2. 3. 4. United States Pharmacopeia XXIV/National Formulary 19. Rockville MD:US Pharmacopeial Convention, Inc; 1999:2698-2702. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American Society of Health-System Pharmacists; 2001:1335-1352. Budavari S, ed. The Merck Index . 12th ed. Whitehouse Station NJ:Merck & Co, Inc; 1996:1119-1120. Price JC. Polyethylene glycol. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients. 3rd ed. Washington DC:American Pharmaceutical Association; 2000:392-398.
206
Podophyllum, Lactic Acid, and Salicylic Acid Wart Mixture
Rx
For 100 mL Podophyllum resin Lactic acid Salicylic acid Acetone Flexible collodion 15 5 10 15 100 g g g mL mL
(American mandrake, May-apple root), which is obtained from various plant families including Podophyllaceae , Coniferae , and Berberidaceae. It is a powdered mixture of the resins extracted from podophyllum by percolation with alcohol and subsequent precipitation from the concentrated percolate upon addition to acidified water. 1,3 Lactic acid (propanoic acid) occurs as a colorless or yellowish, practically odorless, syrupy, hygroscopic liquid. It has a specific gravity of about 1.20 and is miscible with water and with alcohol. The United States Pharmacopeia (USP ) specifies a mixture of lactic acid and lactic acid lactate equivalent to 85% to 90% w/w of C 3H6O3. Lactic acid prepared by the fermentation of sugars is levorotatory, and that prepared synthetically is racemic. 1 Salicylic acid (C 7H6O3, MW 138.12) occurs as white crystals that are usually in fine needles or as a fluffy white crystalline powder. It is stable in air and may have a slightly yellow or pink tint. It has a faint, mint-like odor. Salicylic acid is slightly soluble in water (1 g in 460 mL and 1 g in 15 mL of boiling water) and is freely soluble in alcohol (1 g in 3 mL). It should be protected from light.1 Acetone (C 3H6O, 2-propanone, MW 58.08) occurs as a transparent, colorless, mobile, volatile liquid that has a characteristic odor. A 50% aqueous solution of acetone is neutral to litmus. Acetone is miscible with each of the following: water, alcohol, ether, and most volatile oils. It has a specific gravity of not more than 0.789 and a boiling point of about 56C. Acetone is used as a solvent. 1 Flexible collodion occurs as a clear or slightly opalescent viscous liquid that is colorless or slightly yellow. It has the odor of ether. The odor of camphor becomes noticeable as the odor of ether evaporates. 1
qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Dissolve the podophyllum and salicylic acid in the acetone. 4. Add that mixture to about 50 mL of the flexible collodion. 5. Add the lactic acid while stirring and continue to stir until all the ingredients have dissolved. 6. Add sufficient flexible collodion to volume and mix well. 7. Package in a light-resistant container and label.
PACKAGING
LABELING
Keep tightly closed. Keep away from flame and heat.
STABILITY
A beyond-use date of 6 months can be used for this formula. 1
USE
This solution has been used to treat warts.
QUALITY CONTROL
Final yield compared with theoretical yield, physical observation.
References
1. United States Pharmacopeia XXIV/National Formulary 19 . Rockville MD: US Pharmacopeial Convention, Inc; 1999:2264, 2275, 2290, 2363, 2391, 2698-2702. Spraycar M, ed. Stedmans Medical Dictionary . 26th ed. Baltimore, MD:Williams & Wilkins; 1995:1930-1931. McEvoy GK, ed. AHFS Drug Information 2001. Bethesda MD:American Society of Health-System Pharmacists; 2001:3457-3459.
DISCUSSION
Warts (verruca), which are flesh-colored growths caused by human papillomavirus, are characterized by circumscribed hypertrophy of the papillae of the corium and thickening of the malpighian, granular, and keratin layers of the epidermis. The term also refers to epidermal verrucous tumors of nonviral causes.2 Warts are often treated with keratolytics in a vehicle like flexible collodion, which maintains close contact between the drug and the skin. In this preparation, the solvents evaporate to leave the drug impregnated in the film and thus in intimate contact with the skin. Podophyllum resin occurs as an amorphous powder that varies in color from light brown to greenish yellow. The color darkens when the resin is subjected to a temperature higher than 25C or when it is exposed to light. It has a slight, peculiar, faintly bitter taste. An alcohol solution of podophyllum resin is acid to moistened litmus paper. Podophyllum resin is soluble in alcohol, in which it exhibits a slight opalescence, and it is partially soluble in ether. It is an antimitotic and caustic agent prepared from podophyllum
2. 3.
Vitamin B12 1-mg/1-mL Nasal Spray
Rx
For 10 mL Vitamin B 12 Sodium chloride Methylparaben Propylparaben Propylene glycol Puried water 10 90 10 10 1 10 mg mg mg mg mL mL
qs
1. Calculate the required quantity of each ingredient for the total amount to be prepared. 2. Accurately weigh and/or measure each ingredient. 3. Dissolve the parabens in the propylene glycol. 4. Heat 9 mL of purified water and add the paraben-containing solution and the sodium chloride. 5. Cool and dissolve the vitamin B12. Add additional purified water to volume if required. 6. Filter through a sterile 0.2-g filter into a sterile metered nasal spray container. 7. Package and label.
PACKAGING
LABELING
For nasal administration. Keep out of the reach of children. Clean the nasal tip with an antibacterial agent after each use.
STABILITY
A beyond-use date of 6 months can be used for this solution. 1
USE
Vitamin B 12 nasal spray is used to administer vitamin B 12 noninvasively.
QUALITY CONTROL
Theoretical yield compared with actual yield, pH, clarity, osmolality.
variety of parenteral and nonparenteral pharmaceutical formulations. It is used to prepare isotonic solutions for use in parenteral, ophthalmic, or nasal preparations. Sodium chloride is soluble in water (1 g in 2.8 mL), in glycerin (1 g in 10 mL), and in 95% ethanol (1 g in 250 mL). It can also decrease the solubility of methylparaben in aqueous solution. 1,2 Methylparaben (C8H8O3, methyl hydroxybenzoate, methyl parahydroxybenzoate, MW 152.15) is available as colorless crystals or as a white, crystalline powder that is odorless or almost odorless and has a slight burning taste. An antimicrobial preservative, it is most effective in solutions that have a pH of between 4 and 8, and its efficacy decreases at a higher pH level. One gram of methylparaben is soluble in each of the following: 400 mL of water, 3 mL of 95% ethanol, 60 mL of glycerin, 200 mL of peanut oil, and 5 mL of propylene glycol. It is practically insoluble in mineral oil. Methylparaben is incompatible with each of the following: nonionic surfactants (its antimicrobial activity is reduced), bentonite, magnesium trisilicate, talc, tragacanth, sodium alginate, essential oils, sorbitol, and atropine. It may sorb to some plastics, and it discolors in the presence of iron. 3 Propylparaben (C10H12O3, propyl hydroxybenzoate, propyl parahydroxybenzoate, MW 180.20) is available as a white, crystalline, odorless, tasteless powder. It is most effective in solution at a pH between 4 and 8, and its efficacy decreases at a higher pH level. One gram of propylparaben is soluble in each of the following: 2500 mL of water, 1.1 mL of ethanol, 250 mL of glycerin, 3330 mL of mineral oil, 70 mL of peanut oil, and 3.9 mL of propylene glycol. 4 Propylene glycol (C3H8O2) occurs as a clear, colorless, viscous, practically odorless liquid with a sweet taste resembling that of glycerin. It has a specific gravity of 1.038 g/mL and is miscible with each of the following: acetone, chloroform, 95% ethanol, glycerin, and water. Because propylene glycol is hygroscopic, it should be stored in an airtight container and protected from light. 5 Puried water has been obtained by distillation, ion exchange, reverse osmosis, or some other suitable process. It is miscible with most polar solvents and is chemically stable in all physical states (ice, liquid, and steam). 6
DISCUSSION
The nasal administration of medications is becoming popular. In humans, the mucosal membrane surface available for drug absorption is significant; it enables the rapid, complete absorption of many drugs that have appropriate physicochemical characteristics and are administered in relatively low doses. Vitamin B12 (C 63H88CoN 14O14P, cyanocobalamin, MW 1355.37) occurs as dark red crystals or as an amorphous or crystalline red powder. In the anhydrous form, it is very hygroscopic. When exposed to air, vitamin B 12 may absorb about 12% of its weight in water. It is sparingly soluble in water and is soluble in alcohol. The pH of the USP injection of vitamin B 12 is in the range of 4.5 to 7.0. This vitamin should be stored in a tight container and protected from light. 1 Sodium chloride (MW 58.44) is available as a white crystalline powder or as colorless crystals. It has a saline taste and is used in a
References
1. 2. United States Pharmacopeia XXIV/National Formulary 19 . Rockville, MD:US Pharmacopeial Convention, Inc; 1999:1529, 2373, 2698-2702. Cable CG. Sodium chloride. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:478-481. Reiger MM. Methylparaben. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:340-344. Rieger MM. Propylparaben. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:450-453. Dandiker Y. Propylene glycol. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:442-444. Ellison A, Nash RA, Wilkin MJ. Water. In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients . 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:580-584.
3.
4.
5.
6.
208
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S P E C I A L I T Y
The Treatment of
perpigmentation, scaling, and lichenification. According to the results of one study, 1 atopic otitis externa is present in as many as 86% of dogs and AD-related conjunctivitis occurs in as many as 50% of canine patients. The treatment of canine AD is multimodal and complex. It includes allergen avoidance, the establishment of skin barriers, and the use of anti-inflammatory drugs, allergen-specific immunotherapy (allergy shots), and antibiotics. Using any one of those agents as monotherapy is usually ineffective, and most clinicians combine therapies to successfully treat canine AD. Many treatment products are either not commercially available or are not intended for use in veterinary patients. Many of those that are intended for veterinary use are flavored with offending foodbased allergens. By working with veterinary dermatologists, the compounding pharmacist can play a valuable role in providing dermatologic therapies (tables 1 and 2) that are allergen-free and designed for use in specific veterinary patients.
Allergen Avoidance and Barriers

Gigi Davidson, BS, RPh, DICVP North Carolina State University, College of Veterinary Medicine, Raleigh, North Carolina One of the first steps in managing AD is to remove flare factors (flea saliva, certain foods, dust mite saliva and excrement, molds, pollens, danders, dusts, and other causes of allergic reaction) from the animals environment. However, no controlled studies document the remission of AD after allergen-avoidance therapy alone, and complete prevention of contact with pollens and molds is impossible. At some point, all dogs must visit the outdoors and are then exposed to specific environmental allergens. Bathing the atopic dog frequently (especially after it has been outside) limits the extent of exposure to allergens. Dogs with AD also appear to have an increased sensitivity to flea salivary antigens. A complete flea-avoidance program should be initiated in all patients with active or suspected AD. 2 Improving the integrity of the epidermal lipid barrier of the skin creates an effective barrier against allergens. In atopic humans, topical skin creams have recently been used to prevent contact dermatitis (pure petrolatum provides the best dermal protection), and topically applied fatty acids such as the ceramides can restore the epidermal lipid barrier, 3 although such skin creams have not been clinically tested in dogs with AD. The epidermal ceramides might also be restored by a diet rich in linoleic acid. However, controlled studies of the effectiveness of those agents in treating canine AD have not been performed. Allergies to foods can be controlled by the use of an elimination diet in which common protein meat sources are replaced by a novel protein and carbohydrate to which the dog has not been exposed. Novel protein diets, which may contain lamb or even kangaroo, are used when dogs exhibit an allergic reaction to traditional meat sources such as beef, pork, or chicken. Diets containing hydrolyzed proteins are also available; they are based on the theory that the low-molecular-weight peptides they contain are too small in size to provoke IgE cross-linking on mast cells. Unfortunately, little evidence exists to support or refute the effectiveness of those diets. Until blinded, randomized, controlled studies of the management of canine AD have been conducted, veterinary clinicians must define the clinical course of treatment on a patient-by-patient basis.
A large part of the care provided by most veterinary practices consists of treating dermatologic disorders. Owners usually bring their pet to a veterinary clinic after it has exhibited long bouts of chronic scratching that are annoying and result in superficial lacerations and secondary bacterial infection. Veterinarians treat dogs, cats, and horses for a variety of skin problems, including allergyrelated dermatitis from flea bites or food, skin infections (pyoderma), hormonally induced or immune-mediated skin diseases, and parasites. Atopy is defined by the American College of Veterinary Dermatologists as a genetically disposed tendency to develop IgE-mediated allergy to environmental allergens. The clinical manifestation of atopy is termed atopic disease (AD). Young dogs are often afflicted with AD, which is usually caused by an allergic reaction resulting from exposure to environmental antigenic pollens, mold spores, or house dust. Atopic dermatitis is one of the most common skin problems caused by AD. The pathogenesis of AD is poorly understood. Although there is a genetic predisposition to its development, the rapid increase in the incidence of AD over the last few decades in both humans and animals suggests that the cause is environmental rather than genetic. Many environmental allergens (dust mites; house dust; pollen from grasses, trees, and weeds; mold spores; epidermal antigens that produce contact dermatitis; and insect antigens such as those caused by flea bites) have been implicated in the pathogenesis of canine AD. The clinical signs of canine AD vary from dog to dog, but the most common sign is a primary lesion manifested by pruritus of the face, paws, ears, extremities, or ventrum (chest and belly). Primary lesions may result in secondary lesions, such as those caused by trauma from scratching, chronic inflammation, and secondary bacterial infections. Other signs include red-brown salivary staining, excoriations, self-induced alopecia, dry lusterless hair, hy-
210
S P E C I A L T Y
Anti-Inammatory Agents
Because complete allergen avoidance is not practical, anti-inflammatory drugs (NSAIDs) can be used to reduce the clinical signs of canine AD. NSAIDs can be classified into two categories: drugs such as cyclosporine, which prevent mast cell degranulation, and those that prevent the effects of histamine (H1-receptor antagonists, misoprostol, pentoxifylline, tacrolimus, cyclosporine, glucocorticoids). The latter group of drugs usually inhibits the late-phase allergic reaction, but drugs such as glucocorticoids or cyclosporine (the most effective anti-inflammatory drugs) inhibit both immediate- and late-phase allergic IgE-mediated mast cell activation. Currently, ample evidence 4 indicates that prednisone and/or prednisolone are effective in treating canine AD, and fair evidence 5-8 suggests that cyclosporine, misoprostol, and pentoxifylline are also effective for that purpose. Because almost all medications used to treat canine AD are designed for use in humans, many drugs must be modified for use in canine patients. The compounding pharmacist has an important role in the veterinary care triad and can provide custom-compounded, patient-specific therapies for dogs with AD.
Table 1. Compounds Potentially Useful in Treating Canine Atopic Disease.

Allergen-specific immunotherapy (eg, allergy shots) Barrier creams containing combinations of ceramides, cholesterol, or free fatty acids Chlorpheniramine capsules Flavored suspensions containing chlorpheniramine Medicated treats containing clemastine Dexamethasone 0.1% in an aqueous transermal penetrating base Dexamethasone 0.1% topical lotion Flavored suspensions containing diphenhydramine Medicated treats containing diphenhydramine Hydrocortisone 1% topical shampoos, lotions, ointments, and gels Flavored suspensions containing hydroxyzine Medicated treats containing hydroxyzine Flavored suspensions containing methylprednisolone Medicated treats containing methylprednisolone Misoprostol capsules Medicated treats containing misoprostol Pentoxifylline capsules Medicated treats containing pentoxifylline Flavored suspensions containing prednisone or prednisolone Medicated treats containing prednisone or prednisolone Specific allergen-free treats or medication vehicles (eg, novel protein food sources or flavorings to which the dog is not allergic) Tacrolimus topical lotions (0.1% to 0.3%) Triamcinolone 0.015% topical sprays However, few clinical studies have proven the efficacy of longacting glucocorticoid preparations, which also produce a greater incidence of adverse effects than do short-acting or intermediate-acting glucocorticoids. For example, long-term systemic therapy with any glucocorticoid can lead to hyperadrenocorticism (Cushings disease) and may also trigger a urinary tract infection.18 As a result, long-acting glucocorticoids are not recommended for the treatment of canine AD.
Glucocorticoids
Glucocorticoids are the most commonly prescribed drugs in the treatment of canine AD, for which they are very effective. They exert an anti-inflammatory effect on cytokine production. Their mechanism of action involves influencing or interfering with gene transcription to prevent the activation of immune-mediated inflammatory components such as T-lymphocytes, eosinophils, macrophages, and endothelial, dendritic, and epithelial cells. In addition to exerting their inhibitory effects, glucocorticoids also activate anti-inammatory genes to translate proteins such as leukocyte proteinase inhibitor, lipocortin-1, and interleukin-1 receptor antagonist.9,10 Lipocortin-1 is responsible for the inhibition of the enzyme that converts membrane phospholipids into arachidonic acid, which is the precursor of the potent mediators of inflammation such as prostaglandins, prostacyclin, thromboxanes, and leukotrienes. Various topical glucocorticoid therapies have been used in the treatment of canine AD. A 1% hydrocortisone nonrinse conditioner reduced histamine-induced wheal diameter in dogs but had no effect on late-phase IgE-mediated cutaneous reactions. 11 A 0.015% triamcinolone spray evaluated in several studies12,13 decreased inflammatory wheals as well as dermal cell infiltration after inflammatory challenge. Topically applied dexamethasone 0.1% was effective in treating a small number of clinical cases of canine AD when other agents had failed (T Olivry, G Davidson, unpublished data, 2000-2001). Repeated topical applications of glucocorticoids can produce adverse effects. Epidermal atrophy and hyalinization of the dermal collagen similar to that exhibited by humans receiving prolonged topical glucocorticoid therapy have been reported.14 The long-term use of topical glucocorticoids can result in dramatic skin atrophy and subepidermal vascularization. 15 Oral glucocorticoid formulations are the agents most commonly used to treat canine AD. Treatment regimens with orally administered prednisone, prednisolone, and methylprednisolone have resulted in good-to-excellent control of that disorder.4,16,17
Antihistamines
Veterinary dermatologists frequently recommend using antihistamines to control the symptoms of canine AD. Although currently published studies do not provide enough evidence to support the use of antihistamines for that purpose, many veterinary clinicians concur that several antihistaminic agents may be tried individually in sequence for 7 to 14 days until the efficacy of a protocol can be determined. Using antihistamines to treat dogs with AD is based on the hypothesis (from human evidence) that histamine release from mast cells is primarily responsible for cutaneous inflammatory response. This hypothesis has not yet been proven in dogs, however, and the relative lack of antihistamine
S P E C I A L T Y
Table 2. Treatment Regimens for Canine Atopic Disease.

Drug Chlorpheniramine Regimen 0.4 mg/kg PO BID Adverse Effects Possible lethargy, sedation, diarrhea, vomiting, anorexia, dry mouth, urinary retention Sedation, lethargy, dry mouth, urinary retention Comments In dogs with AD, response rates to chlorpheniramine tend to be low (25% response at best). Extremely bitter taste may be masked by compounding. Controlled studies 19-22 indicate the highest response rate (30%) to clemastine (as opposed to other antihistamines) in dogs with canine AD. Doses may be reduced. Coadministration of ketoconazole, which inhibits the metabolism of cyclosporine and the lipoprotein that binds cyclosporine in the blood, thereby increasing the amount of free cyclosporine. 23
Clemastine
0.04 - 0.1 mg/kg PO BID
Cyclosporine
5 mg/kg PO every day
Nephrotoxicity, hepatotoxicity, hyperlipidemia (reported in humans), gastrointestinal upset, potential neurotoxicity, hypertension
Dexamethasone topical gel
0.1% in 5%
Polyuria, polydipsia, polyphagia, gastric Fewer adverse effects are associated with ulceration, diarrhea, epidermal atrophy, topical use than with systemic use. elevated level of liver enzymes, induction of hyperadrenocorticism (Cushings disease), diabetes, trigger for urinary tract infection Sedation, lethargy, dry mouth, urinary retention, diarrhea, vomiting, anorexia Polyuria, polydipsia, polyphagia, gastric ulceration, diarrhea, elevated level of liver enzymes, epidermal atrophy, induction of hyperadrenocorticism (Cushings disease), diabetes, trigger for urinary tract infection Sedation, lethargy, fine rapid tremors, whole-body rapid tremors, seizures (rarely) Likely to be less effective than clemastine or chlorpheniramine.
Diphenhydramine
2.2 mg/kg PO q 8 hr
Hydrocortisone
1% conditioner applied topically
Fewer adverse effects are associated with topical use as opposed to systemic use.
Hydroxyzine
1 to 2 mg/kg PO BID - TID
May be less effective than clemastine and chlorpheniramine.
efficacy in this species indicates possible other mechanisms of inflammatory response. Antihistamines used with clinical success to treat canine AD include hydroxyzine, diphenhydramine, chlorpheniramine, and clemastine. 19-22 Two studies 25-26 indicate that loratadine and terfenadine are ineffective in treating canine AD, even though loratadine has shown superior histamine-blocking effects in in vitro experiments involving canine cutaneous mast cells. 27 Adverse events caused by antihistamine use in dogs (sedation, panting, excitation, anticholinergic effects, trembling, ataxia, hyperesthesia, hypersalivation, exacerbation of itching) are mild. One case 28 of toxicity from terfenadine in a dog indicates that extreme caution should be used when drugs newly approved for human use are administered to dogs. When evaluating antihistamine use in any dog, most veterinary dermatologists agree that the beneficial effect, if any, occurs within the first 7 to 14 days of treatment and that the adverse effect of sedation may be
responsible in part for the clinical impression of efficacy.
Misoprostol
Misoprostol, a prostaglandin E 1 (PGE1) analog approved as a gastric cytoprotectant, also exerts potent antiallergic effects. Prostaglandin stimulates the production of cyclic adenosine monophosphate (AMP), which blocks the secretion of cytokines by T H 1 cells. Misoprostol also produces an anti-inflammatory effect by inhibiting lymphocyte proliferation, granulocyte activation, and the synthesis of proinflammatory cytokines such as interleukin-1 and tumor necrosis factor- . The effect of misoprostol in the treatment of canine AD has been well researched; according to one study, 7 it produced an improvement of 61% in treated subjects.
Cyclosporine
Cyclosporine is a potent immunomodulatory agent that inhibits the function of many cell types involved in cutaneous inflam-
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S P E C I A L T Y
Table 2, continued
Drug Methylprednisolone Regimen 0.4 to 0.8 mg/kg PO every day x 7 days then q 48 hr Adverse Effects Polyuria, polydipsia, polyphagia, gastric ulceration, diarrhea, epidermal atrophy, elevated level of liver enzymes, induction of hyperadrenocorticism (Cushings disease), diabetes, trigger for urinary tract infection Gastrointestinal distress, diarrhea, abdominal pain, vomiting, flatulence Vomiting, anorexia, tachycardia, central nervous system stimulation Polyuria, polydipsia, polyphagia, gastric ulceration, diarrhea, elevated level of liver enzymes, induction of hyperadrenocorticism (Cushings disease) or diabetes, trigger for urinary tract infection, epidermal atrophy Polyuria, polydipsia, polyphagia, gastric ulceration, diarrhea, elevated level of liver enzymes, induction of hyperadrenocorticism (Cushings disease) or diabetes, trigger for urinary tract infection, epidermal atrophy Nephrotoxicity, hepatotoxicity, gastrointestinal upset Comments Intermediate duration of action (12 to 36 hr) in dogs and thus a good choice for candidate for alternate-day administration
Misoprostol
3 to 6 g/kg PO TID x 30 days 10 mg/kg PO BID - TID 0.5 to 1 mg/kg PO then 0.2 to 0.5 mg/kg PO q 48 hr maintenance
Adverse effects may be reduced by giving misoprostol with food. Pregnant women should avoid all contact with misoprostol. Extensively metabolized to metabolites that are responsible for pharmacologic effects (eg, local therapy is not advised) Long-term therapy should be avoided; long-acting glucocorticoid therapy should be avoided.
Pentoxifylline
Prednisolone
Prednisone
0.5 to 1 mg/kg PO daily then 0.2 to 0.5 mg/kg PO q 48 hr maintenance
Long-term therapy should be avoided; long-acting glucocorticoid therapy should be avoided.
Tacrolimus
0.3% lotion administered 0.1 mL/kg topically daily 0.015% spray topically every day
Tacrolimus is apparently more toxic than cyclosporine when used systemically in dogs, and its use is not recommended. 24 Fewer adverse effects are associated with topical use as opposed to systemic use.
Triamcinolone
Polyuria, polydipsia, polyphagia, gastric ulceration, diarrhea, elevated level of liver enzymes, induction of hyperadrenocorticism (Cushings disease) or diabetes, trigger for urinary tract infection, epidermal atrophy
mation, immune reactions (lymphocytes and Langerhans cells), and allergic response (effector cells such as mast cells and eosinophils). The antiallergic effects (but not the adverse effects) produced by cyclosporine are remarkably similar to those produced by glucocorticoids. Long-term toxicity studies 29 in dogs (45 mg/kg/day orally for 1 yr) indicated that side effects from glucocorticoid treatment included emesis, diarrhea, anorexia, weight loss, generalized cutaneous papillomatosis, hyperplastic gingivitis, and periodontitis, all of which resolved after a 12-week recovery period. In those studies, there were no indications of hepatic, renal, or myelotoxic effects from the use of cyclosporine. A drug interaction with ketoconazole can increase the blood level of free cyclosporine. 23
Tacrolimus
Tacrolimus inhibits T-lymphocyte response to antigens and downregulates cytokine production. Unlike cyclosporine, tacrolimus is effective after topical application. The safety and efficacy of 0.3% tacrolimus lotion in dogs with AD were evaluated in a recent study.30 The degree of erythema significantly decreased in all dogs receiving tacrolimus, and none of the dogs studied suffered adverse effects from treatment. At this time, evidence proving the efficacy of tacrolimus in treating canine AD is insufficient, but the encouraging results from the study cited above indicate that topical tacrolimus may be a valuable therapeutic agent for that purpose. The systemic use of tacrolimus, which is apparently more toxic than cyclosporine, is not recommended. 24
S P E C I A L T Y
Pentoxifylline is a phosphodiesterase inhibitor characterized by multiple immunomodulatory properties. It suppresses interleukin and tumor necrosis factor and decreases leukocyte adhesion and aggregation. In a randomized, blinded, placebo-controlled trial,8 orally administered pentoxifylline at a twice-daily dosage of 10 mg/kg produced a significant improvement in the erythema and pruritus associated with canine AD. None of the dogs studied experienced adverse effects from treatment with pentoxifylline. Because pentoxifylline is rapidly eliminated after oral administration, frequent daily dosing or topical administration may be considered to increase efficacy.
antibodies, unavoidable allergen contact, and signs that have not responded to drugs. Dogs that cannot tolerate the side effects of other drugs and that have owners who can afford the expense of the regimen and are competent at administering injections may also benefit from allergen-specific immunotherapy.
Antibiotic Therapy
Many animals with AD have secondary infections caused by microbes and/or associated secretory toxins that serve as flare factors, increase the production of IgE, and activate dermal inflammatory cells. Because of those potential allergen triggers, antibiotic therapy is instrumental in treating any case of AD. Regardless of whether the clinical signs of infection are present in a dog with AD, the veterinary clinician should evaluate the results of appropriate cultures and sensitivities and treat the patient accordingly. In this article, antibiotic therapy is not examined in detail, but after a clinician has determined the nature of an AD-related microbial infection, systemic and/or topical anti-infective agents are usually used as treatment.
Allergen-Specic Immunotherapy
For many dogs with AD, eliminating exposure to allergens is not possible, and response to pharmacotherapy is unsatisfactory. In those cases, decreasing the immunologic response to allergen exposure may be of benefit. Allergen-specific immunotherapy has been defined as the practice of administering gradually increasing quantities of an allergen extract to an allergic subject to ameliorate the symptoms associated with subsequent exposure to the causative allergen.31 There is little evidence-based experience for the use of immunotherapy in dogs. However, extrapolation from human experience indicates that this modality could be useful in treating dogs with clinically demonstrable allergen-specific IgE
Patient Monitoring
Because frequent adjustments to therapy are required in the treatment of canine AD, follow-up examinations should be scheduled every 2 to 8 weeks after a new treatment protocol has been initiated. Symptoms such as pruritus, self-trauma, pyoderma, and possible adverse reactions to drug therapy should be monitored. After the dog appears to be asymptomatic and an acceptable level of control has been achieved, follow-up examinations should be performed (preferably) every 3 months but less frequently than every 12 months. Periodic evaluations of complete blood count results, a serum chemistry profile, and urinalysis are recommended for dogs receiving immunosuppressive therapy such as glucocorticoids, cyclosporine, or tacrolimus.
Analytical Research Laboratories
Prognosis
Very few cases of AD resolve spontaneously. Treatment is always indicated; without it, the degree of pruritus worsens, and signs and symptoms are present for periods of increasing duration throughout the patients life. Most treated animals, however, become asymptomatic and regain a good quality of life.
Professional Lab Services Research and Development Forensics
Pharmaceutical Analysis including USP Methods. Sterility & Endotoxin Testing
Summary
Canine AD is a complex allergic reaction to environmental allergens, and multifaceted drug therapies that treat the symptoms of that disorder are available. However, because many of those drugs are intended for use only in humans, they are designed for oral administration and subsequent disposition in a gastrointestinal tract that is longer and less acidic than its canine counterpart. As a result, those medications may be less bioavailable in carnivorous veterinary patients. Dogs suffering from AD also benefit from medications (possibly compounded ones) that treat conditions secondary to AD, such as otitis externa or conjunctivitis. The compounding pharmacist can play a valuable role in providing patient-specific preparations, client education, and patient monitoring. He or she can ensure that medication regimens safely achieve the desired effects and do not contain offending allergenic substances.
complete microbiological services.
Stability Studies
(shelf life determination.)
Does your compounded preparation meet the requirements of the USP potency limit? Are you documenting any sterility of your injectables?
Contact ARL for answers to these questions and more!
Call us at 800-393-1595 or visit our website at www.arlok.com

840 Research Parkway, Ste. 546, Oklahoma City, OK 73104 405-271-1144 Fax 405-271-1174
References
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S P E C I A L T Y
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Muse R, Griffin CE, Rosenkrantz WS. The prevalence of otic manifestations and otitis externa in allergic dogs. In: Proceedings of the Annual Meeting of the American Academy of Veterinary Dermatology and the American College of Veterinary Dermatology. Vol. 12. Las Vegas, NV;1996:33. Carlotti DN, Jacobs DE. Therapy, control and prevention of flea allergy dermatitis in dogs and cats. Vet Dermatol 2000;11:83-98. Treffel P, Gabhard B, Juch R. Evaluation of barrier creams: An in vitro technique on human skin. Acta Derm Venereol 1994;74:7-11. Mueller RS, Bettenay SV. Long-term immunotherapy of 146 dogs with atopic dermatitisA retrospective study. Aust Vet Pract 1996;26:128-132. Olivry T, Rivierre C, Jackson HA, et al. Cyclosporine decreases skin lesions and pruritus in dogs with atopic dermatitis: A blinded randomized prednisolonecontrolled trial. Vet Dermatol. In press. Olivry T, Guagure E, Hripret D. Treatment of canine atopic dermatitis with the prostaglandin E1 analog misoprostol: An open study. J Dermatol Treatment 1997;8:243-247. Olivry T, Rivierre C, Jackson HA, et al. A placebocontrolled blinded trial of misoprostol monotherapy for canine atopic dermatitis: Effects on dermal cellularity and cutaneous tumor necrosis factor-a gene transcription. Vet Dermatol 2000;11(suppl 1):47. Marsella R, Nicklin CF. Double-blinded cross-over study on the efficacy of pentoxifylline for canine atopy. Vet Dermatol 2000;11:255-260. Barnes PH. Anti-inammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci 1998;94: 557-572. Adcock IM, Ito K. Molecular mechanisms of corticosteroid actions. Monaldi Arch Chest Dis 2000; 55:256-266. Thomas RC, Logas D, Radosta L, et al. Effects of a 1% hydrocortisone conditioner on haematological and biochemical parameters, adrenal function testing and cutaneous reactivity to histamine in normal and pruritus dogs. Vet Dermatol 1999;10:109-116. DeBoer DJ, Cooley AJ. Use of induced cutaneous immediate type hypersensitivity reactions to evaluate anti-inammatory effects of triamcinolone topical solution in three dogs. Vet Dermatol 2000;11:25-33. DeBoer DF. Efficacy of triamcinolone topical solution for the management of allergic pruritus in dogs. In : Proceedings of the 23rd Annual Meeting of the American Academy of Veterinary Dermatology. Norfolk, VA:American College of Veterinary Dermatology; 2001:16. Kimura T, Doi K. Dorsal skin reactions of hairless dogs to topical treatment with corticosteroids. Toxicol Pathol 1999;27:528-535. Gross TL, Walder EJ, Ihrke PJ. Subepidermal bullous dermatosis due to topical corticosteroid therapy in dogs. Vet Dermatol 1997;8:127-131. Guagure E, Lasvergeres F, Arfi L. Efficacy or oral methylprednisolone in the symptomatic treatment of allergic dermatitis. Prat Med Chir Anim Cie 1996;31:171-175. Paradis M, Scott DW, Giroux D. Further investigations on the use of nonsteroidal and steroidal antiinflammatory agents in the management of canine pruritus. J Am Anim Hosp Assoc 1991;27:44-48. Ihrke PJ, Norton AL, Ling VG, et al. Urinary tract infection associated with long-term corticosteroid
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administration in dogs with chronic skin diseases. J Am Vet Med Assoc 1985;186:43-46. Paradis M, Lemay S, Scott DW. The efficacy of clemastine (Tavist), a fatty acid-containing product (Derm Caps), and the combination of both products in the management of canine pruritus. Vet Dermatol 1991;2:17-20. Paterson S. Use of antihistamines to control pruritus in atopic dogs. J Small Anim Pract 1994; 35:412-419. Miller WH, Scott DW, Wellington JR. A clinical trial on the efficacy of clemastine in the management of allergic pruritus in dogs. Can Vet J 1993;34:25-27. Paradis M, Scott DW, Giroux D. Further investigations on the use of nonsteroidal and steroidal antiinflammatory agents in the management of canine pruritus. J Am Anim Hosp Assoc 1991;27:44-48. Keogh A, Spratt P, McCosker C, et al. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl J Med 1995;333: 628-633. Vaden SL. Cyclosporine and tacrolimus. Semin Vet Med Surg (Small Anim) 1997;12:161-166. Scott DW, Miller WH Jr, Cayatte SM, et al. Failure of terfenadine as an antipruritic agent in atopic dogs: Results of a double-blinded, placebo-controlled study. Can Vet J 1994;35:286-288. Paradis M. Nonsteroidal antipruritic drugs in dogs and cats: An update. Bull Can Acad Vet Dermatol 1996;12:3-7.
27. Garcia G, DeMora F, Ferre L, et al. Effect of H1 antihistamines on histamine release from dispersed canine cutaneous mast cells. Am J Vet Res 1997; 58:293-297. 28. Otto CM, Greentree WF. Terfenadine toxicosis in dogs. J Am Vet Med Assoc 1994;205:1004-1006. 29. Ryffel B, Donatsch P, Madrin M, et al. Toxicological evaluations of cyclosporin A. Arch Toxicol 1983;53:107-141. 30. Marsella R, Nicklin CF. Randomized double blind, placebo-controlled, cross over pilot study to evaluate the use of 0.3% tacrolimus lotion for atopic dermatitis in dogs. In: Proceedings of the Annual Meeting of the American Academy of Veterinary Dermatology. Norfolk, VA:American College of Veterinary Dermatology; 2001:43. 31. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: Therapeutic vaccines for allergic diseases. A WHO Position paper. J Allergy Clin Immunol 1998;102:558-562.
Address correspondence to: Gigi Davidson, BS, RPh, DICVP, North Carolina State University, College of Veterinary Medicine, Raleigh, NC 27606. E-mail: gigi_david son@ncsu.edu.
S P E C I A L T Y
A REVIEW of pH AND OSMOLARITY

Marc Stranz, PharmD Infusion Services Omnicare, Inc Covington, Kentucky Eric S. Kastango, RPh, MBA, FASHP Clinical IQ, LLC Madison, New Jersey Pharmacists have been extemporaneously compounding medications to meet patient needs for centuries. After the industrial revolution, many compounding functions that had been performed by pharmacists were undertaken by pharmaceutical manufacturers, and the pharmacists role gradually became primarily that of dispensing commercial mass-produced medications to patients. During the 1970s and 1980s, some pharmacists complemented dispensing with patient counseling.1 The demand for extemporaneously prepared medications in oral or parenteral dosage forms has increased significantly. Historically, pharmacy as a profession has applied the principles of secundum artem to ensure that only high-quality preparations were compounded. However, those principles have not adequately provided the most robust evidence-based decision-making tools in the past. The delivery of pharmaceutical care requires specialized knowledge about many patient-related and medication-related considerations such as pharmacology, vascular access devices and their placement, compounding considerations (osmolarity, pH, stability, particulate matter), delivery systems, and patient management.2 This article addresses patient morbidity and mortality associated with the effect of osmo-
larity and pH on compounded liquids for parenteral administration. Strategies that minimize the effects of osmolarity and pH are also presented. Vascular damage (phlebitis) caused by infusates of incorrect pH and osmolarity occurs frequently. The development of phlebitis, which increases the patients risk of local catheter-related infection, can be caused by mechanical trauma from catheter insertion, catheter material, catheter dwell time or duration of use, particulate matter, and chemically mediated factors. 3
pH and OSMOLARITY
pH
The pH scale is a measurement of the concentration of hydrogen ions (H+) in a solution. The scale ranges from 0 to 14; 0 is the most acidic, 7 is neutral, and 14 is the most alkaline (ie, basic). It is a logarithmic scale based on the power of 10; a change of 1 pH unit equals a 10-fold change in the concentration of hydrogen ions. The pH of human blood is about 7.35. Any changes in pH (even those that seem insignificant), effect great changes in the hydrogen ion concentration. In Table 1,4 examples of common household and medication acids and bases and their relative pH and
hydrogen ion concentrations are listed. Which pH values damage cells? The degree of cellular damage from either low or high pH is determined by the type of tissue exposed to the pH and the duration of exposure. Phenytoin sodium (Dilantin) applied topically does not produce the same cellular toxicity as it does when administered parenterally. In vitro experiments have demonstrated that solution pH values of 2.3 and 11 kill venous endothelium cells on contact. The nearer the pH value is to 7.4, the less the damage that occurs. Limited research data, however, pertain to the effects of less extreme pH conditions.
Titratable Acidity
Although pH is a measure of hydrogen ion content, titratable acidity is a measure of the reservoir of hydrogen ions within a solution. Phlebitis is more likely to be caused by a solution with a high titratable acidity and a lower pH. Venous endothelial cells at sites distal to the catheter tip are subject to cellular insult because more time is required for the hydrogen ion content in the infusate to be neutralized by the blood. Titratable acidity has not been well-studied to date and requires further investigation.
Table 1. Common Acidic and Basic Medications and Household Products: pH and Hydrogen Ion Concentrations.
H+ 10,000,000 1,000,000 100,000 10,000 1,000 100 10 Neutral 1 Base 1/10 1/100 1/1,000 1/10,000 1/100,000 1/1,000,000 1/10,000,000 Acid pH 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Household Products Hydrochloric acid Stomach acid Lemon juice Vinegar Soda Rainwater Milk Pure water Egg whites Baking soda Tums antacid Ammonia Mineral lime - Ca(OH) 2 Drano Sodium hydroxide Medications 5
Dopamine HCl Potassium chloride a
Furosemide
Ganciclovir sodium Phenytoin sodium
H+ = Concentration of hydrogen ions compared to that in pure water. a Abbott Laboratories, Abbott Park, Illinois.
216
S P E C I A L T Y
Osmolality
Osmosis occurs when, to produce equilibrium, a substance in solution crosses a membrane from an area of lower concentration to an area of higher concentration. The concentration of particles dissolved in solution expressed as osmoles of solute per kilogram of solvent is referred to as osmolality. In human plasma, the concentration of dissolved particles is about 290 x 10 -3 M; therefore, its osmolarity is 290 mOsm/L (285 - 310 mOsm/L). Water, for example, flows from an area of low osmolarity to an area of high osmolarity at a rate directly proportional to the difference (gradient) in osmolality until equilibrium is reached. The osmotic pressure of a solution can be expressed as either osmolality or osmolarity. Osmolality refers to the number of milliosmoles per kilogram of solvent. This value can be calculated or determined experimentally by osmometry. Osmolarity, which is the number of milliosmoles per liter of solution, is widely used in clinical practice because it expresses concentration as a function of volume. Osmolarity cannot be measured experimentally but must be calculated from osmolality by means of a conversion factor. Solutions containing the same concentration of particles are iso-osmotic (isotonic). 0.9% Sodium chloride solution (normal saline solution) is iso-osmotic with blood and the venous endothelium; the solution causes no movement of water into or out of endothelial cells. Cellular damage does
not occur when endothelial cells contact an iso-osmotic solution. Solutions with a lower osmolality (a lower concentration of dissolved particles) than 0.9% sodium chloride solution are considered hypotonic. 0.45% Sodium chloride solution and sterile water for injection are examples of hypotonic solutions. Infused fluid is drawn into venous endothelial cells and blood cells, which have a relatively high osmolality. When those cells absorb too much water, they rupture or undergo hemolysis. Hypotonic solutions such as 0.45% sodium chloride are used to replenish water deficits or to reduce the final osmolarity of certain drugs in solution. Solutions with a higher osmolality (a higher concentration of dissolved particles) than that of normal saline are considered hypertonic. 5% Dextrose and 0.9% sodium chloride injection, any type of amino acid solution, and 50% dextrose injection are examples of hypertonic solutions. The intravenous administration of hypertonic solutions draws fluid from the endothelium and blood cells, which causes the cells to shrink. That vascular insult renders cells susceptible to further damage. The degree and immediacy of that damage are determined by the osmolarity of the infused solution. Potassium chloride solution (2 mEq/mL) has an approximate osmolarity of 4000 mOsm/L. Current recommendations from the United States Pharmacopeia for the labeling of intravenous fluids produced by pharmaceutical manufacturers require that
osmolarity be stated on the product package, but there are no formal requirements for the determination of solution osmolarity. 6 Osmolarity labeling requirements for pharmacy-prepared intravenous admixtures do not exist. Osmolarity data for admixtures can be obtained only from the literature or by calculation from published osmolality values. The formula used to determine drug-solution osmolarity calculations is not accurate and is best determined by direct measurement via osmometry. 2
INFUSION NURSING SOCIETY RECOMMENDATIONS

To minimize or prevent vascular damage from extreme infusate pH or osmolarity, the Infusion Nursing Society (INS) has published recommendations based on a number of factors, including the physiologic location of the venous access device. In Table 2,7 those recommendations are presented.
METHODS of COMPENSATION
Buffering Capacity
As mentioned earlier, the normal range of the pH of blood is between 7.35 and 7.45. That range is necessary for the normal functioning of critical metabolic processes. A pH not within that range is physiologically stabilized by three primary mechanisms: the action of buffer systems, respiratory control, and renal control. Buffer systems use proteins, hemoglobin, and bicarbonatephosphate mixtures. The carbonic acid-bicarbonate system of the body is a chemical buffer mechanism that uses a weak acid and conjugate base to maintain the desired pH range. When acidic or basic drugs are infused, the carbonic acid-bicarbonate system releases the appropriate weak acid or conjugate base to maintain a pH near 7.4. As the infusate leaves the catheter tip, the pH is neutralized by the carbonic acid-bicarbonate system. The time required for neutralization of the pH is a function of the strength of the acid or base and its titratable acidity. The respiratory and renal pH control systems of the body monitor and compensate for pH via a series of complex processes.
Table 2. Infusion Nursing Society Recommendations for Minimization or Prevention of Vascular Damage from Extremes in Infusate pH or Osmolarity.
Vessel Superior vena cava Subclavian vein and/or proximal axillary vein Cephalic and basilic veins in the upper arms
Blood Flow (mL/min)8 2000 800 40 - 95
Osmolarity (mOsm/L) > 900 500 - 900 < 500
Solution pH < 5 or > 9 < 5 or > 9 5-9
S P E C I A L T Y
Laminar Flow
Laminar flow refers to the movement of air or fluid in layers and without fluctuation or turbulence. Pharmacists are familiar with the concept of laminar ow because they use specialized equipment to create aseptic working environments for the preparation of parenteral products. Laminar flow can be applied to the infusion of solutions into the bloodstream. According to the principle of laminar flow, infusate leaving the catheter travels in a layer parallel to but separate from the surrounding blood flow. Neutralization occurs during the slow diffusion of blood at the contact surface between the laminar blood flow and the laminar flow of the infused solution. As the infusate slows to the rate of blood flow, the infusate and blood mingle distal to the catheter tip. At that point, venous endothelial cells are exposed to the irritating solution, especially in smaller veins in which the amount of blood flow cannot further minimize the local effects of the infusate. Animal studies 9 have shown evidence of venous lumen damage distal to the catheter tip. That finding is supported by studies indicating that increasing the infusion rate of irritating solutions reduces the potential for the development of phlebitis; cephalosporins and other antibiotics are irritating to peripheral veins but can be administered in an intravenous push without producing an increased incidence of phlebitis.10-12 Attempts have
been made to use the ratio of the infusion rate to the blood flow rate to estimate the risk of phlebitis caused by irritating intravenously administered solutions. Because the blood and the infusate flow in a laminar manner, the neutralization process and achieving osmotic equilibrium may take longer than expected. If that method of determining the risk of phlebitis is used, the location of the catheter tip and blood ow in the infused area must be known.
CHEMICAL PHLEBITIS In VIVO

Animal Models
To date, the effects of pH and osmolarity have been studied most effectively in animal models. According to Kuwahara et al, 13 the effects of infusions of solutions at various pH values and infusion times were studied. When the effects of 6-hour infusions through peripheral vessels were compared, a solution with a pH of 4.5 resulted in a 100% incidence of severe phlebitic changes, a pH of 5.9 caused mild-to-moderate phlebitic changes in 50% of the animal subjects, a pH of 6.3 caused mild damage in 20% of those subjects, and a pH of 6.5 caused no significant damage. When the pH value was 6.5, extending the duration of the infusion did not produce phlebitis. Other trials14,15 have indicated that a solution with a pH of 3 to 11 did not induce phlebitic changes when drugs were administered over a few minutes. When the same acidic solution volume was infused over 5 hours, 1 hour, or 30 minutes, fewer inflammation-related changes were noted after the more rapid infusions. No trials have studied the effect of slowing the infusion of highly acidic or basic infusates to increase dilution. Both pH and titratable acidity must be considered when the administration of peripheral parenteral nutrition is required.16 Animal studies 16,17 indicate that the higher the titratable acidity of an infusate, the greater the proximal and distal phlebitic changes. When the principles of laminar flow were applied, tolerance to osmolarity in peripheral veins was demonstrated in animal models. When other factors were controlled, those studies indicated that the peripheral tolerance was directly related to the osmolarity and duration of the infusion. The faster the infusion of hypertonic infusates, the greater the vein tolerance, which was 820 mOsm/kg for 8-hour infusions, 690 mOsm/kg for 12-hour infusions, and 550 mOsm/kg for 24-hour infusions.
Human Models
Human tolerance of pH and osmolarity has not been as well researched (or understood) as it has been in animal models; however, human tolerance to pH and osmolarity is similar to that of animals. There is a direct relationship between the pH and osmolarity of an infusate and the development of phlebitis. The incidence of phlebitis increases as infusate pH and osmolarity increase, and it decreases according to the baseline pH and osmolarity of blood. The exact point at which osmolarity and pH become significant risk factors in humans is not known. The outcomes of human studies of osmolarity-induced phlebitis have been inconsistent. Gazitua et al 18 classified three risk levels of phlebitis caused by infusate osmolarity. The lowest risk of phlebitis occurred when a solution osmolarity lower than 450 mOsm/L was used, a moderate risk occurred at 450 to 600 mOsm/L, and the highest risk occurred when the solution osmolarity exceeded 600
218
S P E C I A L T Y
mOsm/L. That study provided evidencebased science used by the INS to define an osmolarity of 500 mOsm/L as the outer limit of peripheral vein tolerance. The ability to tolerate different levels of infusate pH and osmolarity varies significantly among patients. Few human trials have been conducted to measure the effect of pH on peripheral veins. Some studies 18-21 indicate that neutralizing the pH of the infusate to 7 to 7.4 significantly reduces the incidence of phlebitis. To date, no trial of human patients has identified a pH range that corresponds to the potential for the development of phlebitis. The physiochemical properties of medication indicate that very few drug infusions are stable at pH 7. The accepted pH range of 5 to 9 for solutions infused peripherally represents clinically significant variances from the ideal pH of 7.4. However, factors such as blood ow, infusion rate, venous access device, catheter tip location, and variations in patient tolerance to the pH of the infusate influence the occurrence of pH-induced phlebitis in spite of the challenges posed by the pH value of final drug admixtures.
aqueous solubility of the medication may be exceeded and the potential for precipitation exists. Medications that are considered weak bases are similarly affected; their formulation must result in a low pH to ensure solubility. The effect of pH on solubility is best illustrated in parenteral nutrition solutions in which calcium salts (calcium gluconate or calcium chloride) interact with phosphates. The lower the pH of the final solution, the more stable the formulation, because the calcium and phosphate ions remain ionized. As the pH increases, the ions become less ionized, and precipitation can occur. Ready-to-use formulations of medications are not always isoosmotic or of neutral pH. Stability is the principle concern with those formulations. Premade frozen medications (eg, certain antibiotics) are formulated with sterile water or dextrose injection to produce better solution tonicity.
Diluting medications that are extremely acidic (vancomycin hydrochloride) or extremely alkaline (phenytoin sodium) in greater volumes of fluid to affect solution pH is not an effective method of mediating pH-induced effects. A solution that acts as a buffer must affect the titratable acidity of a medication by contributing either carbonic acid or hydroxide. Neither 5% dextrose injection nor 0.9% sodium chloride injection has an inherent buffering capacity; therefore the pH of the final infusate containing those substances is determined by the pH of the medication and not the base solution. Final osmolarity can be altered by using other base solutions such as lactated Ringers solution, 5% dextrose injection, dextrose 5% in lactated Ringers injection (D5LR), or 0.45% sodium chloride injection. The osmolarity of most parenteral medication solutions (antibiotics, antineoplastics, etc) is usually less than 400
Exceptions to the Rules

Some exceptions to the rules of pH and osmolarity cannot be easily explained. Certain isotonic, pH-neutral infusates (eg, amphotericin B, cladribine, erythromycin, foscarnet, imipenem, meropenem, pamidronate, nafcillin, oxacillin, chemotherapeutic drugs) cause phlebitis, perhaps because they can produce a direct cellular insult to the endothelial cells.
Secundum Artem
During manufacturing, the pH of many medications is adjusted with either hydrochloric acid and/or sodium hydroxide to ensure drug stability and a long shelf life. The solubility of weakly acidic or basic medications is a direct function of solution pH, which controls both the portion of medication that is in an ionized form (eg, that is metabolically active) and the solubility of the nonionized form of the medication.6 Sodium salts (phenobarbital, phenytoin, methotrexate) are considered weak acids and must be formulated at a high pH to ensure solubility. If, during the preparation of a solution, the pH is lowered, the
S P E C I A L T Y
mOsm/L. Parenteral nutrition solutions usually have a much higher final osmolarity because of the number of cations and anions in solution.
CONCLUSION
The osmolarity of drug solutions should not be the primary consideration in the prevention of infusion-related phlebitis. Many approaches can be used to ensure that the osmolarity of an infusate (with the exception of parenteral nutrition solutions) remains below the recommended INS guideline of 500 mOsm/L. According to data from anecdotal clinical practice and extensive studies of animal and human subjects, pH is the most significant cause of phlebitis. Current INS standards state that an infusate pH of 5 to 9 can be tolerated by peripheral veins. Animal and human data also suggest that variance from a pH of 7.4 causes damage to venous endothelium tissue. Other unknown mitigating factors prevent phlebitis from occurring in a large percentage of patients who receive infusions. The best method of preventing patient morbidity and mortality caused by infusion therapy is to consider all primary and secondary factors that cause phlebitis, such as the dilution of the medication, the composition of the base infusate solution, the rate of infusion, and the type, size, material, and location of the
venous access device and tip. Additional research on the principle of laminar flow must be conducted to identify methods (such as the intravenous push of antibiotics) of administering highly acidic or highly alkaline infusates.
References
1. 2. 3. RidgeRx Compounding. Available at: http://www.RidgeRx.com/story.ntml. Accessed January 12, 2002. Kastango ES, Hadaway L. New perspectives on vancomycin use in home care. Part 1. IJPC 2001;6:465-469. Pearson ML. Guideline for prevention of intravascular device-related infection. US Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta, Georgia. Available online: http://www.cdc.gov/ncidod/hip/iv/iv.htm. 1999. Accessed January 12, 2002. Carpi A. Acids and bases: An introduction. Available at: http://www. visionlearning.com/library/science/chemistry-2/CHE2.2-acid_base. htm. 2000. Trissel LA. Handbook of Injectable Drugs . 11th ed. Bethesda, MD:American Society of Health-System Pharmacists; 2001. CmcIssues: Consulting services for the pharmaceutical industry Website. Available online: http://www.cmcissues.com/Methods/osmolarity.htm. Accessed on January 10, 2002. Intravenous Nurses Society. Intravenous nursing standards of practice. J Intraven Nurs 2000;23(suppl):S37-S38. Kokotis K. Preventing chemical phlebitis. Nursing 98. Available at: http:// www.springnet.com/ce/p118a.htm. Accessed May 28, 2001. Kuwahara T, Asanami S, Tamura T, et al. Effects of pH and osmolarity on phlebitic potential of infusion solutions for peripheral nutrition. J Toxicol Sci 1998;23:77-85. Poole SM, Nowobilski-Vasilios A, Free F. Intravenous push medications in the home. J Intraven Nurs 1999;22:209-215. Nowobilski-Vasilios A, Poole SM. Development and preliminary outcomes of a program for administering antimicrobials by IV push in home care . Am J Health Syst Pharm 1999;56:76. Vickery TR, Hatheway JG, Edgar SP, et al. Concentrated vancomycin and administration via central venous catheters in the alternate-care setting. Poster presented at: ASHP Midyear Clinical Meeting; 1990; Las Vegas, NV. Kuwahara T, Asanami S, Kawauchi Y, et al. Experimental infusion phlebitis: Tolerance pH of peripheral veins. J Toxicol Sci 1999;24:113-121. Simamora P, Pinsuwan S, Alvarez JM, et al. Effect of pH on injection phlebitis. J Pharm Sci 1995;84:520-522. Hessov I, Bojsen-Mooller M. Experimental infusion thrombophlebitis. Importance of the infusion rate. Eur J Intensive Care Med 1976;2:103-105. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Importance of titratable acidity on phlebitic potential of infusion solution. Clin Nutr 1996;15:129-132. Kuwahara T, Asanamia T, Kubo S. Experimental infusion phlebitis: Tolerance osmolarity of peripheral venous endothelial cells. Nutrition 1998; 14: 496-501. Gazitua R, Wilson K, Bistrian BR, et al. Factors determining peripheral vein tolerance to amino acid infusions. Arch Surg 1979;114:897-900. Fonkalsrud E, Pederson BM, Murphy J, et al. Reduction of infusion thrombophlebitis with buffered glucose solutions. Surgery 1968;63:280-284. Eremin O, Marshall V. Complications of intravenous therapy: Reduction by buffering of intravenous fluid preparation. Med J Aust 1977;2:528-531. Fujita M, Hatori N, Shimizu M, et al. Neutralization of prostaglandin E 1 intravenous solution reduces infusion phlebitis. Angiology 2000;51:719-723.
4.
5. 6.
7. 8. 9.
10. 11.
12.
13. 14. 15. 16.
17.
18. 19. 20. 21.
Address correspondence to: Marc Stranz, PharmD, 100 E. River Center Boulevard, Suite 1700, Covington, KY 41011. E-mail: marc.stranz@omnicare.com.
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S U P P O R T
Introduction
The sorbitan esters, which are commonly used in pharmaceuticals, cosmetics, and food products, are usually regarded as nontoxic, nonirritating materials. They are also called sorbitan fatty acid esters and occur as monoesters and diesters. The sorbitan monoesters include a group of mixtures of partial esters of sorbitol and its monohydrides and dianhydrides with fatty acids. The sorbitan diesters include a group of mixtures of partial esters of sorbitol and its monoanhydride with fatty acids. The sorbitan esters are widely used as lipophilic, nonionic, surfactant emulsifying agents for preparing water-in-oil preparations such as emulsions, creams, and ointments for topical use. They can be used alone to produce stable water-in-oil emulsions and microemulsions, as well as in combination with varying proportions of a polysorbate to produce either water-in-oil or oil-in-water emulsions or creams.1 Sorbitan esters are used for the following purposes in the concentrations listed: as emulsifying agents (concentration range, 1% to 15% when used alone or 1% to 10% when used in combination with hydrophilic emulsifiers), in ointments to increase water retention (1% to 10%), as a solubilizing agent for poorly soluble ingredients in a lipophilic base (1% to 10%), and as a wetting agent for insoluble, active ingredients in a lipophilic base (0.1% to 3%). Three of the sorbitan esters (sorbitan monolaurate, sorbitan monopalmitate, and sorbitan triContinuing Education Goal: To provide compounding pharmacists with supportive information on the selection and use of the sorbitan esters as wetting and emulsifying agents. Objectives: After reading and studying the article, the reader will be able to: 1. Discuss the different sorbitan esters, their preparation, and their nomenclature 2. Select an appropriate sorbitan ester according to the active and other ingredient(s) and the dosage form desired 3. Use a selected sorbitan ester and the dosage form being prepared to determine the appropriate method of compounding and the order of mixing and processing 4. Discuss the properties of the various sorbitan esters and their storage requirements
Featured Excipient: THE
SORBITAN ESTERS
Loyd V. Allen, Jr, PhD, RPh oleate) have been used to prepare an emulsion for intramuscular administration at a concentration of 0.01% to 0.05%. The Food and Drug Administration (FDA) Inactive Ingredients Guide 1 includes the sorbitan esters used in inhalations, intramuscular injections, and ophthalmic, oral, topical, or vaginal preparations. Usually, sorbitan esters occur as a cream to amber-colored liquid or solid that has a distinctive odor and taste. There are many sorbitan esters, but only six (sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, and sorbitan trioleate) are official; they are listed in the United States Pharmacopeia XXV/National Formulary 20 (USP XXV/NF 20 ).2 Brand names of the sorbitan esters include Arlacel or Span (the most common), Ablunol, Alkamuls, Armotan, Capmul, Crill, Drewmulse, Drewsorb, Durtan, Famodan, Glycomul, Hodag, Lamesorb, Liposorb, Montane, Nikkol, Nissan Nonion, Norfox Sorbo, Polycon, Protachem, Prote-sorb, S-Maz, Sorbester, or Sorbirol. The numerical designations accompanying the chemical names of the sorbitan esters are listed in Table 1.
Preparation of Sorbitan Esters

The sorbitan esters are prepared by dehydrating sorbitol to form a hexitan (1,4-sorbitan). This hexitan is then esterified with the appropriate fatty acid. The sesquiesters are equimolar mixtures of the monoesters and the diesters. The presence of the long-chain fatty acids yields a lipophilic molecule. The sorbitan esters (Spans,
Table 1. Nomenclature, Number Designation, and Approximate Molecular Weight of the Sorbitan Esters.
Common Name Sorbitan monolaurate Sorbitan monooleate Sorbitan monopalmitate Sorbitan monostearate Sorbitan sesquioleate Sorbitan trioleate
MW = Molecular weight.
Chemical Name Sorbitan monododecanoate (Z)-Sorbitan mono-9-octadecenoate Sorbitan monohexadecanoate Sorbitan mono-octadecanoate (Z)-Sorbitan sesqui-9-octadecenoate (Z,Z,Z)-Sorbitan tri-9-octadecenoate
No 20 80 40 60 83 85
Formula C 18H34O6 C 24H44O6 C 22H42O6 C 24H46O6 C 33H60O6.5 C60H108O8
MW 346 429 403 431 561 958
S U P P O R T
Table 2. Physicochemical Characteristics of the Sorbitan Esters.

Viscosity (mPa) 3900 - 4900 970 - 1080 Solid Solid 1500 200 - 250 Solubility Water I I I I, D I I
Name Sorbitan monolaurate Sorbitan monooleate Sorbitan monopalmitate Sorbitan monostearate Sorbitan sesquioleate Sorbitan trioleate
HLB 8.6 4.3 6.7 4.7 3.7 1.8
SpG 1.01 1.01 1.00 1.00 0.95
Alcohol, USP Vegetable Oil Sa S S SS M Sb Sc Sc
Mineral Oil S M S S S S
HLB = Hydrophile-lipophile balance. SpG = Specific gravity. MPa = Megapascal.
I = Insoluble. D = Dispersible in warm water. M = Miscible
S = Soluble ( awarm absolute alcohol, bsoluble with haze, ccheck for specific oils). SS = Slightly soluble.
Arlacels, etc) are oil dispersible or oil soluble and have a hydrophilelipophile (HLB) balance of less than 8.6.
HLB Values
The HLB of surface-active agents depends on the chemical make-
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up of the specific agent. Each molecule of a surface-active agent has both a hydrophilic portion and a lipophilic portion, one of which is predominant. If the hydrophilic portion of the molecule is predominant, the ratio of the hydrophilic to the lipophilic portion is high (as is the HLB), the resultant preparation has an aqueous external phase, and an oil-in-water dispersion or emulsion results. If the lipophilic portion is predominant (as it is in the sorbitan esters), the ratio of the hydrophilic to the lipophilic portion is low (as is the HLB), the resultant preparation has an oily external phase, and a water-in-oil dispersion or emulsion is produced.
I N T E R N AT I O N A L J O U R N A L
PHARMACEUTICAL
COMPOUNDING
IJPCs eCompendium
of
Common and Chemical Names

In Table 1, sorbitan esters are listed by common and chemical names and approximate molecular weight. In Table 2, information on the physicochemical properties (HLB values, specific gravity, viscosity, and solubility in different liquids) of those esters is featured. The flash point for the sorbitan esters is greater than 149C. In this article, only the six official sorbitan esters included in the USP XXV/NF 20 are described.
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Sorbitan monolaurate (Arlacel 20, Span 20) occurs as a yellow to amber-colored oily liquid that has a bland, characteristic odor. It is insoluble in water but is soluble in mineral oil. It is slightly soluble in cottonseed oil and in ethyl acetate and has a pour temperature of 16C to 20C. Sorbitan monolaurate should be packaged in a tight container. 1-2 Sorbitan monooleate (Arlacel 80, Span 80) occurs as a viscous
yellow to amber-colored oily liquid that has a bland, characteristic odor. It is insoluble in water and in propylene glycol but is miscible with mineral and vegetable oils. It has a pour temperature of -12C and should be packaged in a tight container. 1-2
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222
Sorbitan monopalmitate (Arlacel 40, Span 40) occurs as a

cream-colored waxy solid that has a faint fatty odor. It is insoluble in water but is soluble in warm absolute alcohol. In warm
S U P P O R T
Table 3. Approximate Percentages of the Sorbitan Esters According to Use.

Application Wetting agent Solubilizing agent Emulsifying agent (water-in-oil; alone) Increase water-holding capacity of ointments Percent 0.1 - 3 1 - 10 1 - 15 1 - 10
Emulsifying agent (water-in-oil; in combination) 1 - 10
between them, and an effective attraction caused by van der Waals forces results. This strengthens the interfacial film and the stability of an oil-in-water emulsion against particle coalescence. In the formulation of stable emulsions, the type of emulsion formed is a function of the HLB value of the combination of sorbitan esters used. Experimentation is often required to determine the combination of ingredients that produces the most stable emulsion. Sorbitan esters are stable and relatively easy to use in the formulation of stable preparations; they are stable in the presence of strong acids and bases, although a mixture of sorbitan esters with those materials results in gradual saponification. 1
References
mineral oil and peanut oil, it is soluble but exhibits a haze. It melts at 43C to 48C. Sorbitan monopalmitate should be packaged in a well-closed container.1-2
1. Lawrence MJ. Sorbitan esters (sorbitan fatty acid esters). In: Kibbe AH, ed. Handbook of Pharmaceutical Excipients. 3rd ed. Washington, DC:American Pharmaceutical Association; 2000:511-514. US Pharmacopeial Convention, Inc. United States Pharmacopeia XXV/National Formulary 20 . Rockville, MD:US Pharmacopeial Convention, Inc; 2002:2397, 2622-2624. Martin A. Physical Pharmacy. 4th ed. Philadelphia PA:Lea & Febiger; 1993:488-490.
Sorbitan monostearate (Arlacel 60, Span 60) occurs as a creamcolored to tan, hard, waxy solid that has a bland odor and taste. It is insoluble in water and in acetone but is dispersible in warm water. It is soluble above 50C in mineral oil but exhibits a haze. Sorbitan monostearate melts at 53C to 57C and should be packaged in a well-closed container. 1-2 Sorbitan sesquioleate (Arlacel 83) occurs as a viscous yellow to amber-colored oily liquid. It is insoluble in water and in propylene glycol but is soluble in each of the following: alcohol, isopropyl alcohol, cottonseed oil, and mineral oil. It should be packaged in a tight container. 1-2 Sorbitan trioleate (Arlacel 85, Span 85) occurs as a yellow to ambercolored oily liquid. It is insoluble in water and in propylene glycol but is soluble in each of the following: alcohol, isopropyl alcohol, corn oil, cottonseed oil, and mineral oil. Sorbitan trioleate should be packaged in a tight container. 1-2
2.
3.
Sorbitan Esters in Formulations

In Table 3, the uses for and concentrations of the sorbitan esters are listed. The HLB value of each of the sorbitan esters and the required HLB value of each ingredient in a formulation can be used to select one or a combination of sorbitan esters a formulation. A combination of emulsifiers (rather than a single agent) can be used to produce a more stable emulsion. For example, the molecular association of polysorbate 40 (Tween 40) and sorbitan monooleate (Span 80) in the stabilization of emulsions has been discussed.3 The hydrocarbon portion of the sorbitan monooleate molecule is in the oil globule, and the sorbitan radical is in the aqueous phase. Because the sorbitan heads of the sorbitan monooleate molecules are bulky, the hydrocarbon tails of the molecules are prevented from closely associating in the oil phase. Added polysorbate 40 orients at the interface so that part of the hydrocarbon tail of the sorbitan monooleate molecule is in the oil phase and the remainder of the chain (with the sorbitan ring and the polyoxyethylene chains) is in the water phase. The hydrocarbon chains of the polysorbate 40 molecule are arranged in the oil so that the sorbitan monooleate 80 chains are
S U P P O R T
Standard Operating Procedure:
Developing Standard Operating Procedures

Loyd V. Allen, Jr, PhD, RPh Pharmacy compounding requires the development and maintenance of standard operating procedures (SOPs) to ensure quality and minimize the number of errors that occur. A commitment to maintaining quality must be a priority of top management, and it must also involve all individuals in the organization. The purpose of the quality system is to ensure adequate controls throughout the compounding and dispensing processes. The heart of any quality system involves the use of SOPs, which are written approved documentation that is followed in the day-to-day operation of the pharmacy. A good document system supports but does not guarantee a good-quality system. Documents are written to link people with their operational responsibilities. Failure and error often occur when: Individuals do not know their responsibilities.
Individuals have not been properly trained. Individuals have not been provided the resources necessary to perform their work. Individuals do not take their responsibilities seriously. SOPs are step-by-step instructions (which must be approved by qualified individuals), for the reliable, consistent performance of routine tasks involved in formulation development, purchasing, compounding, testing, maintenance, the handling of materials, quality assurance, and dispensing. SOPs should exist for all compounding, quality control, packaging, and labeling functions. Master formula records should also be written to provide adequate instruction in and the documentation of compounding procedures, as well as for the safe operation, cleaning, maintenance, and care of the facility and equipment. SOPs usually consist of the following topics: title or number, purpose or scope, responsibility, equipment/materials, process or procedures, information about the company, and the signatures of authors or those designated pertinent responsibilities within the respective department. SOPs should include detailed task performance, the name of the operator assigned to the task, and the reason(s) for which the task must be performed. SOPs should be written either by or with the assistance of the individual(s) who perform that task and should be reviewed (at least annually) by those involved with the performance of the task.
Now includes all 2001 SOPs
Includes the following SOPs:

Monitoring Air Temperature and Humidity Calibration of Hot Plates Cleaning Glassware Cleaning, Inspecting and Flow-Accuracy Testing of Ambulatory Pumps Electronic Balance Maintenance/Calibration Performing Class A Prescription Torsion Balance Performance Tests Pipette Calibration Use, Standardization and Care of a pH Meter Assignment of a Beyond-Use Date for Compounded Preparations Assignment of Beyond-Use Dates Basic Compounding Documentation: The Batch Control Sheet Basic Compounding Documentation: The Master Formula Form General Aseptic Procedures Carried Out at a Laminar Airflow Workbench Maintenance of a Horizontal Laminar Airflow Hood Operation of a Dry-Heat Sterilizing Oven and Validation of this Procedure Particulate Testing for Sterile Products Performing Physical Quality Assessment for Suppositories, Troches, Lollipops and Sticks Performing Physical Quality Assessment of Ointments/Creams/Gels Quality Assessment for Injectable Solutions Quality Assessment of Oral and Topical Liquids Quality Assessment of Parenteral Nutrition Products Quality Assessment of Special Hard-Gelatin Capsules Quality Assessment of Powder-Filled, Hard-Gelatin Capsules Environmental Compounding Purchasing Chemicals for Pharmaceutical Compounding Certificates of Analysis of Materials Used for Pharmaceutical Compounding Establishing and Maintaining a Compounding Pharmacy Reference Library Maintenance of the Cleanroom Developing a Capsule Formulation Training Personnel
SOPS

for Compounding Pharmacy
30 Standard Operating Procedures prepared and compiled by the International Journal of Pharmaceutical Compounding now at your fingertips in a convenient CD-ROM.
Open the PDF file on your computer and print copies for your records. Some pages have interactive form fields that can be filled-in and printed. Includes Adobe Acrobat Reader for Windows 95, 98, 2000 or NT. Organized in the following categories: Facility; Equipment; Personnel; Process, General; Process, Aseptic; Product and Other.
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224
S U P P O R T
STANDARD OPERATING PROCEDURE

Title Purpose/scope Number
Responsibility
Equipment/materials
Procedure 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Company name Date written Date approved Date approved Written by Approved by Approved by
P E E R
R E V I E W E D
Stability of Ampicillin Sodium, Nafcillin Sodium, and Oxacillin Sodium in AutoDose Infusion System Bags
Abstract
The objective of this study was to evaluate the physical and chemical stability of ampicillin sodium 1 g/100 mL, nafcillin sodium 1 g/100 mL, and oxacillin sodium 1 g/100 mL, each of which was admixed in 0.9% sodium chloride injection and packaged in an AutoDose Infusion System bag. Triplicate test samples were prepared by reconstituting the penicillin antibiotics and bringing the required amount of each drug to a final volume of 100 mL with 0.9% sodium chloride injection. The test solutions were packaged in AutoDose bags, which are ethylene vinyl acetate plastic containers designed for use in the AutoDose Infusion System. Samples were stored protected from light and were evaluated at appropriate intervals for up to 7 days at 23C and up to 30 days at 4C. Physical stability was assessed by means of a multistep evaluation procedure that included both turbidimetric and particulate measurement as well as visual inspection. Chemical stability was assessed with stability-indicating high-performance liquid chromatographic (HPLC) analytical techniques based on the determination of drug concentrations initially and at appropriate intervals over the study periods. All the penicillin admixtures were initially clear when viewed in normal fluorescent room light. When the admixtures were viewed with a Tyndall beam, a trace haze was observed with the ampicillin sodium and nafcillin sodium mixtures but not with the oxacillin sodium mixture. Measured turbidity and particulate content were low and exhibited little change in the ampicillin sodium and oxacillin sodium samples throughout the study. The nafcillin sodium samples stored at room temperature remained clear, but a microprecipitate developed in the refrigerated samples between 14 and 21 days of storage. All samples were essentially colorless throughout the study. HPLC analysis indicated some decomposition in the samples. Ampicillin sodium, which was the least stable, exhibited a 10% loss after 24 hours at 23C. In the samples stored at 4C, ampicillin losses were 6% and 11% after 3 days and 5 days, respectively. Nafcillin sodium exhibited a 10% loss after 5 days at 23C. Less than 3% loss occurred after 14 days at 4C, but the microprecipitation that developed resulted in the termination of that portion of the study. Oxacillin sodium was the most stable; it exhibited less than a 10% loss after 7 days at 23C and less than a 5% loss after 30 days at 4C. Ampicillin sodium, nafcillin sodium, and oxacillin sodium exhibited physical and chemical stability consistent with previous studies on these drugs. The AutoDose Infusion System bags did not adversely affect the physical and chemical stability of those three penicillin antibiotics. Yanping Zhang, BS Lawrence A. Trissel, BS, RPh Clinical Pharmaceutics Research Division of Pharmacy The University of Texas M. D. Anderson Cancer Center Houston, Texas is available on the stability of ampicillin sodium, nafcillin sodium, or oxacillin sodium in EVA containers. Consequently, studies must be conducted to determine the physical and chemical stability of the antibiotic solutions of those drugs in AutoDose Infusion System bags before they are used in the clinical setting. The purpose of this study was to evaluate the physical and chemical stability of three common penicillin antibiotic solutions that were packaged in AutoDose Infusion System bags and were stored and evaluated at appropriate intervals for up to 7 days at 23C and up to 30 days at 4C.

Materials
Empty AutoDose Infusion System bags that had been sterilized by gamma irradiation (Tandem Medical, Inc, San Diego, California) were supplied by the manufacturer. The following materials were obtained commercially: ampicillin sodium injection (Lot # 0D19993, Apothecon, Princeton, New Jersey) and its reference standard (Lot J, United States Pharmacopeia, Rockville, Maryland), nafcillin sodium injection (Lot # 0B18804, Apothecon), and its reference standard (Lot H, United States Pharmacopeia), and oxacillin sodium injection (Lot # 08540, Apothecon) and its reference standard (Lot I, United States Pharmacopeia). The reference standards were used without further purification. The mobile phase components were all of a grade suitable for HPLC analysis. The water used was also HPLC grade and was prepared immediately before use.
Introduction
The AutoDose Infusion System (Tandem Medical, Inc, San Diego, California) is a new, simplified infusion system for the administration of antibiotics that is suitable for patient or caregiver operation and for use by healthcare providers. In the AutoDose system, specially designed multichamber drug solution reservoirs (AutoDose bags) composed of ethylene vinyl acetate (EVA) are used. In a simple automated process, the system provides an infusion line flush, antibiotic administration, a second infusion line flush, and the reinstillation of heparin sodium lock solution. Although studies 1 of the physical and chemical stability of many antibiotics in glass and polyvinyl chloride (PVC) containers have been reported, no published information
Methods
Preparation and Sampling of Solutions. Each of the penicillin antibiotics was reconsti-
226 International Journal of Pharmaceutical Compounding

Vol. 6 No. 3 May/June 2002
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Table 1. High-Performance Liquid Chromatographic Analytical Methods Used To Determine the Stability of Ampicillin Sodium, Nafcillin Sodium, and Oxacillin Sodium in AutoDose Infusion System Bags.
Ampicillin a 90% 0.067 M sodium phosphate, monobasic (pH 4) 10% acetonitrile Column Symmetry C 18, 5 m, 250 x 4.6 mm id, Cat # WA7054275 Flow rate 1.0 mL/min Detection 254 nm, 0.5 AUFS Sample dilution 1:50 water Sample injection volume 20 L Retention times Ampicillin 8.6 min Nafcillin Oxacillin Decomposition products 3.6, 4.7, 5.2, 6 min Mobile phase d
a
Nafcillin b 70% 0.05 M sodium acetate (pH 7) 30% acetonitrile Kromasil C 18 5 m, 250 x 4.6 id, Cat # 00G-3033-E0 1.0 mL/min 280 nm, 0.5 AUFS 1:100 water 10 L 9.4 min 2.4, 3.2, 3.5, 6.1, 6.4, 8.2 min
c
Oxacillin c 76% 0.04 M sodium acetate (pH 7) 24% acetonitrile Kromasil C 18 5 m, 250 x 4.6 id, Cat # 00G-3033-E0 1.25 mL/min 225 nm, 0.5 AUFS 1:100 water 10 L 10.8 min Multiple 2.2 - 2.6, 3.7, 4.3, 6.1, 7.3, 9.6 min
Precision: 100.1 0.2 g/mL, mean SD, n = 10; percent relative standard deviation, 0.1%; standard curves range, 100 to 300 g/mL; correlation coefficient, > 0.9999; intraday and interday coefficients of variation, 0.6% and 1.1%, respectively. Precision: 100.2 0.2 g/mL, mean SD, n = 10; percent relative standard deviation, 0.2%; standard curves range, 50 to 150 g/mL; correlation coefficient, > 0.9999; intraday and interday coefficients of variation, 0.5%
and 0.8%, respectively. Precision: 99.9 0.2 g/mL, mean SD, n = 10; percent relative standard deviation, 0.2%; standard curves range, 25 to 150 g/mL; correlation coefficient, > 0.9999; intraday and interday coefficients of variation, 1.6% and 0.4%, respectively. Mobile phases delivered isocratically.
tuted with 0.9% sodium chloride injection (Lot # C466706, Baxter Healthcare Corporation, Deerfield, Illinois) according to the instructions in the product labeling. After dissolution had occurred, the appropriate amounts of the reconstituted antibiotic solutions were brought to a final volume of 100 mL with 0.9% sodium chloride injection. The test solutions were packaged in AutoDose Infusion System bags for testing. All manipulations were performed in a biological safety cabinet. The nominal concentration for the antibiotics used in this testing was 1 g/100 mL. Triplicate test solutions of each antibiotic were prepared. The test solutions were stored at 4C and 23C and were protected from light. Aliquots were removed from each bag initially and at appropriate time intervals up to 7 days at 23C and up to 30 days at 4C. Sample evaluation was discontinued when the drug content decreased to below 90% of the initial concentration or a physical instability was observed. Physical Compatibility. The physical stability of the admixtures was assessed by vi-
sual examination and by measuring turbidity and particle size and content. 2-4 Five milliliters of each sample solution was transferred to 15-mL borosilicate glass culture tubes (Kimble, Division of OwensIllinois, Toledo, Ohio) with polypropylene screw caps (Kimble). The tubes had been previously triple-washed in highperformanceliquid-chromatographicgrade water and dried. To minimize the effects of scratches and imperfections in the glass, a thin layer of silicone oil was applied to the tube exteriors. Visual examinations were performed in normal diffuse fluorescent room light by means of a high-intensity monodirectional light (Tyndall beam; Dolan-Jenner Industries, Woburn, Massachusetts) viewed with the unaided eye. 3 The turbidity of each sample was measured by means of a color-correcting turbidimeter (Ratio X/R, Hach Company, Loveland, Colorado). Triplicate determinations were made on each of the samples. The particle content of the samples was quantified with a light obscuration
particle sizer/counter (Model 8003, HiacRoyco, Division of Pacific Scientific Company, Silver Spring, Maryland) to determine particle content in the size range of 1.04 to 112 m (the validated detection limits of the particle sizer/ counter). Triplicate determinations were made on those samples. Physical instability was defined as visible particulate matter, haze, color change, or a change (increase or decrease) in measured turbidity of 0.5 nephelometric turbidity unit (NTU) or more. 2-4 Analysis by High-Performance Liquid Chromatography (HPLC). Antibiotic concentrations were determined by means of stability-indicating HPLC assay methods. The details of the analytical methods developed for use in this study are cited in Table 1. Two high-performance liquid chromatographs (Alliance 2960 and LC Module-1 Plus, Waters Corporation, Milford, Massachusetts) were used for analysis of the drugs; each consisted of a multisolvent delivery pump, an autosampler, and a multiple wavelength ultraviolet
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Table 2. Stability of Ampicillin Sodium 1g/100 mL, Nafcillin Sodium 1 g/100 mL, and Oxacillin Sodium 1 g/100 mL in 0.9% Sodium Chloride Injection in AutoDose Infusion System Bags at 4C and 23C.
Percentage of Initial Concentration Remaininga Ampicillin Sodium b Nafcillin Sodiumc 23C 4C 23C 4C 90.7 0.8 79.6 0.3 e 97.2 1.1 94.2 0.9 89.1 1.2
c
Time (days) 1 3 5 7 14 21 30
a b
Oxacillin Sodium d 23C 4C 96.9 0.7 95.8 0.7 93.3 0.7 90.7 0.2 98.4 1.1 99.0 0.9 98.7 0.9 96.1 1.2 95.6 1.0 95.5 0.7
99.0 1.3 96.7 1.7 90.3 1.8 85.5 0.8
99.5 1.2 98.8 1.3 98.5 1.3 97.8 1.9 Precipitation e, f Precipitation e, f
Mean SD for duplicate determinations of triplicate samples, n = 6. Initial concentrations of the triplicate samples were 10.4, 10.6, and 10.3 mg/mL for the samples stored at 23C and 10.6, 10.3, and 10.4 mg/mL for the samples stored at 4C.
Initial concentrations of the triplicate samples were 9.8, 10.0, and 9.7 mg/mL for the samples stored at 23C and 9.9, 10.0, and 9.8 mg/mL for the samples stored at 4C. Initial concentrations of the triplicate samples were 9.7, 9.7, and 9.9 mg/mL for the samples
e f
stored at 23C and 9.7, 9.9, and 9.8 mg/mL for the samples stored at 4C. Analysis not performed at this time point. Microprecipitation observed.
light detector. The systems were controlled and integrated by personal computers equipped with chromatography management software (Millennium 32 Chromatography Manager, Waters Corporation). Duplicate HPLC determinations were performed on triplicate samples of each test admixture solution. The analytical methods for each of the drugs were demonstrated to be stability indicating by accelerated degradation. The antibiotic solutions were mixed with each of the following: 1 N sodium hydroxide, 1 N hydrochloric acid, and 3% hydrogen peroxide and were also subjected to heating. Loss of the intact drugs was observed, and there was no interference by the degradation product peaks or other drug peaks with the peak of the intact subject drug. The initial concentrations of ampicillin sodium, nafcillin sodium, and oxacillin sodium were defined as 100%, and subsequent sample concentrations were expressed as a percentage of initial concentration. The stability of the drug was defined as not less than 90% of the initial drug concentration remaining in the admixtures.
Results and Discussion

All of the admixtures were initially clear when viewed in normal fluorescent room light. Ampicillin sodium and nafcillin sodium exhibited a trace haze when viewed with a Tyndall beam; oxacillin sodium exhibited no visually apparent haze. The admixtures had measured turbidities of less than 0.5 NTU. Changes in measured haze were found to be negligible in the ampicillin sodium and oxacillin sodium samples during the study. The nafcillin sodium samples exhibited slight increases
in measured haze of 0.4 NTU or less. The samples were essentially colorless throughout the study. Measured particulates of 10 m or larger were found to be few in number in all ampicillin sodium and oxacillin sodium samples and remained so throughout the observation periods for each drug at both storage temperatures. The nafcillin sodium samples were initially clear, and the room temperature samples remained clear throughout the observation period. However, the refrigerated samples were clear during 14 days of storage, but a microparticulate precipitation developed after 21 days. The refrigerated nafcillin sodium samples were determined to be physically unstable at that time point because of that precipitation, and the study was terminated. The results of the HPLC analysis for each of the test drugs are shown in Table 2. Ampicillin sodium was the least stable of the three penicillins tested. The stability of that drug was adequate for only 24 hours at a room temperature of 23C and for 3 days under refrigeration at 4C. An unacceptable drug loss occurred after those time points. The nafcillin sodium samples were more stable. Nafcillin sodium remained stable for 5 days with an approximate 10% loss of drug in 5 days at 23C. However, a drug loss of about 15% was found after 7 days of storage at room temperature. When the samples were stored under refrigeration, less than a 3% loss of drug had occurred after 14 days. The analysis of the samples was terminated after that time point because of the microparticulate precipitation (Table 2). Oxacillin sodium exhibited the greatest stability of the three penicillins evaluated in this study. At a room temperature of
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23C, a drug loss of about 10% had occurred after 7 days of storage. Under refrigeration, the drug remained stable throughout the study and exhibited a drug loss of less than 5% after 30 days of storage at 4C (Table 2). The stability of ampicillin sodium, nafcillin sodium, and oxacillin sodium in the AutoDose Infusion System bags parallels that reported in previously published results1 of the stabilities of those drugs in infusion solutions stored in glass and PVC containers. The absence of an adverse effect on drug stability is also consistent with the results of evaluations 5-8 of other drugs stored in AutoDose Infusion System bags.
References
1. 2. Trissel LA. Handbook on Injectable Drugs. 11th ed. Bethesda, MD:American Society of Health-System Pharmacists; 2000. Trissel LA, Bready BB. Turbidimetric assessment of the compatibility of taxol with selected other drugs during simulated Y-site injection. Am J Hosp Pharm 1992;49:1716-1719. Trissel LA, Martinez JF. Turbidimetric assessment of the compatibility of taxol with 42 other drugs during simulated Y-site injection. Am J Hosp Pharm 1993;50:300-304. Trissel LA, Martinez JF. Physical compatibility of melphalan with selected drugs during simulated Y-site administration. Am J Hosp Pharm 1993;50:2359-2363. Xu QA, Trissel LA, Saenz CA, et al. Stability of three cephalosporin antibiotics in AutoDose Infusion System bags. J Am Pharm Assoc . In press. Xu QA, Trissel LA, Saenz CA, et al. Stability of gentamicin sulfate and tobramycin sulfate in AutoDose Infusion System bags. IJPC. 2002;6:152-154. Zhang Y, Trissel LA. Stability of ciprofloxacin and vancomycin hydrochloride in AutoDose Infusion System bags. Hosp Pharm 2001;36:1170-1173. Zhang Y, Trissel LA. Stability of piperacillin and ticarcillin I Autodose Infusion System Bags. Ann Pharmacother 2001;1360-1363.
3.
4.
5. 6. 7. 8.
Conclusion
Ampicillin sodium, nafcillin sodium, and oxacillin sodium exhibited physical and chemical stability consistent with the results of other studies. The EVA reservoir used in the AutoDose Infusion System did not adversely affect the physical and chemical stability of those three penicillin antibiotics.
Acknowledgment
This study was supported by a grant (LS00-240) from Tandem Medical, Inc, San Diego, California.
Address correspondence to: Lawrence A. Trissel, BS, RPh, Division of Pharmacy, Box 90, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
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Compatibility Screening of Precedex During Simulated Y-Site Administration with Other Drugs
Abstract
The physical compatibility of Precedex with 95 selected other drugs during simulated Y-site injection was evaluated by visual observation, turbidity measurement, and electronic particle content assessment (when appropriate). Five-milliliter samples of Precedex 4 g/mL in 0.9% sodium chloride injection were combined with 5 mL of each of 95 other drugs. The other test drugs included antiinfectives, analgesics, antihistamines, diuretics, steroids, and other supportive-care drugs undiluted or diluted in 0.9% sodium chloride injection or 5% dextrose injection (for amphotericin B). Visual examinations were performed with the unaided eye in normal diffuse fluorescent light and with a Tyndall beam (a high-intensity monodirectional light beam) to enhance the visualization of small particles and low-level turbidity. The turbidity of each sample was measured as well, as was the particle content of samples with no visible incompatibility. Evaluation of the samples was performed initially and at 1 and 4 hours after preparation. Ninety-three of the 95 test drugs were compatible with the Precedex dilution during the 4-hour observation period; however, both amphotericin B and diazepam resulted in precipitation. Precedex, which is incompatible with amphotericin B and diazepam, should not be administered simultaneously with those drugs. Lawrence A. Trissel, BS, RPh Christopher A. Saenz Division of Pharmacy, The University of Texas, M. D. Anderson Cancer Center Houston, Texas Delshalonda S. Ingram Kimberly Y. Williams Texas Southern University Houston, Texas Julie P. Retzinger, RN Abbott Laboratories, Hospital Products Division Abbott Park, Illinois manipulations were carried out in a Class 100 biological safety cabinet.
Methods
Visual examination of all samples was performed with the unaided eye in normal laboratory fluorescent light. Combinations with no obvious visual incompatibility were examined further with a Tyndall beam, a high-intensity monodirectional light source (Dolan-Jenner Industries, Woburn, Massachusetts) as described elsewhere. 4 Inspections were performed over the first 15 minutes after sample preparation and at intervals of 1 and 4 hours after sample preparation. The samples were stored at room temperature (approximately 23C) under constant fluorescent light. Control solutions for this study included the following: Precedex 4 g/mL in 0.9% sodium chloride injection Precedex 4 g/mL in 0.9% sodium chloride injection diluted to 2 g/mL as an equal parts mixture with 0.9% sodium chloride injection Precedex 4 g/mL in 0.9% sodium chloride injection diluted to 2 g/mL separately with 5% dextrose injection Secondary additive solutions Incompatibility was defined as any visible particulate matter, substantial haze, or change in turbidity from that in the controls; a color change; or gas evolution. The samples were also assessed immediately after preparation and at 1 and 4 hours after preparation by means of a color-correcting turbidimeter (Ratio X/R, Hach
Introduction
Precedex (dexmedetomidine, Abbott Laboratories, Abbott Park, Illinois) is an 2-adrenoreceptor agonist that produces sedation and is used in initially intubated and mechanically ventilated patients treated in an intensive care setting. 1 Precedex is administered as an intravenous infusion by means of a controlled-infusion device over periods not exceeding 24 hours. 1 In addition to Precedex, patients may be receiving many other drugs (anti-infectives, antiemetics, antihistamines, diuretics, steroids, analgesics, or other supportive-care drugs) by simultaneous or sequential Y-site administration. The potential exists for the development of physical incompatibilities during the Y-site administration of Precedex with those other agents or components of their formulations. The compatibility of Precedex with a number of drugs is cited in the labeling. 1 Its compatibility with many other drugs is unknown. The purpose of this study was to evaluate the physical compatibility of Precedex diluted for infusion during simulated Y-site administration with 95 other drugs by means of visual observation, turbidity measurement, and electronic particle content measurement (where warranted).

Materials
Precedex (Lot 60-462-DK, Abbott Laboratories, Inc) was supplied as a 100-g/mL injection in 2-mL vials. For this testing, the Precedex injection was diluted to a concentration of 4 g/mL in 0.9% sodium chloride injection, USP, (Lot 70-135-JT, Abbott Laboratories), which is recommended in the product labeling.1 The 95 secondary additives were studied at the concentrations cited in Table 1. Allen et al 2 reported that the mixing of an intravenous fluid in an administration set with a secondary additive through a Yinjection site occurs in a 1:1 ratio. To simulate this inline mixing, a 5-mL sample of Precedex 4 g/mL was combined with a 5mL sample of each of the study drug solutions individually in colorless 15-mL borosilicate glass screw-cap culture tubes (Kimble, Div of Owens-Illinois, Toledo, Ohio) with polypropylene caps (Kimble) as described elsewhere. 3 Except for drugs that should not be filtered, the sample solutions were filtered through 0.22-m filters (Millex-GS, Millipore Corporation, Bedford, Massachusetts) into the tubes. Each combination was prepared in duplicate, and the order of drug addition was reversed between the two samples. All

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Table 1. Solutions and Drugs Tested for Compatibility with Precedex.

Drug Supportive-care and other drugs Alfentanil hydrochloride Aminophylline Amiodarone hydrochloride Bretylium tosylate Bumetanide Butorphanol tartrate Calcium gluconate Chlorpromazine hydrochloride Cimetidine hydrochloride Cisatracurium besylate Dexamethasone sodium phosphate Diazepam Digoxin Diltiazem hydrochloride Diphenhydramine hydrochloride Dobutamine hydrochloride Dolasetron mesylate Dopamine hydrochloride Droperidol Enalaprilat Ephedrine hydrochloride Epinephrine hydrochloride Esmolol Famotidine Fenoldopam mesylate Furosemide Granisetron hydrochloride Haloperidol lactate Heparin sodium Hydrocortisone sodium succinate Hydromorphone hydrochloride Hydroxyzine hydrochloride Inamrinone lactate Isoproterenol hydrochloride Ketorolac tromethamine Labetalol Lidocaine hydrochloride Lorazepam Magnesium sulfate Meperidine hydrochloride Methylprednisolone sodium succinate Metoclopramide hydrochloride Milrinone lactate Taylor Abbott Wyeth-Ayerst American Regent Bedford Apothecon American Pharmaceutical Partners Elkins-Sinn American Regent Glaxo Wellcome American Regent Abbott Elkins-Sinn Baxter Parke-Davis Astra Hoechst Abbott American Regent Bedford Taylor American Regent Baxter Merck Abbott American Regent SmithKline Beecham McNeil Abbott Pharmacia & Upjohn Astra Elkins-Sinn Abbott Abbott Abbott Abbott Astra ESI Lederle American Pharmaceutical Partners Astra Pharmacia & Upjohn Faulding Sanofi 61230 59-141-DK 060092 0299 165886 9K16110 302962 039022 9391 0B1498 0233 608253B 100086 00H108 01509P 90Z007 70-008-35 63-206-DK 0612 188660 51080 0795 0042 0613K D29002A 0606 70K49 X2512 70-546-DK 82DXY 002002 119034 65-121-DK 56-487-DK 67-11-DK 702003A 001019 010010 100636 004003 09DYX 0054-51 B670TJ 0.5c 2.5 4 4 0.04 0.04 40 2 12 0.5 1 5c 0.25 c 5c 2 4 2 3.2 2.5 c 0.1 5 0.05 10 2 0.08 3 0.05 0.2 100 c,d 1 0.5 2 2.5 0.02 15 c 2 10 0.5 100 10 5 5c 0.2 Manufacturer Lot Number Concentration (mg/mL) a,b
Continued on next page Company, Loveland, Colorado) as previously described.4,5 Some drug products are inherently hazy. The use of the turbidimeter permits quantification of that haze and the assessment of any changes, whether visually apparent or not. For relatively clear drugs such as Precedex, an incompatibility has been defined as an increase in measured turbidity exceeding 0.5 nephelometric turbidity unit (NTU) that did not occur upon simple dilution alone. All combinations without visible incompatibility were evaluated further with an electronic particle sizer-counter (Model 8003, Hiac-Royco, Div of Pacific Scientific Company, Silver Spring, Maryland) to document the absence of substantial subvisual particle burden. Three-milliliter portions were tested to evaluate particles that ranged in size from 1.04 to 112 m (the validated detection limit of the particle sizercounter).

Precedex 4 g/mL in 0.9% sodium chloride injection appeared clear and colorless in normal diffuse uorescent room light and
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Table 1, continued
Drug Nalbuphine hydrochloride Nitroglycerin Norepinephrine bitartrate Ondansetron hydrochloride Potassium chloride Procainamide hydrochloride Prochlorperazine edisylate Promethazine hydrochloride Propofol Ranitidine hydrochloride Rapacuronium bromide Remifentanil hydrochloride Rocuronium bromide Sodium bicarbonate Sodium nitroprusside Sufentanil citrate Theophylline Verapamil hydrochloride Manufacturer Astra American Regent Abbott Glaxo Wellcome Abbott Elkins-Sinn SmithKline Beecham Elkins-Sinn Astra-Zeneca Glaxo Wellcome Organon Abbott Organon American Regent Baxter Abbott Abbott Abbott Apothecon Apothecon Apothecon Pfizer Pfizer Bristol-Myers Squibb Lilly Bristol-Myers Squibb Roerig Hoechst-Roussel Zeneca Merck Glaxo Wellcome Fujisawa Roche Glaxo Wellcome Bayer Abbott American Pharmaceutical Partners Abbott Pfizer Bristol-Myers Squibb American Pharmaceutical Partners Pharmacia & Upjohn Ortho-McNeil Baxter Ortho-McNeil Lederle Lederle Gensia Sicor SmithKline Beecham SmithKline Beecham Gensia Sicor Abbott
c d e
Lot Number 908034 0275 70-495-DK 0ZP2298 36-168-DK 080037 110C43 090151 4Z86B 0ZP0206 300495B 660015Z 3500450 0597 99J102 64-512-DK 51-192-JT 67-266-DK 9E11917 0B26137 0D19993 T499A 116733 0A3688 1547A30 0E31701 W179B 040497 3071C 3838K 0ZP1418 302173 U6173 9ZP1344 0BAA 65-384-DK 100671 69879Z7 PS095612 0A20878 100477 98D24Z07 W7413 PS103515 7GAB5 800-104 464-693 99H123 62 655 DA RR 3693 00A123 69840Z7
f g h
Concentration (mg/mL)a,b 10c 0.4 0.12 1 0.1 e 10 0.5 2 10c 2 20 c 0.25 1 1 c,e 2f 0.05 c 4c 1.25 5 0.6 g 20 20/10 2 40 20 20 40 20 20 20 40 20 20 30 1 10 1 5 2c 2 5 2c 5 5c 4 40 40/5 4/0.8 30 31 5 10
Anti-infective drugs
Amikacin sulfate Amphotericin B Ampicillin sodium Ampicillin sodium-sulbactam sodium Azithromycin Aztreonam Cefazolin sodium Cefepime hydrochloride Cefoperazone sodium Cefotaxime sodium Cefotetan sodium Cefoxitin sodium Ceftazidime h Ceftizoxime sodium Ceftriaxone sodium Cefuroxime sodium Ciprofloxacin Clindamycin phosphate Doxycycline hyclate Erythromycin lactobionate Fluconazole Gatifloxacin Gentamicin sulfate Linezolid Levofloxacin Metronidazole Ofloxacin Piperacillin sodium Piperacillin sodium-tazobactam sodium Sulfamethoxazole-trimethoprim Ticarcillin disodium Ticarcillin disodium-clavulanate potassium Tobramycin sulfate Vancomycin hydrochloride
a b
Nominal concentration. Tested in 0.9% sodium chloride injection, USP, unless specified otherwise.
Tested undiluted. Units per milliliter. Milliequivalents per milliliter.
Protected from light. Tested in 5% dextrose injection, USP. Sodium carbonate formulation.
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Table 2. Measured Turbidities of Selected Admixtures of Precedex.

Test Drug and Sample Precedex 4 g/mL in NS a Precedex 2 g/mL in NS b Precedex 2 g/mL in D5W c Amphotericin B A B Diazepam A B
NS = 0.9% Sodium chloride injection. D5W = 5% Dextrose injection. A = Test drug solution added to Precedex. B = Precedex added to test drug solution.
Mean SD Nephelometric Turbidity Unit(s) (n = 3) 0 hr 1 hr 0.074 0.003 0.072 0.002 0.079 0.005 0.089 0.004 0.083 0.002 0.089 0.003 3.90 0.12 7.08 0.11 21.4 0.3 20.3 0.3 15.6 0.2 15.6 0.1 0.092 0.002 0.092 0.003 188 2 281 6 209 4 282 6
a b
4 hr 0.081 0.077 0.085 7.92 22.2 16.3 0.098 241 261
0.002 0.004 0.002 0.16 0.3 0.2 0.001 2 1
Representative Precedex infusion admixture. Representative Precedex infusion samples diluted with an equal volume of 0.9% sodium chloride injection to a concentration of 2 g/mL as a control.
Representative Precedex infusion samples diluted with an equal volume of 5% dextrose injection to a concentration of 2 g/mL as a control.
when viewed with a Tyndall beam; measured turbidity was less than 0.1 NTU. Similarly, dilution with an equal volume of 5% dextrose injection or 0.9% sodium chloride injection resulted in solutions with essentially no haze and measured turbidities of less than 0.1 NTU throughout the 4-hour observation period. Of the 95 drug combinations tested with Precedex, 93 were physically compatible. The combination solutions were visually clear with no haze or particulate formation under normal diffuse fluorescent room light and when viewed with a Tyndall beam. Measured haze levels for the compatible combinations of Precedex and solutions were near the expected level. The absence of substantial particle burden in the samples with no visually apparent incompatibility was documented via electronic particle counting. Those compatible combinations exhibited little change in measured turbidity throughout the study period and had a low particle content in the size range of 1.04 to 112 m. However, amphotericin B and diazepam exhibited physical incompatibility (gross precipitation) when combined with Precedex.
Diazepam
When diazepam was mixed with Precedex, a dense white turbid precipitate that could easily be seen in normal room light developed (Table 2). Because of its poor water solubility, diazepam is formulated for injection by means of a mixed solvent system that includes propylene glycol 40%, ethanol 10%, benzyl alcohol 1.5%, and benzoic acid/sodium benzoate 5%. 6 The final diazepam concentration in those samples after dilution for testing was 2.5 mg/mL, which is well above the aqueous solubility of diazepam (0.05 mg/mL). 7 A similar precipitate forms when diazepam is diluted to 2.5 mg/mL with 5% dextrose injection alone or with other drugs. 6,8-11 Consequently, the precipitate that formed is the result of diluting diazepam in an aqueous medium rather than a specific incompatibility with the Precedex formulation.
Conclusion
Precedex is physically compatible for 4 hours at room temperature with 93 drugs evaluated in this study during simulated Ysite administration. However, precipitation resulted when Precedex was combined with amphotericin B or diazepam. As a result, those drugs should not be administered simultaneously with Precedex.
Amphotericin B
Gross precipitation visible to the unaided eye was observed when amphotericin B was admixed with Precedex. Such gross precipitation has been reported to occur when many other drugs were mixed with amphotericin B. 6 In addition, the measured turbidity for that combination was substantially higher than that seen with Precedex or amphotericin B alone (Table 2).
Acknowledgment
Supported by a research grant (LS01-0361) from Abbott Laboratories, Inc, Abbott Park, Illinois.
Allen LV Jr, Levinson RS, Phisutsinthrop D. Compatibility of various admixtures with secondary additives at Y-injection sites of intravenous administration sets. Am J Hosp Pharm 1977;34:939-943. 3. Trissel LA, Martinez JF. Physical compatibility of melphalan with selected drugs during simulated Y-site administration. Am J Hosp Pharm 1993;50:2359-2363. 4. Trissel LA, Bready BB. Turbidimetric assessment of the compatibility of taxol with selected other drugs during simulated Y-site injection. Am J Hosp Pharm 1992;49:1716-1719. 5. Trissel LA, Martinez JF. Turbidimetric assessment of the compatibility of taxol with selected other drugs during simulated Y-site injection. Part 2. Am J Hosp Pharm 1993;50:300-304. 6. Trissel LA. Handbook on Injectable Drugs. 11th ed. Bethesda, MD: American Society of HealthSystem Pharmacists; 2000. 7. Trissel LA. Trissels Stability of Compounded Formulations . 2nd ed. Washington, DC: American Pharmaceutical Association; 2000. 8. Trissel LA, Williams KY, Gilbert DL. Compatibility screening of linezolid during simulated Y-site administration with other drugs and infusion solutions. J Am Pharm Assoc 2000;40:515-519. 9. Trissel LA, Gilbert DL, Williams KY. Compatibility screening of gatifloxacin during simulated Ysite administration with other drugs. Hosp Pharm 1999;34:1409-1416. 10. Trissel LA, Martinez JF, Gilbert DL. Compatibility of cisatracurium besylate with selected drugs during simulated Y-site administration. Am J Health Syst Pharm 1997;54:1735-1741. 11. Trissel LA, Williams KY, Baker MB. Compatibility of Hextend during simulated Y-site administration with other drugs. IJPC 2001;5:69-73. Address correspondence to: Lawrence A. Trissel, BS, RPh, Division of Pharmacy, Box 90, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX. 77030.
2.
References
1. Precedex [package insert]. Abbott Park, IL: Abbott Laboratories; 2000.
P E E R
R E V I E W E D
Stability of Cefotaxime Sodium After Reconstitution in 0.9% Sodium Chloride Injection and Storage in Polypropylene Syringes for Pediatric Use
Abstract
A stability-indicating high-performance liquid chromatographic assay method was used to study the stability of cefotaxime sodium (50 mg/mL) in 0.9% sodium chloride injection in polypropylene syringes at 5C and 25C. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on 5 injections was 1.1. There were at least three products of decomposition that separated from the intact drug. At 5C, the decomposition was less than 3% when stored for 18 days, and at 25C, the loss in potency was less than 10% after 1 day of storage. When stored for 18 days at 5C, the pH value decreased from 5.3 to 5.2. The pH value of the injection decreased from 5.3 to 5.0 when stored at 25C for 1 day. The drug was not adsorbed onto the syringes, and the intensity of the light yellow color did not change significantly during storage at 5C but increased during storage at 25C. V. Das Gupta, PhD Pharmaceutics Division, University of Houston, Houston, Texas [Waters Associates, Milford, Massachusetts]) equipped with an injector (Model 7125, Rheodyne, Cotati, California) and a recorder (Omniscribe 5213-12, Houston Instruments, Austin, Texas) were used. The column used (Cat # 58220U, Supleco C 8, 15 cm, 4.6 mm id, 5 m) was obtained from Supleco Co, Bellefonte, Pennsylvania. All pH values were measured with a Beckman SS-3 Zeromatic pH meter (Beckman Instruments, Fullerton, California).
Introduction
Cefotaxime sodium (Figure 1) powder for injection is used extensively to treat many different diseases, such as urinary tract infections and lower respiratory tract infections. Before it is used, it is dissolved in 0.9% sodium chloride injection to a concentration of 50 mg/mL. The resulting admixture is usually filled into 5-mL polypropylene syringes for pediatric use. The manufacturer recommends that the resulting admixture be used within 24 hours when stored at room temperature and within 7 days when stored at 5C in the refrigerator. 1 Gupta and Gunter 2 studied the stability of cefotaxime sodium in 0.9% sodium chloride injection and 5% dextrose injection at a concentration of 10 mg/mL. The resulting injections were stored in polyvinyl chloride (PVC) bags at room temperature and at 5C. According to those authors, the loss in potency was
less than 10% after 42 days of storage at 5C and after 1 day of storage at 25C. The purpose of this investigation was to determine the stability of cefotaxime sodium injection (50 mg/mL) in 0.9% sodium chloride when packaged in polypropylene syringes and stored at 5C and 25C and to determine whether the drug is adsorbed onto the syringes.
Chromatographic Conditions
The mobile phase contained 9.5% (v/v) acetonitrile in water containing 0.02 M ammonium acetate buffer. The pH of the mobile phase was approximately 6.9. The flow rate was 1.3 mL/min, the sensitivity was 0.7 AUFS at 290 nm, the chart speed was 30.5 cm/hr, and the temperature was ambient.

Chemicals and Reagents
All the chemicals and reagents were USPNF or ACS grade and were used without further purification. The cefotaxime sodium powder for injection was from commercial lot # 120416 (Aventis Pharmaceutical Company, Kansas City, Missouri).
Preparation of Injection for Stability Studies

Cefotaxime sodium (0.5 g per vial of free base) was used to prepare the injections for stability studies. The powder for injection, which was equivalent to 5 g of cefotaxime, was dissolved in sufficient 0.9% sodium chloride injection (Lot # PS105619, Baxter Healthcare Corp, Deereld, Illinois) to bring it to 100 mL (50 mg of cefotaxime per milliliter of injection). The injection was immediately filled into 5-mL polypropylene syringes (Cat # 301-603, Becton Dickinson & Co, Franklin Lake, New Jersey). The syringes were divided into 2 groups (9 syringes per group). One group was stored in the refrigerator at 5C ( 1C), and another group was stored in the refrigerator at 25C ( 1C). On day zero, the injection was assayed and the pH value was recorded. The contents of the syringes were assayed again at appropriate intervals, and the pH values were recorded. A 10-mL quantity of injection was also stored at 25C in a 25-mL volumetric flask to determine whether the drug exhibited prob-
Equipment
A high-performance liquid chromatography (HPLC) system (an M-45 pump and a Model 484 multiple wavelength detector
Figure 1. Structure of Cefotaxime Sodium. OCH3 N N C CONH H H2N S H O N
COONa CH2OCOCH3

P E E R
R E V I E W E D
Table 1. Assay Results for Cefotaxime Sodium Injection (50 mg/mL) Stored in Becton-Dickinson 5-mL Syringes.a
Percent of the Label Claim Based on 100% on Day Zero When Stored at 5C 25C ND 98.3 ND 89.8 100.2 81.8 99.7 ND 97.1 ND Percent RSD n=5 1.1 1.1 1.0/1.1 1.0 1.1
Time (days) 1 2 3 9 18
a
related to the concentrations (60 to 110 g/mL), the results were calculated by means of a simple equation: (Ph)a/Ph)s x 100 = Percentage of the label claim found where (Ph)a is the peak height of drug of the assay solution and (Ph)s is the peak height of the standard solution. The results are presented in Table 1.

Assay Method
The assay method developed is precise and accurate and has a percent RSD of 1.1 based on 5 readings. Apparently, the large injection volume (80 L) did produce accurate and precise results without the use of an internal standard. The concentrations of the drug were directly related to the peak heights (range tested, 60 to 110 g/mL).
At 5C, there was no significant change in the physical appearance of the injection, and at 25C, the injection gradually discolored from light yellow to dark yellow. The pH value at 5C decreased from 5.3 to 5.2 after 18 days of
storage, at 25C it decreased to 5.0 after 1 day of storage, and it further decreased to 4.7 after 3 days of storage. ND = Not determined on this day. RSD = Relative standard deviation.
lematic adsorption (ie, onto the polypropylene syringes).
Preparation of Standard Solutions

A 105.3-mg quantity of the powder for injection was accurately weighed (105.3 mg is equivalent to 100 mg of cefotaxime free base) and was dissolved in sufficient water to make 100 mL of solution. Those stock solutions were used to prepare solutions of lower concentrations as needed. Because the percent relative standard deviation (RSD) was very good (1.1) as a result of the use of 80 L of injection, the internal standard was not used in this study. The most commonly used standard solution of the drug (100 g/mL) was prepared by diluting 2.5 mL of the stock solution to 25 mL with water.
taining the same concentration of the drug (based on the label claim) was injected. Because peak heights of the drug are directly
Figure 2. Sample Chromatograms of Cefotaxime Sodium and Its Products of Decomposition.

1
D
3
Preparation of Assay Solutions

A 2.0-mL quantity of the assay solution was diluted to 100 mL with water. It was then further diluted 2.5 mL to 25 mL with water.
Decomposition of Cefotaxime Sodium

Inject Inject
A 25-mL quantity of the freshly prepared standard solution (100 g/mL) was boiled in a 150-mL beaker on a hot plate. After 40 seconds, the solution was allowed to cool, the volume was brought to 25 mL with water, and the solution was injected into the chromatograph.
Detector Response
Inject
Inject 2 3
3 0 4 Time (Minutes) 0 4 0
4 4 0 4
Assay Procedure and Calculations

An 80-L quantity of assay solution was injected into the chromatograph under the conditions described. For comparison, a similar volume of the standard solution con-
Peaks 1 through 4 represent cefotaxime and its products of decomposition (2 through 4), respectively. Chromatogram A is from a standard solution, and B is from an assay solution after 3 days of storage at 25C (Table 1). Chromatogram C is identical to B but was developed at 262 nm (AUFS 1.3) and shows incomplete separation. Chromatogram D is from a decomposed sample (see text) in which only 62.3% of the drug remained intact. For chromatographic conditions, see the text.
P E E R
R E V I E W E D
It is important that the volume of injection (80 L) be kept the same to ensure a linear relationship between the concentrations and the peak heights. The standard solution, which was decomposed by heat, produced at least 3 additional peaks from the products of decomposition (Figure 2D). All products of decomposition eluted before the drug peak. Although the sensitivity of the assay method was higher by about 45% at 262 nm, the wavelength of 290 nm was preferred because of the complete separation of the drug from the products of decomposition (Figure 2B vs Figure 2C). Apparently, one product of decomposition did not absorb light at 290 nm. At 5C, the loss in potency of cefotaxime after 18 days of storage was less than 3%, and the pH value of the injection had decreased from 5.3 to 5.2. Therefore, at 5C a beyond-use date (BUD) of at least 18 days is appropriate. The manufacturer has recommended a BUD of only 7 days. 1 There was no adsorption of drug onto the syringes because the injection, which was stored in the glass volumetric flask for 1 day, produced results similar to those of the sample, which was stored in polypropylene syringes. The potency of cefotaxime injection had decreased to 98.3% (Table 1) after 1 day of storage at 25C, and the pH value had decreased from 5.3 to 5.0. After 2 days of storage at 25C, the potency was
89.8%, and the pH value was 4.9. After 3 days of storage at 25C, the potency had decreased to 81.8%, and the pH value was 4.7. When cefotaxime injection is stored at 25C, a BUD of 1 day is the maximum. At 5C, there was no significant change in the appearance of the injection after 18 days of storage, and at 25C, the intensity of the light yellow color increased with the length of storage.
Conclusion
Cefotaxime sodium (50 mg/mL) in 0.9% sodium chloride injection, when stored in 5-mL polypropylene syringes, was stable for 1 day at room temperature and for at least 18 days when stored at 5C.
References
1. 2. Claforan [package insert]. Kansas City, MO:The Aventis Pharmaceuticals; June, 2000. Gupta VD, Gunter JM. Stability of cefotaxime sodium and moxalactam disodium in dextrose 5% and sodium chloride 0.9% injections. Am J IV Ther Clin Nutr 1983;10:20, 27-29.
Address correspondence to: V. Das Gupta, PhD, Pharmaceutics Division, University of Houston, 1441 Moursund St, Houston, TX 77030. VGupta@UH.EDU
I n d e x
ASEPTIC COMPOUNDING PRODUCTS
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236
C A L C U L A T I O N S
The dose of a drug is 2.5 mg and is supplied as a solution with a concentration of 1:200 w/v. This solution is administered with a dropper that has a drop factor of 12 gtt/mL. How many drops would be needed to supply this dose?
1 2
Calculations
Shelly J. Prince, PhD, RPh Southwestern Oklahoma State University School of Pharmacy Weatherford, Oklahoma A patient is to use an albuterol inhaler by inhaling 2 puffs every 4 to 6 hours as needed. An albuterol inhaler contains 200 inhalations. How long should this inhaler last for this patient?
2.5 mg/dose x 1 g/1000 mg x 200 mL/1 g x 12 gtt/mL = 6 gtt/dose You need to prepare 12 suppositories, each of which contains 350 mg of drug. You know that the calibrated volume of the suppository mold to be used is 2.3 mL; therefore, you weigh 350 mg of the drug and mix it with 1 g of the suppository base that you will use to prepare the prescription. You melt this mixture and pour it into a cavity in your suppository mold. You also melt a small amount of the suppository base alone and pour it into the cavity to completely ll it. After the suppository has cooled, you remove it from the mold and nd that it weighs 1.95 g. How much drug and suppository base will you need to prepare this prescription (allow for 2 extra suppositories)? 1.95 g/supp - 0.35 g drug/supp = 1.6 g of base/supp 350 mg/supp x 14 supp = 4900 mg = 4.9 g of drug needed 1.6 g/supp x 14 supp = 22.4 g of base needed
5 6
Maximum dose = 2 inhalations q 4 hr = 12 inhalations/day 200 inhalations x 1 day/12 inhalations = 16.67 days Five college students were asked how many hours they spent exercising per week with the following results: Student # 1: 2 hr Student # 2: 4.2 hr Student # 3: 0.75 hr Student # 4: 6.5 hr Student # 5: 3.25 hr What are the mean, median, and standard deviations for those data? Array: 0.75 hr, 2 hr, 3.25 hr, 4.2 hr, 6.5 hr Mean = (0.75 + 2 + 3.25 + 4.2 + 6.5)hr/5 = 16.7 hr/5 = 3.34 hr Median = middle or third value = 3.25 hr The formula for standard deviation ( ) is as follows: = Sum of (deviations) 2 = Number of values-1 (x-x)2 = n-1 d2 n-1
The Cockcroft-Gault equation for the calculation of creatinine clearance (CrCl) in men is as follows:
CrCl (mL/min) = [(140 - age in yr) x body weight in kg]/(72 x serum creatinine in mg/dL) What would be the creatinine clearance for a 78-year-old man who weighs 210 lbs and has a serum creatinine level of 2.8 mg/dL? Patients body weight = 210 lb x 1 kg/2.2 lb = 95.45 kg CrCl = [(140 - 78) x 95.45 kg]/(72 x 2.8 mg/dL) = 29.35 mL/min
Rx Zephiran Chloride Solution (17% w/v) Puried water qs
qs 240 mL
Sig: One (1) tsp diluted to 1 GAL with water to make a 1:8500 dilution A. What would be the concentration in milligrams per milliliter of Zephiran chloride in the dispensed solution? 1 g/8500 mL x 3785 mL/GAL x 1 GAL = 0.445 g of Zephiran chloride in 1 GAL of 1:8500 solution Therefore, each teaspoonful of the dispensed solution should contain 0.445 g of Zephiran chloride 0.445 g/tsp x 1000 mg/g x 1 tsp/5 mL = 89.06 mg/mL B. How many milliliters of Zephiran chloride 17% solution should be used to prepare the prescription? 89.06 mg/mL x 240 mL x 1 g/1000 mg = 21.37 g of Zephiran chloride needed 21.37 g x 100 mL/17 g = 125.73 mL
First, find the deviations by subtracting the mean from each value. Then, square each deviation as shown below: Value d d2 0.75 hr - 3.34 hr = -2.59 hr 6.7081 hr2 2 hr - 3.34 hr = -1.34 hr 1.7956 hr2 3.25 hr - 3.34 hr = -0.09 hr 0.0081 hr2 4.2 hr - 3.34 hr = 0.86 hr 0.7396 hr2 6.5 hr - 3.34 hr = 3.16 hr 9.9856 hr2 Sum of (deviations) 2 = 19.237 hr2 = 19.237 hr2 = 2.19 hr 5-1
Address correspondence to: Shelly J. Prince, PhD, RPh, School of Pharmacy, Southwestern Oklahoma State University, 100 Campus Drive, Weatherford, OK 73096
C O N T
E D
Two Hours of Continuing Education from the International Journal of Pharmaceutical Compounding
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PROGRAM EXAMINATION. Please indicate your exam responses by circling only ONE answer for each question.
Basics of Compounding for Iontophoresis, Part 1. Page 194

1. Using patches and gels for transdermal administration is effective primarily for drugs.
6.
In some cases, iontophoresis can eliminate the need for injections.
12. Which polarity is required for dexamethasone sodium phosphate? A. Positive B. Negative 13. Which of the following veterinary drugs requires positive polarity? A. B. C. D. E. Ceftiofur sodium Prednisolone sodium succinate Ketoprofen Phenylbutazone Gentamicin sulfate
A. True B. False 7. A. B. C. D. E. 8. Iontophoresis was introduced in which year? 1848 1879 1908 1924 1945 Originally, most of the work on iontophoresis was investigated for the administration of drugs into the: Oral cavity Ear Eye Nose Skin Which current densities can usually be tolerated by the body with little or no discomfort? 0.5 0.5 0.5 0.5 0.5 A/cm 3 mA/cm3 mA/cm 2 A/cm 2 W/cm 3
A. Ionizable B. Nonionizable 2. A. B. C. D. E. 3. The rate-limiting factor for absorption across the skin is the: Stratum Stratum Stratum Stratum Stratum corneum germinativum granulosum spinosum lucidum
14. Which of the following can use either negative or positive polarity? A. B. C. D. E. Acetic acid Estriol Idoxuridine Potassium iodide Water
Which energy form does iontophoresis, a facilitated diffusion method, use? Ultrasound Electricity Penetration enhancers Light Radiation How many electrodes are required for iontophoresis? One Two Three Four Five Iontophoresis works well when drugs in a solid form are used.
A. B. C. D. E. 4. A. B. C. D. E. 5.
A. B. C. D. E. 9.
15. Which of the following can be administered iontophoretically for the treatment of attention deficit disorder? A. B. C. D. E. Atropine sulfate Calcium chloride Hyaluronidase Idoxuridine Methylphenidate hydrochloride
A. B. C. D. E.
10. Iontophoresis devices of the future will be very similar in size to the transdermal patches of today. A. True B. False 11. Which of the following drugs does not require positive polarity? A. B. C. D. E. Atropine sulfate Fentanyl citrate Lithium chloride Morphine sulfate Sodium salicylate
Featured Excipient: The Sorbitan Esters. Page 221

16. The sorbitan esters are . A. B. C. D. E. Hydrophilic, anionic Hydrophilic, nonionic Lipophilic, anionic Lipophilic, nonionic Lipophilic, cationic and
A. True B. False 5. Iontophoresis is a form of controlled drug delivery.
A. True B. False
238
C O N T
E D
17. Sorbitan esters will produce which type of emulsions? A. Oil-in-water B. Water-in-oil 18. Other names for the sorbitan esters include: A. B. C. D. E. Arlacel Span Glycomul Liposorb All the above
20. The Arlacels are usually prepared from which starting material? A. B. C. D. E. Dextrose Lactitol Mannitol Polyglycol Sorbitol
23. The Span easiest to pour because it has the lowest viscosity is: A. B. C. D. E. Sorbitan Sorbitan Sorbitan Sorbitan Sorbitan monolaurate monooleate monostearate sesquioleate trioleate
21. Which of the following sorbitan esters is a solid at room temperature? A. B. C. D. E. A. B. C. D. E. Arlacel Arlacel Arlacel Arlacel Arlacel 20 40 80 83 85 monolaurate monopalmitate monostearate sesquioleate trioleate
24. The Spans are very soluble in water. A. True B. False 25. Which of the following would float highest if layered on water? A. B. C. D. E. Sorbitan Sorbitan Sorbitan Sorbitan Sorbitan monolaurate monooleate monopalmitate sesquioleate trioleate
19. In which concentrations are the Spans usually used alone to prepare emulsions? A. B. C. D. E. < 0.1% 0.2% to 0.9% 1% to 15% 16% to 20% 21% to 25%
22. The most lipophilic Span is: Sorbitan Sorbitan Sorbitan Sorbitan Sorbitan
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P O S T S C R I P T I O N
Post cription
Patsy Angelle, PD, FIACP, FACA Prescription Compounds, Baton Rouge, Louisiana Table 1. Compounding for Sensitive Patients.
Ingredients Tolerated by Most Allergy-Prone Patients Acacia Acesulfame potassium Cellulose Lecithin (except in soy-sensitive patients) Pectin Potassium sorbate Sorbitol Stevia Ingredients To Avoid Articial colors and avors, including FD & C Aspartame Butylated hydroxytoluene Products derived from corn Lactose Monosodium glutamate Nitrates Sugar and syrups Vanillin
Building Relationships with Special Patient Populations

The paradigm of improved health care can begin or end with the compounding pharmacist. Compliance variables have long been an issue, especially in special patient populations such as those with allergies or severe dietary restrictions. Patients who are unable to take commercially available prescribed medications or supplements receive less effective health care. Compounding pharmacists can be very effective in resolving those difficulties. Relationships are the texture of life and are fast becoming an integral facet in successful independent pharmacies. As rapport between the patient and the pharmacist develops, the exchange of information improves the quality of health care rendered.
Patient Prole
Being attentive during the dialogue with a patient will make your work easier and more efficient as you develop a profile for him or her. During the initial conversation, you can collect demographic information, open the lines of communication, and establish the framework of the patient-pharmacist-physician relationship. This triad is the best foundation for providing excellent health care. During your initial meeting with the patient, document his or her preferences regarding flavors, foods, and colors; specific dislikes; and color, dye, or food restrictions. Write specific notes and details that will help you to remember the patients health condition and special requests or concerns. Using a prepared outline designed for each of the subsets of patients with whom you work facilitates that documentation.
ents. Prepare flavor samples for patients who might need a little extra care. Keep in mind that the cellular chemistry of your patient is stressed. Add nothing to formulations that will further compromise the patients biochemical or physiologic status. Consider all ingredients when you develop formulas. Every patient is different, and an existing formula may require adjustments to fit individual needs. Table 1 lists ingredients that can be used for the treatment of more sensitive patients as well as ingredients to be avoided. That list is not all-inclusive. If additives must be used, consider their properties and pharmacokinetics and use them sparingly. If you are uncertain about whether to use an ingredient, omit it. Simple is better.
Professional Priorities
Adopt an attitude of service to the patient, the caregiver, and the physician. Enjoy your work. Keep seeking knowledge and increasing your expertise. As compounding pharmacists, we are members of the healthcare team, and our level of skill must be excellent. In our work, we must give sincere consideration to humanitarian values. Time-consuming formulations that require multiple ingredients, extra preparation, and the use of dispensing devices affect the monetary bottom line, but the essence of compounding is not always linked to financial compensation. Taking extra steps to solve problems will deliver a bounty far greater than that of reimbursement. Special patient populations need us. Stretch your abilities to meet challenges, go the extra mile, and make a difference for your patients!
Prescription Preparation for Patients with Special Pharmaceutical Needs

Before compounded prescriptions are prepared and dispensed for patients with special needs, consider the following factors: 1. Use pure, active ingredient powders as a first choice. Decrease particle size as much as is reasonable. Coarse residues can be more of a hindrance to the texture-sensitive patient than are unpleasant tastes or odors. If a mixture appears coarse when it is wet, homogenize it or use an ointment mill to reduce the particle size further. 2. Some fillers and binders in conventional tablet preparations may not be tolerated by the patient. Review the inactive ingredient lists closely. Hint: If you must use tablets with coatings or shells, sift after trituration and before final incorporation. 3. Color tracers used to ensure proper dispersion should be carefully chosen with regard to patient sensitivity. 4. Proper selection of dosing containers and devices makes administration easier. Keep your patient and caregiver in mind when those selections are made. 5. Flavor only as necessary. Consider pH and volume changes with every addition. Mask bitter medications appropriately by selecting proper alternatives for the dispersion of active ingredi-
Suggested Reading
Allen LV Jr. The Art, Science, and Technology of Pharmaceutical Compounding. Washington, DC: American Pharmaceutical Association; 1998. Gennaro AR, Chase GD, Marderosian AD. Remington, The Science and Practice of Pharmacy. 20th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000. Reynolds JEF, ed. Martindale: The Extra Pharmacopoeia. 30th ed. London: The Pharmaceutical Press; 1993. Address correspondence to: Patsy Angelle, PD, FIACP, FACA, Prescription Compounds, 7414 Picardy, Suite C, Baton Rouge, LA 70808. E-mail: rxcmpds@bellsouth.net
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M AY / J U N E

COMPOUNDING FOR HEALTH, WELLNESS, AND GERIATRIC PATIENTS

International Journal of Pharmaceutical Compounding 161 Vol. 6 No. 3 May/June 2002

Loyd V. Allen, Jr, PhD, RPh

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

GOOD PRACTICES for GOOD HEALTH

The Importance of Diet

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

The Essential Role of Glucose and Insulin

The Keys to Good Health

International Journal of Pharmaceutical Compounding 165 Vol. 6 No. 3 May/June 2002

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

Changes in the American Healthcare System

The Practice Site

Consider the Possibilities

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

Table 1. Sample of a Precounseling Questionnaire for Elderly Patients.

Please describe any concerns about particular medicines.

International Journal of Pharmaceutical Compounding 169 Vol. 6 No. 3 May/June 2002

The Patients Medicine Cabinet

Dene Essential Goals for Your Patients and Your Practice

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

Estrogen Replacement Therapy in the Treatment of

Decreased Accumulation of -Amyloid

Increased Synthesis of ACh

International Journal of Pharmaceutical Compounding 171 Vol. 6 No. 3 May/June 2002

Prevention of Cerebral Vasculature Disruption

Enhanced Expression of Neurotrophins

Anti-Inammatory Activity of -Amyloid

Increased Utilization of Glucose

Regeneration of Neurons in the Brain

Increase in the Number of Synapses

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

Facilitating Myelin Production and Proliferation

International Journal of Pharmaceutical Compounding 173 Vol. 6 No. 3 May/June 2002

Components of Hormone Replacement Therapy

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

International Journal of Pharmaceutical Compounding 175 Vol. 6 No. 3 May/June 2002

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

The Benets of Networking

If At First You Dont Succeed. . .

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

What Goes Around Comes Around: The Path to Success

International Journal of Pharmaceutical Compounding 179 Vol. 6 No. 3 May/June 2002

WELLNESS, NUTRITION, and GERIATRICS

Drug-Induced Nutrient Depletion Handbook, 2nd ed

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

Recipes & Remedies: Prescription for Healthy Living

Geriatric Dosage Handbook, 7th ed

International Journal of Pharmaceutical Compounding 181 Vol. 6 No. 3 May/June 2002

THE ROAD TO WELLVILLE

Healthful Habits and Remedies from a Century Ago

Leaders of the Wellness Movement

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002

Formula 1. Mild Laxative.

4 oz 1/2 oz 1/2 oz 2 lbs

Illness and the Intellect

The Pharmacists Toast

International Journal of Pharmaceutical Compounding 185 Vol. 6 No. 3 May/June 2002

How To Perform a Study in Your Pharmacy with Little or No Effort

Sources of Assistance in Performing a Study

How To Find Your Intern or Resident

International Journal of Pharmaceutical Compounding Vol. 6 No. 3 May/June 2002