SYNOPSIS FOR

M.PHARM 3rd SEMESTER PROJECT (Pharmaceutics)

Submitted by Kuldeep Saikia, B.Pharm Roll No: 01

Under the guidance of Prof. L.K.Nath

Department of Pharmaceutical Science, Dibrugarh University Year 2012-13

Title of the study:

Statistical optimization and Pharmacokinetic lornoxicam based pulsatile press coated tablet. evaluation of

Introduction:
Oral drug delivery is the largest segment of the total drug delivery market. It is the most preferred route for drug administration. The oral controlled-release systems show a typical pattern of drug release in which the drug concentration is maintained in the therapeutic window for a prolonged period of time, thereby ensuring sustained therapeutic action [1]. They prevent the peak valley, fluctuation with reduction in dose of drug, reduced dosage frequency, avoidance of side effect and improved patient compliance. However there are certain conditions for which such a release pattern is not suitable. These conditions demands complete release of drug after lag time
[2]

. In other words, they require pulsatile drug delivery system (PDDS). The pulsatile

system is gaining a lot of interest, as the drug is released completely after defined lag time (Fig. 1). Pulsatile drug delivery is time and site- specific drug delivery, thus providing spatial and

Figure1. Schematic representation of different drug delivery systems, with (A) sigmoidal release after lag time, (B) delayed release after lag time, (C) sustained release after lag time and (D) extended release without lag time.

temporal delivery and increasing patient compliance. Pulsatile drug delivery is defined as the rapid and transient release of certain amount of molecules within a short time period immediately after a predetermined off-released period, i.e., lag time, or these systems have a peculiar mechanism of delivering the drug rapidly and completely after a lag time, i.e., a period of no drug release. Such a release pattern is known as pulsatile release [1].

Chronopharmacotherapy, the drug regime based on circadian rhythm, regulates many body functions in human beings, viz., metabolism, physiology, behavior, sleep patterns, hormone production, etc. Human beings greatly vary in their biochemical and physiologic status over a 24-hour period due to the existence of a number of circadian rhythms
[3]

. These systems are

beneficial for the drugs having chronopharmacological behavior (where night time dosing is required), first pass effect and having specific site of absorption in gastro intestinal tract (GIT). Diseases wherein PDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, and hypercholesterolemia [4]. Rheumatoid arthritis can be distinguished by the time of day when the patients joints are most painful and morning stiffness. The pain mostly increases at morning and decreases as the days go on. Non-steroidal anti-inflammatory drugs are taken for relieving the morning pain and stiffness of rheumatoid arthritis so the medicines are taken late at night and it is better for the treatment. In recent animal studies it is showing that joint inflammation in rats fluctuates over a 24-hours period support these observations by both patients and physicians because in chronotherapeutics the treatment is mainly based on these fluctuations are matched with the rhythms of the diseases [5].
Lornoxicam, also known as chlortenoxicam, is a member of the oxicam group of NSAIDs with extremely potent anti-inflammatory and analgesic activities. It is widely used for the symptomatic treatment of pain and inflammation in patients with rheumatoid arthritis and osteoarthritis. Like all other NSAIDs, lornoxicam mechanism of action is based on decreasing prostaglandin synthesis by inhibition of cyclooxygenase enzymes. However, lornoxicam has a relatively superior gastrointestinal (GI) tolerability when compared with other NSAIDs which is advantageous in terms of fewer side effects.Added to that, Lornoxicam shows a distinct pHdependent solubility characterized by poor solubility in low pH conditions present in the stomach [6,7].

A dry-coated tablet was recently renewed as a novel system to deliver a drug in a pulsatile way, at predetermined times following oral administration. This novel system is not only rate controlled but is also time controlled. The dry-coated tablets were prepared by a direct compression method. This compression method eliminates the time-consuming and complicated coating or granulation processes and also improves the stability of the drug by protecting it from moisture [8].

Literature Review:
1. Zilpe C.R., Dhumale A. J. et.al.
[9]

have developed metoprolol succinate based press

coated tablet for pulsatile release containing hydroxyl propyl cellulose as hydrophilic polymer. Tablets containing 80 % HPMC K100 and 20% HPMC K4M in coat showed satisfactory results as they gave burst release of the drug exactly after 6 hours which was the prerequisite but time required for burst release was increased with increased amount of HPMC K4M in polymer coat. It was concluded that as viscosity and concentration of polymers was increased, release rate of drug was retarded. 2. Prajapati B.G., Patei G.N., Solanki H.K.
[10]

have formulated time controlled pulsatile

release propranolol hydrochloride compressed coated tablet using HPMC K4M and ethyl cellulose. The results revealed that the amount of HPMC K4M and amount of Ethyl cellulose showed significant effect on the release of drug from the tablets. From drug release kinetic study it was concluded that optimize batch follows Zero order drug release mechanism. 3. Prasanth V.V., Mitesh P. Modi et.al. [11] have formulated enteric coated time release press coated tablets of theophylline using HPMC, low substituted hydroxyl propyl cellulose, ethyl cellulose and eudrajit L100 at different ratio. The system was found to be satisfactory terms of release of the drug after a predetermined lag time when the greatest need of drug in early morning to treat the disease. 4. Salunkhe A.K., Dias R. J.et.al.
[12]

have developed a floating pulsatile drug delivery

system of Metoprolol tartrate using different grades of HPMC and sodium bicarbonate. The study has shown that optimized concentration of HPMC and sodium bicarbonate

give satisfactory lag time of 6 hours and 12 hours of floating time. The in vivo X-ray study indicated that the FPRT may increase the gastric residence time.

5. Naik J.B., Zine S.P. [13] have undergone development of single unit floating-pulsatile site specific drug delivery system for chronotherapeutic release of aceclofenac. It revealed that dry coating of drug is necessary for providing pulsatilerelease pattern. The polymer coating level and amount of polymer playes a major role for providing buoyancy and pulsatile release pattern. At the same time experimentally it was found that the viscosity of polymer did not play any major role.
[14]

6. Mayee R.V. and Shinde P.V.

have developed press coated tablet by using ethyl

cellulose combined with HPC of aceclofenac and the formulation had shown a suitable intial lag time of 6 hours before the burst release.
[15]

7. Patil B. S. , Motagi A. M.

have developed time controlled pulsatile release lisinopril

tablets with swelling and rupturable layer. From the in-vitro release profile of the formulation it can be concluded that it will be one of the promising delivery system for the treatment f hypertension.

8. Januguade B. U, Patel S. S. et.al.[16] have developed oral press-coated Montelukast Sodium tablets by using direct compression and wet granulation method to achieve the predetermined lag time. From the study it has been concluded that press-coated tablet coated by dry mixing and by wet granulation showed variation in the lag time. As compared to dry mix blend method, the wet granulation method gives less lag time. 9. Devi N. K. D., Mrudula B.S. , Rani A.P.[17] have formulated chronomodulated drug delivery system of montelukast sodium for burst release after a lag time using xanthan gum and ethyl cellulose. It has shown that inspite of high viscosity and better cross linking property of Xanthan gum it can be certainly ruptured at high RPM with in no time

after its exhaustive swelling time of 3hrs during invitro dissolution. The addition of ethyl cellulose made it possible to come up the situation of easy rupturing at high pressures.

10. Patel Dharmeshkumar, Patel M.R. et. al.

[4]

have formulated a press coated pulsatile

release of lornoxicam using ethyl cellulose and sodium alginate as hydrophobic and hydrophilic polymer respectively. The study has concluded that the lag time of the pulsatile release can be controlled by maintaining the ratio of ethyl cellulose and sodium alginate.

Objective of the Study:

The purpose of the study is to develop a single unit pulsatile system providing a burst release of drug after a lag time. Different ratio of hydrophilic (hydroxyl propyl cellulose and polyethylene oxide) and hydrophobic (ethyl cellulose) polymers is used with the help of statistical method. By the mechanism of burst release with lag time, the aim is to ensure adequate protection in the early mornings when the episode of rheumatoid arthritis commonly occurs.

Methods for collection of data related to the study:

1. To perform the preformulation study of drug. 2. To perform the drug- excipient compatibility study. 3. To prepare lornoxicam press coated tablet using ethyl cellulose, polyethylene oxide and hydroxyl propyl cellulose at different concentrations using statistical technique. 4. To evaluate the prepared core tablet and final tablet. 5. To perform the in-vitro evaluation of prepared tablet. 6. To perform the in-vivo evaluation of the prepared tablet using rabbit. 7. To perform the statistical evaluation of the collected data.

Materials:
1. Drug: Lornoxicam

2. Superdisintegrants: Sodium starch glycolate, Cross carmellose sodium

3. Polymers: Ethyl cellulose, Polyethylene oxide, Hydroxy propyl cellulose.

4. Excipients: Microcrystalline Cellulose (Avicel PH- 102), lactose, starch, Magnesium Stearate, etc.

References:
Jain Deepika, Raturi Richa et.al. ; Recent technologies in pulsatile drug delivery systems; Biomatter 1:1; July/August/September 2011; 57-65.
2.

1.

Jessy Shaji, Amol B Shinde; Oral multiparticulate pulsatile drug delivery system: A Review; Int.Res. J. Phrm. 2(2) 2011 22-27.

3.

Patel Sunil, Modasiya Moin.K.et.al.; Design And Development Of Floating Pulsatile Drug Delivery System Using Meloxicam; IJPRBS, 2012: Volume1 (2): 215-235.

4.

Patel Dharmeshkumar, Patel M.R.et.al.; Formulation and In-Vitro Evaluation of Pulsatile Release Tablet of Lornoxicam; Am. J. PharmTech Res. 2012; 2(3).

5.

Singh

Rupali,

Sharma

Pramod

Kumar,

Malviya

Rishabha;

Review

on

Chronotherapeutics - A New Remedy in the Treatment of Various Diseases; European Journal of Biological Sciences 2 (3) 2010; 67-76.

6.

Kidd B, Frenzel W, A multicenter, randomized, double blind study comparing lornoxicam with diclofenac in osteoarthritis, J Rheumatol 1996; 23: 16051611.

7.

Zhang Y, Zhong D, Si D, Guo Y, Chen X, Zhou H, Lornoxicam pharmacokinetics in relation to cytochrome P450 2C9 genotype, Br J Clin Pharmacol 2005; 59: 1417.

8.

Lin SY, Yoshiaki K, Current status and approaches to developing press-coated chrono delivery drug systems. J Controlled Release 2012; 157(3): 331-353.

9.

ZILPE C.R., DHUMALE A. J. et.al.; Development and Evaluation of Pulsatile Press Coated Tablet to Control Early Morning BP Surge; IJPWR; VOL 3( 2) (Mar-June) 2012.

10.

Prajapati B.G., Patei G.N., Solanki H.K.; Formulation And Stastical Optimization Of Time Controlled Pulsatile Release Propranolol Hydrochloride Compressed Coated Tablet; e -Journal of Science & Technology; (5), 4, July 2010; 9-19.

11.

V.V. Prasanth, Modi Mitesh P. et.al.; Formulation and evaluation of enteric coated time release press coated tablets of theophylline for chronopharmacotherapy; Scholars Research Library, Der Pharmacia Lettre, 2012, 4 (2):599-606.

12.

Salunkhe Anuradha K., Dias Remeth J. et.al.; Formulation and evaluation of floating pulsatile drug delivery system of Metoprolol tartrate; Scholars Research Library, Der Pharmacia Lettre, 2011, 3(3): 147-160.

13.

Naik J.B., Zine S.P.; DEVELOPMENT OF SINGLE UNIT FLOATINGPULSATILE SITE SPECIFIC DRUG DELIVERY SYSTEM FOR

CHRONOTHERAPEUTIC RELEASE OF ACECLOFENAC; IJABPT Volume: 2(2), April-June -2011; 339-348.

14.

Mayee RV,

Shinde PV;

DEVELOPMENT AND EVALUATION OF PRESS

COATED TABLET BY USING RUPTURABLE MATERIAL (EC) COMBINED WITH ERODIBLE MATERIAL (KLUCEL EXF) OF ACECLOFENAC; Int J Pharm 2012; 2(2): 380-385.

15.

Patil Basawaraj S., Motagi Abhishek M. et.al.; Development and evaluation of time controlled Pulsatile releaseLisinopril tablets with swelling and Rupturable layer; J. Ph. Res., 2012,5(4),1910-1913.

16.

Janugade B. U., Patil S. S. et.al.; Formulation And Evaluation Of Press-Coated Montelukast Sodium Tablets For Pulsatile Drug Delivery System; Int.J. ChemTech Res.; 2009,1(3). 690-691.

17.

Devi N. Kanaka Durga, Mrudula B.Sai, Rani A.Prameela; Chronomodulated drug delivery system of Montelukast sodium; Scholars Research Library, Der Pharmacia Lettre, 2010, 2(5): 316-329.