Expanding Role of Drug Delivery System in Modern Health Care System

Expanding Role of Drug Delivery System in

Modern Health Care System:
Introduction:-
Drug delivery is the method or process of administering a pharmaceutical compound to
achieve a therapeutic effect in humans or animals. Drug delivery technologies are patent
protected formulation technologies that modify drug release profile, absorption, distribution
and elimination for the benefit of improving product efficacy and safety, as well as patient
convenience and compliance.
The global market for advanced drug delivery systems was more than € 37.9 billion in 2000
and is estimated to grow and reach € 75B by 2005 (i.e., controlled release €19.8B, needle-less
injection € 0.8B, injectable/impantable polymer systems €5.4B, transdermal € 9.6B,
transnasal €12.0B, pulmonary € 17.0B, transmucosal €4.9B, rectal €0.9B, liposomal drug
delivery € 2.5B, cell/gene therapy € 3.8B, miscellaneous €1.9B).

Concepts of Advanced Drug Delivery System (DDS):-

A. Controlled Release Drug Delivery System:-

The basic goal of a controlled drug delivery is to optimize the biopharmaceutical,
pharmacokinetic and pharmacodynamic properties of drug in such a way that its utility is
maximized through reduction inside effects and cure or control of condition in the shortest
possible quantity of drug administered by the most suitable route. The type of delivery system
and the route of administration of the drug presented in controlled release dosage form depend
upon the physicochemical properties of the drug and its biopharmaceutical characteristics.
In ideal dosage regimen in the drug therapy of any disease is the one, which immediately
attains the desired therapeutic concentration of drug in plasma (or at the site of action) and
maintains it constant for the entire duration of treatment.This is possible through
administration of a conventional dosage form in a particular dose and at a particular
frequency. But, in most cases, the dosing interval is much shorter than the half-life of the drug
resulting in a number of limitations associated with such a conventional dosage form.

An ideal controlled drug delivery system is the one, which delivers the drug at a
predetermined rate, locally or systemically, for a specified period of time.

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Advantages of controlled drug delivery system over a conventional dosage form are:
1. Less dosing frequency;
2. Shorter treatment period;
3. Improved patient convenience and compliance due to less frequent drug administration;
4. Reduction in fluctuation in steady-state levels and therefore better control of disease condition
and reduced intensity of local or systemic side effects;
5. Increased safety margin of high potency drugs due to better control of plasma levels;
6. Maximum utilization of drug enabling reduction in total amount of drug administered.

Approaches to Extend GI Transit time of Drug:-

1. The Use of Passage Delaying Excipients
The use of passage-delaying excipients has been proposed as an attempt to develop a form
that exerts some influence on its own transit. Preliminary in vivo results depict a major
problem related to the highly variable inter subject reactions.

2. Heavy Pellets
The use of dosage forms of high density that might remain in the stomach longer when
positioned in the lower part of the antrum has been proposed as a means to increase the GI
transit duration. The effectiveness of this approach has not been confirmed. In vivo data is
scarce for both animal studies and clinical investigations.

3. The Use of Large Single- Unit Forms

Delivery devices have been prepared in such a way that their size increases after ingestion to
such an extent that gastric emptying is totally inhibited, even when the pyloric sphincter is in
its non-contracted state. Unfolding stratified medicated polymer sheets or swelling balloon
hydro-gels are examples of such delivery systems. Erodible gastric retention devices
fabricated from various polymeric blends were also examined for assessment of their gastric
retention potential. These uncommon delivery systems have never passed beyond the
experimental stage, and clinical data is unavailable. In any event, the size effect approach
should be abandoned as it entails the hazard of permanent retention.
4. Floating Dosage forms
The floating sustained release dosage forms present most of the characteristics of hydrophilic
matrices and are known as ‘hydrodynamically balanced systems’ (‘HBS’) since they are able
to maintain their low apparent density while the polymer hydrates and builds a gelled barrier
at the outer surface.

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The drug is released progressively from the swollen matrix, as in the case of conventional
hydrophilic matrices. These forms are expected to remain buoyant (three to four hours) on the
gastric contents without affecting the intrinsic rate of emptying because their bulk density is
lower than that of the gastric contents.

B. Bio-Adhesive Drug Delivery System:-

Bio-adhesion may be defined as the state in which two materials, at least one of which is of a
biological nature, are held together for extended periods of time by interfacial forces. For drug
delivery purposes, the term Bio-adhesion implies attachment of a drug carrier system to a
specific biological location. The biological surface can be epithelial tissues, or the mucous
coat on the surface of a tissue. If adhesive attachment is to a mucous coat, the phenomenon is
referred as muco-adhesion.
The mucosal layer lines a number of the body including the gastrointestinal tract, the
urogenital tract, the ear, nose and eye. These represent potential sites for the attachment of
any bio-adhesive system and hence, the muco-adhesive drug delivery system includes the
following:

Mucoadhesive gastrointestinal membrane:-

It is known that, the surface epithelium of the stomach and intestine retains its integrity
throughout the course of its lifetime, even though it is constantly exposed to a high
concentration of hydrochloric acid (as high as 0.16 N) and powerful protein splitting enzymes,
like pepsin. This self-protective mechanism is due to the fact that, the specialized goblet cells
located in the stomach, duodenum and transverse colon continuously secrete a large amount
of mucous that remains closely applied to the surface epithelium. The mucus contains mucin,
an oligosaccharide chain with terminal sialic acid (pKa= 2.6), which is capable of neutralizing
the hydrochloric acid and withstanding the action of pepsin and thus protects the epithelial
cell membrane.

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Fig.1 : Interaction of Muco-adhesive Drug Delivery System with Mucus Layer on

Gastrointestinal Surface Epithelium

C. Colonic Drug Delivery System:-

Over the past two decades the major challenge for scientist is to target the drugs specifically
to the colonic region of g.i.t. Previously colon was considered as a innocuous organ solely
responsible for absorption of water, electrolytes & temporary storage of stools. But now it is
accepted as important site for drug delivery.Colon is used to treat:-
• Seriousness from constipation and diarrhoea to the debilitating inflammatory bowl diseases
(ulcerative colitis & Crohn’s disease) through to colon carcinoma which is two third cause of
cancer in both man & women.
• Colon can be utilized as portal for the entry of drugs into the blood stream for the systemic
therapy.
• Colon having the lower level of luminal & mucosal digestive enzymes as compared with the
small intestine reduces the chances of drug degradation.
• Colon delivery also a mean of achieving chronotherapy of disease that are sensitive to
circadian rhythm such as asthma & arthritis.

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Future directions of Novel drug delivery systems:-

1. Bioadhesive systems:-
Bioadhesive systems for drug administration via the buccal and nasal cavities are nearing the
market; in the case of nasal bioadhesion, bioadhesive micro-particles are used. A bioadhesive
formulation for drug administration to the vagina is in use. The gastrointestinal tract is
proving a more difficult site because of the rapid turnover of mucus, and relatively constant
transit time, but intensive research is in progress. Micro- and nano-particles, coated with
either bio/mucoadhesive polymers or specific biological bioadhesives, are showing some
promise, but will require considerable research and development before reaching the market.

2. Intrapulmonary and Endotracheal Routes of Administration:-

According to current guidelines recommended for the management of cardiac arrest, the
American Heart Association has recommended that when intravenous or intraosseous routes
cannot be established, endotracheal administration of some resuscitation drugs be used.
Medications that can be absorbed through the trachea include lidocaine, epinephrine, atropine,
naloxone, and vasopressin (American Heart Association [AHA], 2005). Although the optimal
dose of these drugs has yet to be established, two to two and one half times the recommended
intravenous dose is used (AHA, 2005).

Recent studies investigated the intrapulmonary route of drug administration. One study
suggests that intrapulmonary vancomycin may have efficacy in acute lung injuries, such as
meconium aspiration syndrome in neonates (Jeng, Lee, & Soong, 2007). Televancin is also
being studied for intrapulmonary use. Because the antibacterial activity is not affected by
pulmonary surfactant, further studies of intrapulmonary televancin for use in treating gram-
positive respiratory infections are underway (Gotfried et al., 2008).

3. Implantable Technology for Pain Management :-

Chronic pain affects as much as one half of the adult population at some point during their
lives, and 10% of this population experiences pain that is considered to be disabling.
Management of chronic pain can be difficult, and numerous treatment options have been
studied. Since Melzack and Wall first outlined their Gate-Control Theory of Pain in 1962,
understanding the neuroscience of pain has improved significantly (Chaudhari & Mackenzie,
2007). This has led to the development of implantable neuromodulatory technologies for
refractory pain. Neuromodulation seeks to reduce afferent activity within pain pathways by

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targeted drug delivery into cerebrospinal fluid, allowing drug delivery directly to the neural
tissues (Chaudhari & Mackenzie, 2007).
4. Disposable Infusion Pumps :-
Another novel form of drug delivery is the disposable infusion pump. These have been in
clinical use for more than 20 years, and their use has increased dramatically (Skryabina &
Dunn, 2006). These devices are predominantly used by ambulatory infusion centers and by
home healthcare organizations to deliver such therapies as chemotherapy, antimicrobials,
analgesia, and anesthesia. Disposable infusion pumps use the same physical principle as other
infusion pumps for delivery of medications: mechanical restriction within the flow path
determines the speed of the pressurized fluid. The pressure generated by these pumps is
approximately 250 to 600 mm Hg. This can be compared with electric pumps, which generate
5 to 1,200 mm Hg.
5. Surgically Implanted Medication Delivery :-
Surgically implanted medication delivery systems are noteworthy for their ease of use. They
also improve adherence, a major concern in the pharmacological treatment of individuals with
serious psychiatric illnesses (Irani et al., 2004). A subcutaneous surgically implanted
medication delivery system inserted under the skin eliminates the need for oral medication,
definitively addressing the adherence issue. One system delivers psychoactive medication for
as long as 14 months, significantly decreasing the need for adherence checks in this
historically difficult population. The implant is biodegradable and does not require a second
surgical procedure.
6. Intranasal Delivery :-
Intranasal formulation is a remarkable and easy mode of drug delivery. It is a needle-free,
patient-friendly route that does not contribute to biohazardous waste (Wermeling, Miller, &
Rudy, n.d.). Pharmacokinetically, the absorption rate is so rapid that it results in a faster onset
of action compared with oral and intramuscular administration. In addition, hepatic first-pass
metabolism is avoided (Wermeling et al., n.d.). (The metabolism of an administered dose of a
drug by the liver before it reaches systemic circulation is referred to as the first-pass
metabolism.) For many oral drugs, a clinically significant portion of the drug taken is
destroyed during first-pass metabolism, requiring a higher oral dose for a given effect
(Wynne, Woo, & Olyaei, 2007).
7. Medication Adherence :-
Medication adherence can be problematic with older adults. One of the most basic forms of
medication delivery, the pillbox, is continually being updated. An interactive pillbox can be a
useful tool in reminding this population about their medication times. Pillboxes are available
that can hold as much as a 1-month supply of medications, with separate compartments for as
many as four drugs. After programming, the box will beep at the time a medication is due to

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be taken, indicate the appropriate compartment, and display the number of pills to take. When
the compartment lid is lifted, an audio message instructs the patient on the number of pills to
take, along with specific information about how that medication should be taken. The data are
gathered and can be transmitted via phone lines to the caregiver to confirm the time at which
the medication was taken. Even patients thought to be compliant accidentally skip doses of
medication, a silent problem improved by these devices. Pillboxes with multiple
compartments are particularly helpful for older patients when dealing with multiple pill
regimens.
8. Contact Lens Sustained Release :-
Contact lens sustained-release drug delivery systems are currently under investigation. Ocular
drug bioavailability is known to be very poor. It is estimated that 95% of medication delivered
by eyedrops is lost as the medication mixes with tears and drains into the nasal canal (in-
Pharma Technologist.corn, 2005, January). This medication delivery method is wasteful and
can lead to unwanted local and systemic side effects. New drug delivery systems are being
developed using polymers in contact lenses, which hold therapeutic agents within their
matrices to increase drug bioavailability to the eye. As the contact lens comes in contact with
the eye, channels open that permit sustained drug delivery (Young, 2004). Researchers in
Singapore have developed a new contact lens ophthalmic drug delivery system that has the
ability to control the flow of drug by varying the width of the channels. In this manner, the
drug delivery rate can be controlled and the drug remains effective for longer periods.
Because the lenses are made in a one-step process, cost of manufacture is kept low. Potential
applications include medication delivery for a range of eye diseases, including glaucoma, a
leading cause of blindness that is currently difficult to treat, and loading wound-healing drugs
in the lenses to treat corneal wounds. The lens material can also be modified to produce self-
lubricating contact lenses to relieve the discomfort of contact lens wearers suffering from dry
eyes (Alvarez-Lozano, Hiratani, & Concheiro, 2006; in-Pharma Technologist, 2005).
9. Depot Technology :-
Depot technology offers potential improvement over daily dosing by maintaining constant
blood levels for medications that are more typically delivered by daily injection. The
technique is applicable for local and systemic drug administration. The medication is first
mixed with polymers, which are engineered to biodegrade at a desired rate. The solution is
then injected in the patient either subcutaneously or intramuscularly with a fine-gauge needle.
Once injected, the solution solidifies and becomes an implant that acts as a depot system,
releasing medication over days or months.
10. Automated Anesthesia :-
Possibly on the market in the next 5 years will be McSleepy, the first automated general
anesthesia delivery system. The software system continuously titrates and delivers appropriate
doses of standard drugs based on its monitoring of brainwave patterns, muscle contractions,

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heart rate, and blood pressure readings without manual intervention. According to researchers,
"The system can calculate the appropriate drug doses for any given moment of anesthesia
faster and more precisely than a human. It has been designed to analyze biological
information and constantly adapt to changes, even recognizing monitoring malfunction"
(Canadian Press, 2008).
11. Nanotechnology :-
A new generation of drug delivery systems is being created as a result of the ability to design
nanoparticles and their matrixes. Nanoparticles are very small molecules with a diameter of 1
to 100 nm. Drugs can be coupled to or encapsulated within these specialized molecules.
Advantages of using nanoparticles as drug delivery systems include increased drug
bioavailability and precise delivery of therapeutic agents to target organs, tissues, and cells
(Leary, Liu, & Apuzzo, 2006). "Presently only 1 of 100,000 molecules of therapeutic
intravenous drug reaches its desired destination. As a result of this, clinicians are faced with
deciding whether to increase the drug dosage, which can lead to side effects, or reduce the
dosage, which can limit the therapeutic effect" (Bulletin Board, 2008). Valuable clinical
breakthroughs in using nanotechnology have already occurred in the areas of oncology,
cardiovascular medicine, neurology, and orthopedics.

Fig . 4 : Multistage Nanoparticle Drug Delivery Mechanism: Illustration

A new multi-stage drug delivery system developed in the laboratory of nanomedicine pioneer Dr. Mauro Ferrari, delivers
therapeutic or diagnostic agents directly at the site of a tumor or other problem area. This illustration shows the final stage of
the intravenous journey with the arrival of a nanocarrier which is about 100 times smaller than a strand of hair and its payload
of anti-cancer medication. (A) shows the injected nanocarrier landing on the inner wall of a tumor-associated blood vessel, (B)
the release of nanoparticles that penetrate both the blood vessel wall and the tumor cell membrane and, (C) the delivery to the
tumor of doses of a cancer killing medication. Ferrari is testing the system on human tumors in animal models. (Illustration by
Matthew Landry)

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FIgure 5:-. Schematic of nanosystems that may function as combined drug delivery and imaging agents for
targeting T cells: (A) liposomal systems, (B) solid biodegradable nanoparticulates, and (C) macromolecular
dendrimer complexes. PEG indicates polyethylene glycol; Gd-DTPA, gadolininum-diethylene triamine
pentaacetic acid.

12. Cervical Drug Delivery System:-

The Cervical Drug Delivery System (DDS) is a new device that will allow a physician for the
first time to apply a wide range of FDA approved chemotherapy and antiviral drugs to the
cervix to treat cervical lesions detected by a standard Pap or other test. Because of the
rounded shape and the environmental characteristics of the cervix, up to now it has been
impossible for a physician to provide any form of localized medical therapeutic treatment for
a detected cervical lesion. The physician's only choice of treatment has been surgery. If the
lesion is not in an advanced stage, the patient is typically sent home with the recommendation
that she come back in three to six months to check and see if the lesion has developed further
toward cancer, so it can then be surgically treated. Clearly this limited form of treatment has
its drawbacks.

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Fig. 6: Cervical Drug Delivery System

The key component of the DDS is a patch that contains a formulary FDA approved drug. This
patch is designed such that it will adhere to the tissue and the drug released off the patch will
be applied directly onto the surface of the cervix where the lesion is. This will provide
targeted drug delivery in terms of the direction of the application and the amount of drug
absorbed into the tissue. Although this specific DDS deals with the application of a drug onto
the cervix, the invention can be generalized to other body surfaces and can deliver more than
one type of drug.
13. RF-MicroChannel™ Technology:-
Israel21C profiles an innovative transdermal drug delivery system from a start up
TransPharma Medical Ltd. Together with Teva Pharmaceutical Industries of Israel, the
company is currently developing a proprietary transdermal hPTH (1-34) product to treat
osteoporosis while eliminating the need for daily injections.

Fig. 7: RF-MicroChannel™ technology

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Working Principle of RF Microchannel Technology:

A densely spaced array of microelectrodes is placed against the skin. A high frequency
alternating current is transferred through each of the microelectrodes to create localized
ablation of the skin cells in close proximity to the electrodes. This process takes only
milliseconds and produces well-defined and completely safe RF-MicroChannels. The RF-
MicroChannels penetrate only the outer layer of the skin, where there are no blood vessels or
nerve endings. This means no pain or trauma to the skin.

14. Micro and nano drug delivery systems in cancer therapy:-

Currently, a variety of drug delivery approaches are FDA-approved or are in clinical
development as anticancer treatments, including polymer microcapsules and microspheres,
liposomes, polymer conjugates and nanoparticles (Figure 8). Others such as chemotherapy
wafers, microchips and osmotic pumps are also in testing stage to treat human cancers but
will not be the scope of this work since they have been reviewed in detail elsewhere (Moses et
al, 2003b). This article focuses on the potential of micro and nanotechnology as well as
polymer conjugation as a platform for developing drug delivery systems in cancer treatment.

Tremendous opportunities exist for using micro and nanoparticles as controlled drug delivery
systems for cancer treatment (Panyam and Labhasetwar, 2003; Birnbaum and Brannon-
Peppas, 2004). The term “microparticle” refers to a particle with a diameter of 1-1000 mm,
while “nanopaticle” is used when the particle is <1 mm in size. However, under this term it is
possible to distinguish several reservoirs including micro/nano-capsules, micro/nano-spheres,
liposomes, etc. All these devices differ not only in the structure (Figure 9) but also in their
biopharmaceutical properties and therapeutic uses (Orive et al, 2003b). The fabrication
protocol of each particle differs also considerably and the scale-up could be a challenge for
some of these devices.

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Figure 8. Examples of different drug delivery approaches that are FDA-approved or are in clinical development
as anticancer treatments. Reproduced from Moses et al, 2003

CONCLUSION:-
The delivery of any drug: at the right time in the target where it is needed and at the level that
is required (i.e. therapeutic level) is essential to realize the full potential of any therapeutically
active molecules. These requirements are more important in the case of drugs with higher
toxicity (e.g. chemotherapies) which could lead to serious side effects.
In the last few years, a great number of new drug delivery technologies have been optimized
including the micro and nano-systems as well as polymer conjugation. Together, these drug
delivery systems would not only improve drug administration and the efficiency and safety of
conventional therapies, but also revolutionize the pharmaceutical and biomedical industries,
as well as the modern health care systems.
The development of modern drug delivery systems has improved the therapeutic and
toxicological properties of existing drug molecules and also facilitated the implementation of
new ones. By including the drug in technologically optimized drug delivery systems or

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conjugating the drugs with different polymers, it is possible to modify the pharmacokinetics
and bio-distribution system of the drugs, improving its quality, efficacy and safety.
Some of the strongest arguments for the use of modern drug delivery systems are that they
avoid or at least reduce some potential disadvantages including toxicity, pain management,
short in vivo half-lives and repeated administrations.
The possibility of designing different drug delivery systems for a controlled and continuous
release of the therapeutic molecule has impact broadly the clinical application. It improves the
life-quality of the patients resulting into Improved Health Care System.
Medication delivery systems that concentrate medications only where needed and used could
reduce the destruction of surrounding tissues while minimizing side effects. The benefits of
such systems in the treatment of both acute and chronic conditions are clear.
From both a financial and a global health care perspective, finding ways to administer
injectable-only medications in oral form and delivering costly, multiple-dose, long-term
therapies in inexpensive, potent, and time-releasing or self-triggering formulations are also
needed.
Progress in the development of novel drug delivery systems is bringing researchers and
clinicians closer to meeting the goals of maximum efficacy with minimal toxicity and
inconvenience. The need for research into drug delivery systems extends beyond ways to
administer new pharmaceutical therapies; the safety and efficacy of current treatments may be
improved if their delivery rate, biodegradation, and site-specific targeting can be predicted,
monitored, and controlled.
Research demonstrates that patient adherence is improved when side effects are minimized; it
is imperative that modern drug delivery systems efficiently and precisely deliver medications
in a fashion that the patient finds acceptable and tolerable. Patients themselves are demanding
modern drug delivery systems that are convenient, easy to use, and affordable.
Hence, the quality of modern health care system has been broadly affected by the modern
Drug Delivery system. As technological innovation spreads throughout medicine; so does the
"cutting edge" come to drug delivery systems.

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Alicia R. Gasc½n, José Luis Pedraz,Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of
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Contact Details:-
Bibek Singh Mahat, M. Pharm. 1st Year, 1st Semester, Batch of 2009; Kathmandu University,
School of Science, Department of Pharmacy, www.ku.edu.np/pharmacy,
Email: bsm@student.ku.edu.np

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