Expanding Role of Drug Delivery System in Modern Health Care System:

Expanding Role of Drug Delivery System in Modern Health Care System

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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.

References:-

1. Novel drug delivery systems: future directions. (Pharmacology Update)(Report) By Angelia Colwell Berkowitz

& Diane M. Goddard, Journal of Neuroscience Nursing - April, 2009.

2. Recent Advances in Novel Drug Delivery Systems, Costas Kaparissides, Sofia Alexandridou, Katerina Kotti and

Sotira Chaitidou, Posted: March 25th, 2006 ; http://www.azonano.com/oars.asp



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3. Pharma Voice: Intracellular drug delivery systems: A new paradigm, Intracellular Drug Delivery Systems

(ICDDS) could be the solution for many infections. Manan Desai and Aditya Pattani

4. Brahmankar D. M., Jaiswal S. B. Controlled Release Medication in Biopharmaceutics and Pharmacokinetics a

Treatise. 1st edition, Vallabh Prakashan, Delhi, 1995; 335-371.

5. Lachman Leon, Lieberman H. A., Kanig J. L.The Theory and Practice of Industrial Pharmacy. 3 rd edition,

Varghese Publishing House, Bombay, 1987; 430-456.

6. Chien Y. W. Novel drug Delivery Systems. Marcel Dekker, 1982; 171-177.

7. Gastric retention system for oral drug delivery. Drug Delivery Oral.2005.

http://www.bbriefings.com/pdf/890/PT04_moes.pdf

8. Jian-Hwa Guo, PhD ,Carbopol polymers for pharmaceutical drug delivery applications. Excipient Updates. Drug

Delivery Technology. http://www.drugdeliverytech.com/cgibin/articles.cpi?idArticle=159

9. Seham S. Abd E Hady, Nahed D. Mortada, Gehanne A. S. Awad, Noha M. Zaki, Ragia A. Taha. Development

of in situ gelling and mucoadhesive mebeverine hydrochloride solution for rectal administration. Saudi

Pharmaceutical Journal. 2003; 11(4):159-171.

10. Khalid U. Shah, PhD & Jose G. Rocca, PhD. Lectins as next generation mucoadhesive for specific targeting of

the gastrointestinal tract. Gastrointestinal Targeting, Drug Delivery Technology.

http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=245.

11. Improved Drug Delivery Using Microemulsions: Rationale,Recent Progress and New Horizons-Critical Reviews

in Therapeutic Carrier Systems.18(1):77-140(2001)

12. Science Direct-Journal of Controlled Release-Croslinked hyaluronic acid hydrogel films: new biomaterials for

drug delivery

13. Charman W.N., Chan H.-K., Finnin B.C. and Charman S.A., “Drug Delivery: A Key Factor in Realising the

Full Therapeutic Potential of Drugs”, Drug Development Research, 46, 316-27, 1999.

14. Santini Jr, J.T., Richards A.C., Scheidt R., Cima M.J. and Langer R., “Microchips as Controlled Drug-Delivery

Devices”, Angew. Chem. Int. Ed., 39, 2396-407, 2000.

15. Micro and nano drug delivery systems in cancer therapy, Review Article, Gorka Orive, Rosa Mar£a Hern΅ndez,

Alicia R. Gasc½n, José Luis Pedraz,Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of

Pharmacy, University of the Basque Country, Vitoria–Gasteiz, Spain

Contact Details:-

Bibek Singh Mahat, M. Pharm. 1st Year, 1

st Semester, Batch of 2009; Kathmandu University,

School of Science, Department of Pharmacy, www.ku.edu.np/pharmacy,

Email: [email protected]

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