Mucosal Drug Delivery - A Review

S.Ganga

An 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. ^[1]

“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.” ^[1]

Advantages ^{[1, 2]}

Advantages of controlled drug delivery system over a conventional dosage form are:

• Less dosing frequency;
• Shorter treatment period;
• Improved patient convenience and compliance due to less frequent drug administration;
• Reduction in fluctuation in steady-state levels and therefore better control of disease condition and reduced intensity of local or systemic side effects;
• Increased safety margin of high potency drugs due to better control of plasma levels;
• Maximum utilization of drug enabling reduction in total amount of drug administered;

Commercialization Of Mucosal Drug Delivery

Mucosal drug delivery technologies are expanding exponentially with applications in every imaginable route of administration because of the indisputable therapeutic benefit this delivery technology brings. Benefits include site-specific targeting, less frequent dosing, and maintaining effective plasma concentration without increased consumption^[10]

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). ^[11]

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. ^[12]

Design And 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.

Development of Novel Drug Delivery System for Oral Controlled Release Drug Administration^[3]

• Osmotic pressure controlled gastrointestinal drug delivery system
• Hydrodynamic pressure controlled gastrointestinal drug delivery system
• Membrane permeation controlled gastrointestinal drug delivery system
• Gel diffusion controlled gastrointestinal drug delivery system
• Ph controlled gastrointestinal drug delivery system
• Ion exchange controlled gastrointestinal drug delivery system

Methods Of Oral Controlled Drug Delivery System

Gastro Retentive Drug Delivery System

During the last decade, many studies have been performed concerning sustained release dosage form of drugs, which have aimed at the prolongation of Gastric Emptying Time (GET). Various other approaches have been tried to retain the dosage form in the stomach as way of increasing the overall rotation time and include floating system, high density pellets, bioadhesive system, swelling system and shape system.gastro retentive drug delivery systems have made it possible to deliver the drug for ling periods of time and in a way , such that no loss in bioavailability is encountered.

Approaches to Extend GI Transit time of Drug^[4]

• The use of passage-delaying excipients (for example triethanolamine myristate);

• The utilisation of specially designed dosage forms such as ‘heavy pellets’ and large single-unit delivery systems;

• Bio (muco)adhesive and buoyant forms;

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. Another analogous approach consists of using passage-delaying drugs, for example propantheline, which is generally considered undesirable because of potential side effects.

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. Clarke, et al. has suggested that there may be a threshold density in the order of 2.4–2.6g/cm3,above which gastric and small intestine residence times of pellets are prolonged.1 This threshold value is much higher than density values used in previous studies (~1.5g/cm3).

If these results are confirmed by clinical studies, the technical difficulty will be the formulation of real pellets containing significant amounts of drug and with a density greater than 2.6g/cm3. Barium sulphate can be used as a diluent (d = 4.9g/cm3).

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. To our knowledge, such 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. The passage of much smaller conventional single unit scan already be impeded in patients with narrow gastro duodenal lumen. This might lead to serious life threatening effects if multiple dosing is prescribed.

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. 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.

Many results have demonstrated the validity of the concept of buoyancy in terms of prolonged GRT of the floating forms, improved bioavailability of drugs and improved clinical situations. These results also demonstrate that the presence of gastric content is needed to allow the proper achievement of the buoyancy retention principle (for example Prolopa ®HBS hard gelatin capsules).

Among the different hydrocolloids recommended for floating form formulations, cellulose ether polymers are most popular, especially hydroxypropylmethylcelluloses. Fatty material with a bulk density lower than one may be added to the formulation to decrease the water intake rate and increase buoyancy. Parallel to formulation studies, investigations have been undertaken in animals and humans to evaluate the intra gastric retention performances of floating forms. These assessments were realized either indirectly through pharmacokinetic studies with a drug tracer, or directly by means of X-ray and gamma scintigraphic monitoring of the form transit in the GI tract. As an example, much work has been devoted to the in vivo study of the diazepam HBS capsules developed by Hoffmann-La Roche, i.e. Valium® CR and Valrelease®.

When a floating capsule is administered to the subjects with a fat and protein meal, it can be observed that it remains buoyant at the surface of the gastric content in the upper part of the stomach and moves down progressively while the meal empties. The reported gastric retention times range from four to 10 hours. Pharmacokinetic and bioavailability evaluation studies confirm the favorable incidence of this prolonged gastric residence time.

Bioadhesive Drug Delivery System

The original concept of bioadhesive polymers as platforms for oral controlled drug delivery was to use these polymers to control and to prolong the GI transit of oral controlled delivery systems for all kinds of drugs. Several in vitro and ex vivo methods to test the bioadhesive properties of polymers and/or of coated microparticles have been described. Where as bioadhesion has found interesting applications for other routes of administration (buccal, nasal, rectal and vaginal), it now seems that the controlling approach of GI transit has been abandoned before having shown any significant clinical outcome. According to in vivo results obtained in animals and in humans, it does not seem that mucoadhesive polymers are able to control and slow down significantly the GI transit of solid delivery systems. Attention should be paid to possible occurrence of local ulcerous side effects due to the intimate contact of the system with mucosa for prolonged periods of time. As an example, oesophageal lodgement is known to be a potential cause of drug-induced injuries that can range from local irritation to perforation, depending on the ulcerogenic properties of the drug.

Muco(Bio)Adhesive Drug Delivery System

Bioadhesion 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 Bioadhesion 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 mucoadhesion.

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 bioadhesive system and hence, the mucoadhesive drug delivery system includes the following:

The recent advances in the delivery of drugs through mucoadhesive gastrointestinal delivery system is reviewed as below.

· Buccal Delivery System

· Oral Delivery System

· Vaginal Delivery System

· Rectal Delivery System

· Nasal Delivery System

· Ocular Delivery System

Mucoadhesive Drug Delivery System Include:

Buccal Drug Delivery

Rectal Drug Delivery:

Nasal Drug delivery:

Ocular drug delivery:

Mucoadhesive gastrointestinal membrane ^[3]

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.

The surface epithelium adhesive properties of mucin have been found out and recently applied to the development of gastrointestinal drug delivery devices based on bio (muco) adhesive polymers.

The concept of using mucoadhesive polymer to extend the GI transit time is elaborated in the figure 2. The drug delivery system coated with mucoadhesive polymer binds to the mucin molecules in the mucus lining and is therefore retained on the surface epithelium for extended periods of time. The drug molecules contained in the drug delivery device coated with mucoadhesive polymer are constantly released for absorption.

Fig. 2: Interaction of Mucoadhesive Drug Delivery System with Mucus Layer on Gastrointestinal Surface Epithelium

A bio (muco) adhesive polymer is a natural or a synthetic polymer capable of producing an adhesive interaction with a biological membrane, which is then called a bioadhesive polymer, or with the mucus lining on the GI mucosal membrane, which is thus called a mucoadhesive polymer.

A bio (muco) adhesive polymer is known to have the following molecular characteristics:

• It has molecular flexibility;
• It contains hydrophilic functional groups;
• It poses a specific molecular weight, chain length and conformance.

The different types of polymers used in the mucoadhesive drug delivery system are:

• Carboxy methyl cellulose
• Carbopol
• Polycarbophil
• Tragacanth
• Sodium alginate
• Hydroxyl propyl methyl cellulose
• Gelatine
• Pectin
• Acasia
• Povidone

Commonly used macromolecular pharmaceutical expients have been evaluated and found to have bio (muco) adhesive properties. This is illustrated in the following table 1.

Table 1: Relative Mucoadhesive Performance of Some Potential Bio (muco) adhesive Pharmaceutical Polymers

a- Percentage of a standard, tested in vitro; b- Assessed in vivo.

From the rank of order of bioadhesion, it appears that, the polyanions with a high charge density are highly active. Among the various polyanions evaluated, it was found that, the polymers containing carboxylic groups, such as polyacrylic polymer, show a high level of bioadhesion.

From the data summarized in figure 3 and 4, the maxima of bioadhesion and the minimal polymer concentration needed to attain the maximal bioadhesion are determined and compared in table 2.

The results indicate that, the most hydrophilic polyacrylic polymer, carbopol 934, is the most active bioadhesive polymer with the maxima of bioadhesion (399Pa) attained at a polymer concentration of only 0.15%.

Fig 3: Relationship Between The Measured Bioadhesion of an Aqueous Solution of Polyacrylic Acid (PAA), a Binary (BCP) and a Ternary (TCP) Polyacrylic copolymer and the concentration of Polymer (or Copolymer)^[3]

The copolymerisation of polyacrylic acid reduces the bioadhesive capacity of polyacrylic polymer, and copolymers thus require a higher polymer concentration to achieve the maxima of bioadhesion. The most hydrophobic polyacrylate ternary copolymer, scopacryl D340, appears to be more bioadhesive than the medium hydrophilic binary copolymer, scopacryl D339. Both are, however, active bioadhesives at a polymer concentration much higher than that of carbopol (fig.3, 4). It was also observed that the addition of pharmaceutical excipients into the bioadhesive polyacrylate polymer tends to reduce the bioadhesion, which is dependent upon the type and concentration of excipients added (fig. 3, 4).

Fig 4: Effect of Excipients on the Measured Bioadhesion of an Aqueous

Solution of a Ternary (TCP) Polyacrylic Copolymer (TSP) and its Dependence on Excipient Concentration.

[TCPa =TCP + Lactose; TCPb = TCP + Potato Starch; TCPc = TCP + Microcrystalline Cellulose.]^[3]

Carbopol® polymers are polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. They are produced from primary polymer particles of about 0.2 to 6 micron average diameter. The flocculated agglomerates cannot be broken down into the ultimate particle when produced. Each primary particle can be viewed as a network structure of polymer chains interconnected by cross-links. Without the cross-links, the primary particle would be a collection of linear polymer chains intertwined but not chemically bonded. Carbopol polymers, along with Pemulen® and Noveon® polymers are all cross-linked. They swell in water up to 1000 times their original volume (and 10 times their original diameter) to form a gel when exposed to a pH environment above 4.0 to 6.0. Because the pKa of these polymers is 6.0 to 0.5, the carboxylate groups on the polymer backbone ionize, resulting in repulsion between the negative charges, which adds to the swelling of the polymer. The glass transition temperature of Carbopol polymers is 105°C (221°F) in powder form. However, the glass transition temperature decreases significantly as the polymer comes into contact with water. The polymer chains start gyrating, and the radius of gyration becomes increasingly larger. Macroscopically, this phenomenon manifests itself as swelling. ^[5]

Although Carbopol polymers have enjoyed success in controlled-release solid dose formulations since the 1960s, the number of companies developing and commercializing controlled-release tablets using Carbopol and Noveon polymers has increased significantly in recent years. In response to this commercial interest, we have tested a variety of excipients and active drug ingredients in tablet models using both direct-compression and wet granulation methods. These polymers can be successfully formulated into a variety of different tablet forms, including the traditional swallowable tablets, chewable tablets, buccal tablets, sublingual tablets, effervescent tablets, and suppositories; providing controlled-release properties as well as good binding characteristics.^[5]

Tablet formulations using Carbopol polymers have demonstrated zero-order and near zero-order release kinetics.^1-5 These polymers are effective at low concentrations (less than 10%) and feature extremely rapid and efficient gelation characteristics under both simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) test conditions. They also produce tablets of excellent hardness and low friability over a range of compression forces, as well as demonstrably longer dissolution times at lower concentrations than other controlled-release excipients. Greater formulating latitude in dosage forms is therefore a possible using Carbopol polymer as the functional controlled-release excepient. ^[5]

Carbopol polymer 71G NF is a useful and versatile controlled-release additive for tablet formulations in direct compression with the following characteristics:

• Good tableting formulation flowability,
• Good tablet hardness with press-operating latitude,
• Good tablet friability over variations in press speed and compression pressure,
• Long drug release profiles (often zero order),
• Release profiles can be controlled by varying Carbopol 71G NF polymer levels,
• Can be processed by wet granulation if desired, and
• Can give Drug Release Profiles similar to Carbopol 971P NF polymer, but with less dust and better handling characteristics.

Carbopol and Noveon polymers are: ^[5]

· Are safe and effective inoral and topical application

· Are bioadhesive, enebling increased bioavailability of ophthalmic, nasal, buccal, intestinal, rectal and vaginal formulation.

· May protect proteins and peptides from degradation by proteolytic enzymes, enebling increased bioavailability of protein-or peptide-based formulations, and

· Are approved by many of the world’s pharmacopoeias, facilitating regulatory approvals worldwide.

Recently, Harris et al investigated the feasibility of using bio (muco) adhesive polymers to extend the GI transit time in rats and humans. The results obtained in rats indicated that, among the polymers investigated, polyacrylic polymers, such as carbopol and polycarbophil, are most likely to be of use in delaying gastrointestinal transit; however, the major delay is due to a decrease in the gastric emptying time. On the other hand, transit through the upper small intestine is much more rapid than transit through the lower small intestine. Along with this, the concentration and physical state of a bioadhesive polymer tends to affect the GI transit time. However, the results generated in humans were not conclusive.

Approaches to Incorporate Drug into Bio (muco) adhesive Polymer for the Preparation of Oral Drug Delivery Systems

For water-soluble polymers, it is possible to coat the surface, totally or partially, of a sheet or macro- or micro- size capsule-shaped drug delivery device. In this case, the duration of retention on the mucosal tissues is generally controlled by the dissolution rate of the bio (muco) adhesive polymer. A cross-linked bio (muco) adhesive polymer must first be hydrated to become an effective bio (muco) adhesive, and when it is, it often separates from the rate-controlling drug delivery system or causes a premature release of drug, especially water-soluble drugs.

Table 2: Bioadhesion of Polyacrylate Polymer and Copolymer to Pig Intestine^[3]

Methods For Evalution Of Mucoadhesion^{[4, 5, 6, 7, 8]}

Mucoadhesion can be evaluated by different types of invitro and invivo methods

Types of Invitro method

• Shear stress method
• Detachment force measurement
• Fluorescent probe method
• Flow channel method
• Falling liquid film method
• Swelling properties of films

Description of some of the method mentioned above:

Shear stress method:

Two smooth, polished plexi glass box were selected; one block was fixed with adhesive araldite on a glass plate, which was fixed on leveled table. The level was adjusted with the spirit level. To the upper block, a thread was tied and the thread was passed down through a pulley as shown in fig.6.the length of the thread from the pulley to the pan was 12cm. At the end of the thread a pan of weight 17gm was attached into which t6he weights can be added.

Detachment force measurement

This is the method used to measure in vitro mucoadhesive capacity of different polymers. It is a modified method developed by Martti Mrvola to assess the tendency of mucoadhesive materials to adhere to the oesophagus. The assembly as shown in fig 7. Consist of single organ bath, a stand, glass rod, and a pan for keeping beaker and reservoir for addition of water into beaker.

Method:

Immediately after slaughter, the intestine was removed from the sheep and transported to the laboratory in tyrode solution and kept in at 4^oc.

The composition of tyrode solution is(gm/lit):

1.Sodium chloride: 8

2.Potassium chloride: 0.2

3.Calcium chloride.2H20: 0.134

4.Sodium Bicarbonate: 1.0

5.Sodium dihydrogen phosphate: 0.05

6.Glucose H20: 1.0

7.Magnesium chloride: 0.01-0.1

During the experiment, the solution was aerated with pure oxygen and kept at 37c.

Segments of 6-7cm long were cut from the intestine. The lower end of the segment was tied off and was then tied to aerator tube and the upper end was tied around a glass tube of diameter 15mm.

Recording of Adherence

The 6mm paracetamol plane tablets, paracetamol tablets layered on side with mucoadhesive polymer, and the paracetamol in matrix tablets (in the ratio of 2:1) were prepared. VH/AB fine hole drilled in the tablets to be tested with fine needle in the center. A thread was passed through it and tied around the tablet . The other end of the thread is tide to the glass rod suspended from the stand. The length of the thread is such that in resting state the tablet should be in the middle of the piece. To the other end of the glass rod, a pan was tied in which a beaker was placed. After inserting VH/AB tablet into GI segment and lightly pressing the GI segment with tablet by a forceps, the assembly should be kept undistributed for a fixed time interval of 30 min and 1 hr. Then, water was added to burette slowly drop by drop into beaker. The amount of water required to pull out the tablet from intestinal segment represents force required to pull the tablet against adhesion.

The force in Newton is calculated by the following equation:

F=0.00981 W/2

Where, W=is the amount of water

The characteristic to be studied:

1.The effect of the contact time for which the product remains in the intestine and the force needed to detach it,

2.The strength of different mucoadhesive polymers and the effect of amount of polymer in the formulation on the force needed to detach it.

Evaluation of a Novel Buccal Adhesive System (NABS) ^[9]

Swelling Studies

NBASs (n=3) were weighed individually (designated as W₁) and placed separately in petri dishes containing 4 mL of phosphate buffer (pH 6.6) solution. At regular intervals (0.5, 1, 2, 3, 4, 5, and 6 hours), the NBASs were removed from the petri dishes and excess surface water was removed carefully using the filter paper. The swollen NBASs were then reweighed (W₂), and swelling index (SI) was calculated using the following formula.

In Vitro Drug Release

In vitro release studies were performed in phosphate buffer solution (pH 6.6, 150 mL) at 37°C using a modified dissolution apparatus. The modified dissolution apparatus consisted of a 250-mL beaker as a receptor compartment and a glass rod attached with a grounded glass disk (2-cm diameter) as a donor tube. The back surface of NBAS or sustained release buccal tablet was attached to the glass disk with instant adhesive (cynoacrylate adhesive). The donor tube was then dipped into the receptor compartment containing dissolution medium, which was maintained at 37°C ± 0. 2°C, and stirred at a constant speed using a magnetic bead. Aliquots (5 mL each) were withdrawn at preset times (0.08, 0.16, 1, 2, 3, 4, 5, and 6 hours), filtered through a 0.2-µ filter, and then the amount of PH released was estimated by measuring the absorbance at 290 nm using a UV spectrophotometer (n = 3). The dissolution medium of same volume (5 mL) prewarmed at 37°C ± 0.2°C was replaced to maintain its constant volume and sink condition. The cumulative amount of drug release was calculated and used while plotting the release and release kinetics curves.

Conclusion:

Mucoadhesive drug delivery systems are being studied from different angles, including development of novel mucoadhesives, design of the device, mechanisms of mucoadhesion and permeation enhancement. With the influx of a large number of new drug molecules from drug discovery, mucoadhesive drug delivery will play an even more important role in delivering these molecules. The different types of polymers used in NDDS are polycarbophil, carbopol, CMC, Tragacanth, sodium alginate, HPMC, etc are most useful in controlled release dosage forms as a mucosal polymers. There are various methods for the evaluation of mucoadhesion and some of them are shear stress method,

detachment force measurement, fluorescent probe method, flow channel method, falling liquid film method and swelling properties of films. The technology of Mucosal drug delivery has been studied in details over the past 30 years and numerous excellent reviews are available. This brief review is intended to introduce the practical aspects in commercialization of polymeric drug delivery products. For more comprehensive review, the reader can refer to the many excellent review articles listed at the end of this review.

References:

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2.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.

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

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5. ,Jian-Hwa Guo, PhD ,Carbopol polymers for pharmaceutical drug delivery applications. Excipient Updates. Drug Delivery Technology. http://www.drugdeliverytech.com/cgi-bin/articles.cpi?idArticle=159.

6. 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.

7. 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.

8. Kok Khiang Peh, Choy Fun Wong. Polymeric films as vehicle for buccal delivery: Swelling, mechanical and bioadhesive properties. Journal of Pharmacy and Pharmaceutical Sciences. 1999; 2(2):53-61.

9. Kashappa Goud, H. Desai, and T.M. Pramod Kumar.Preparation and evaluation of a novel buccal adhesive system.AAPS PharmSciTech. 2004; 5(3):article 35.

10. Joe McDonough and Wade Schlameus.Uncontrolled growth of controlled selease drug delivery technology and markets. Pharmaceutical Research and Microencapsulation Specialists at the Southwest Research Institute.

11. Costas Kaparissides, Sofia Alexandridou, Katerina Kotti and Sotira Chaitidou.Recent advances in novel drug delivery systems. Azojono Journal Of Nanotechnology.2006; 10:2240/1110.

12. Woodley, John .Bioadhesion: New Possibilities for Drug Administration. Leading Article.Clinical Pharmacokinetics. 2001; 40(2):77-84.

13. Juan Manuel Llabot, Ruben Hilario Manzo and Daniel Alberto Allemandi. Double-layered mucoadhesive tablets containing nystatin. AAPS PharmSciTech 2002; 3 (3) article 22

14. K.P.R. Chowdary and Y. Srinivasa Rao .Design and in vitro and in vivo evaluation of mucoadhesive microcapsulesof glipizide for oral controlled release: a technical note. AAPS PharmSciTech 2003; 4 (3) Article 39.

15. M.S. El-Samaligy, N.N. Afifi, E.A. Mahmoud .Increasing bioavailability of silymarin using a buccal liposomal delivery system: Preparation and experimental design investigation. International Journal of Pharmaceutics 2006; 308:140–148.

16. Libero Italo Giannola , Viviana De Caro , Giulia Giandalia ,Maria Gabriella Siragusa , Claudio Tripodo , Ada Maria Florena , Giuseppina Campisi . Release of naltrexone on buccal mucosa: Permeation studies, histological aspects and matrix system design. European Journal of Pharmaceutics and Biopharmaceutics. 2007.

17. Ana Figueiras , Rui A. Carvalho , Laura Ribeiro , Juan J. Torres-Labandeira Francisco J.B. Veiga .Solid-state characterization and dissolution profiles of the inclusion complexes of omeprazole with native and chemically modified b-cyclodextrin.ssuropean Journal of Pharmaceutics and Biopharmaceutics. 2007.

18. Axel Schneeweis, Christel C. Muller-Goymann. Controlled release of solid-reversed-micellar-solution (SRMS) suppositories containing metoclopramide-HCl. International Journal of Pharmaceutics. 2000; 196:193–196.

19. Ulrich Klotz, Matthias Schwab .Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease. Advanced Drug Delivery. 2005; 57:267-279.

20. ST Lim, B Forbes, GP Martin, and MB Brown. In vivo and in vitro characterization of novel micro particulates based on hyaluronan and chitosan hydroglutamate.AAPS PharmSciTech2001; 2 (4) article 20.

21. Sambhaji Pisal, Vijay Shelke, Kakasaheb Mahadik,Shivajirao Kadam. Effect of organogel components on in vitro nasal delivery of propranolol hydrochloride. AAPS PharmSciTech 2004; 5 (4) Article 63.

22. E. Gavini , A.B. Hegge , G. Rassu a, V. Sanna , C. Testa ,G. Pirisino , J. Karlsen , P. Giunchedi.Nasal administration of carbamazepine using chitosan microspheres: in vitro/in vivo studies. International Journal of Pharmaceutics .2006; 307:9-15.

23. Sonal R. Patel , Hui Zhong , Ashutosh Sharma , Yogeshvar N. Kalia. In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.European Journal of Pharmaceutics and Biopharmaceutics.2007; 66: 296–301.

24. Hongxia Lin , Matthias Gebhardt , Shengjie Bian , Kyoung Ae Kwon ,Chang-Koo Shim, Suk-Jae Chung, Dae-Duk Kim. Enhancing effect of surfactants on fexofenadine·HCl transport across the human nasal epithelial cell monolayer. International Journal of Pharmaceutics.2007; 330:23–31.

25. Jean-Louis Bourges, Sandrine E. Gautier, Florence Delie, Riad A. Bejjani, Jean-Claude Jeanny, Robert Gurny, David Ben Ezra, and Francine F. Behar-Cohen. Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticses. Investigative Ophthalmology and Visual Science. 2003; 44:3562-3569.

26. De Campos A.M.;Diebold Y.;Carvalho E.L.S.;Sánchez A.,José Alonso M. Chitosan nanoparticles as new ocular drug delivery systems: in vitro stability, in vivo fate, and cellular toxicity. Pharmaceutical Research, Springer. 2004; 21(5): 803-810(8).

About Authors:

S.Ganga

corresponding author

School of Pharmacy and Technology Management, SVKM’S NMIMS University, VL Mehta Road, Vile Parle (W), Mumbai-400056, INDIA

Ph: 91-22-26134577 / 26183688, FAX: 91-22-26114512, E-Mail: gangach@rediffmail.com

Mayur Bafna