A REVIEW ON PLANT DERIVED NATURAL GUMS/POLYMERS IN MUCOADHESIVE DRUG DELIVERY SYSTEM FOR IMPROVING PATIENT COMPLIANCE

Polymers are often utilised in the design of novel drug delivery systems such as those that target delivery of the drug to a specific region in the gastrointestinal tract or in response to external stimuli to release the drug. This can be done via different mechanisms including coating of tablets with polymers having pH dependent solubilities or incorporating non-digestible polymers that are degraded by bacterial enzymes in the colon. Non-starch, linear polysaccharides are resistant to the digestive action of the gastrointestinal enzymes and retain their integrity in the upper gastrointestinal tract. Matrices manufactured from these polysaccharides therefore remain intact in the stomach and the small intestine, but once they reach the colon they are degraded by the bacterial polysaccharidases. This property makes these polysaccharides exceptionally suitable for the formulation of colon-targeted drug delivery systems.[3]

This review discusses the use of plant-derived polymers in the formulation of mucoadhesive drug delivery systems. Specific reference is made to the use of natural polymers in the design of novel dosage forms such as modified release matrix type tablets and other new drug delivery systems under investigation.

Mechanism of Mucoadhesion
Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains.

Mucoadhesion has the following Mechanism:
1. Intimate contact between a bioadhesive and     membrane (wetting or swelling phenomenon)
2. Penetration of the bioadhesive into the tissue or into the surface of the mucous membrane (interpenetration).

Residence time for most mucosal routes is less than an hour and typically in minutes, it can be increased by the addition of an adhesive agent in the delivery system which is useful to localize the delivery system and increases the contact time at the site of absorption. The adhesion is prolonged due to the formation of vandervaals forces, hydrogen bonds and electrostatic bonds. [6][1]

Factors affecting Mucoadhesion
The mucoadhesion of a drug carrier system to the mucous membrane depends on the below mentioned factors.
1) Polymer based factors
- Molecular weight of the polymer,
- Concentration of polymer,
- Polymer swelling factor,
- Stereo chemistry of polymer.

2)  Physical factors
- pH at polymer substrate interface
- Applied strength,
- Contact time.

3)  Physiological factors
- Mucin turnover rate
- Diseased state

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Ideal Muco Polymer Characteristics:
1. Polymer must have a high molecular weight to promote the adhesiveness between the polymer and mucus.
2. long chain polymers-chain length must be long enough to promote the interpenetration and it should not be too long that diffusion becomes a problem.
3. High viscosity
4. Degree of cross linking. Highly cross linked polymers swell in presence of water and retain their structure.
Swelling favours controlled release of the drug and increases the polymer/mucus interpenetration.
5. Flexibility of polymer chain- this promotes the interpenetration of the polymer within the mucus network.
6. Concentration of the polymer- an optimum concentration is required to promote the mucoadhesive strength. Itdepends however, on the dosage form. For solid dosage form the adhesive strength increases with increase in the polymer concentration.
7. Charge and degree of ionization-  The mucoadhesive strength can be attributed as anion>cat ion>nonionic
8. Optimum hydration- excessive hydration leads to decreased mucoadhesive strength due to formation of a slippery mucilage.
9. Optimum Ph – mucoadhesion is optimum at low pH conditions but at higher pH values a change in the conformation occurs into a rod like structure making them more available for inter diffusion and interpenetration. At very elevated pH values, positively charged polymers like chitosan form polyelectrolyte complexes with mucus and exhibit strong mucoadhesive forces.
10. High applied strength and initial contact time
11. It should be non toxic, non irritable, biocompatible preferably biodegradable.[12]

A mucoadhesion promoting agent or the polymer is added to the formulation which helps to promote the adhering of the active pharmaceutical ingredient to the oral mucosa.

Mucoadhesive polymer should have the following characteristic properties.

Disadvantages of synthetic polymers in pharmaceutical sciences:
The synthetic polymers have certain disadvantages such as high cost, toxicity, environmental pollution during synthesis, non-renewable sources, side effects, and poor patient compliance.

Acute and chronic adverse effects (skin and eye irritation) have been observed in workers handling the related substances methyl methacrylate and poly- (methyl methacrylate) (PMMA).

Reports of adverse reactions to povidone primarily concern the formation of subcutaneous granulomas at the injection site produced by povidone. There is also evidence that povidone may accumulate in organs following intramuscular injections].

Acute oral toxicity studies in animals have indicated that carbomer-934P has a low oral toxicity at a dose of up to 8 g/kg. Carbomer dust is irritating to the eyes, mucous membranes and respiratory tract.

Studies in rats have shown that 5% polyvinyl alcohol aqueous solution injected subcutaneously can cause anemia and can infiltrate various organs and tissues.

It has been shown that poly glycolides, polylactides and their co-polymers have an acceptable biocompatibility but exhibit systemic or local reactions due to acidic degradation products. An initial mild inflammatory response has been reported when using poly-(propylene fumarate) in rat implant studies.

Plant derived Natural Mucoadhesive polymers for better patient compliance in mucoadhesive drug delivary systems:
Various plant based gums/polymers are now a days takes  more  interest because of there non toxicity, biocompatibility, cost effective ness and readily availability.

Tamarind Gum:
Tamarind xyloglucan is obtained from the endosperm of the seed of the tamarind tree. Tamarind Gum, also known as Tamarind Kernel Powder (TKP) is extracted from the seeds. Tamarind gum is a polysaccharide include non carcinogenicity, biocompatibility, mucoadhesivity, high drug holding capacity and high thermal stability . This has led to its application as excipient in hydrophilic drug delivery system .

Diclofenac sodium matrix tablets containing TKP was investigated. The tablets prepared by wet granulation were evaluated for its drug release characteristics. The result of this study demonstrated, that isolated TKP can be used as a drug release retardant. It was observed that the swelling index increased with the increase in concentration of TKP. Increase in polymer content resulted in a decrease in drug release from the tablets. The drug release was extended over a period of 12 hrs. and followed zero order  kinetics .

TKP was also examined for its sustained release property using both water soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water insoluble drugs (indomethacin) . The release rates from the matrix tablets were found to be dependent on the drug solubility. Zero order release was achieved for indomethacin from TKP.

Mucoadhesive buccal patches using tamarind gum as mucoadhesive polymer for controlled release of benzydamine (BNZ) and lidocaine (LDC) were prepared and evaluated .  The patches adhered for over 8 h to the upper gums of the volunteers, and were perfectly tolerated. BNZ hydrochloride was released in vivo and in vitro with practically identical profiles[9][10].

Isapgulla husk (Psyllium):
Psyllium seed husks, also known as ispaghula, isabgol, or simply as psyllium, are portions of the seeds of the plant Plantago ovata.
Psyllium seed husk is used as binder, disintegrant and release retardant .

In an attempt, psyllium and acrylic acid based pH sensitive novel hydrogels for the use in colon specific drug delivery was studied. The hydrogel was evaluated for the swelling mechanism and drug release mechanism from the polymeric networks. The effects of pH on the swelling kinetics and release pattern of drugs have been studied by varying the pH of the release medium. It has been observed that swelling and release of drugs from the hydrogels occurred through non-Fickian or anomalous diffusion mechanism in distilled water and pH 7.4 buffer. It shows that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable.[7]

Khaya gum:
Khaya gum is a polysaccharide obtained from the incised trunk of the tree Khaya grandifoliola (family Meliaceae). It is known to contain highly branched polysaccharides consisting of D galactose, L-rhamnose, D-galacturonic acid and 4-O- 60 methyl-D-glucoronic acid . Khaya gum has been shown to be useful as a binding agent in tablet formulations. Khaya gum is a hydrophilic polymer and has been shown to possess emulsifying properties comparable with acacia gum. The fact that the gum is naturally available, inexpensive and non-toxic has also fostered the interest in developing the gum for

pharmaceutical use. Further work has also shown its potential as a directly compressible matrix system in the formulation of mucoadhesive  controlled release tablets .

Khaya gum has been successfully evaluated as a controlled release agent  in comparison with hydroxypropylmethylcellulose (HPMC) using paracetamol (water soluble) and indomethacin (water insoluble) as model drugs. Khaya gum matrices provided a controlled release of paracetamol for up to 5 h. The release of paracetamol from khaya gum matrices followed timeindependent

kinetics and release rates were dependent on the concentration of the drug present in the matrix. A combinationof khaya gum and HPMC gave zero-order time-independent release kinetics [8].

Fenugreek seeds:
Trigonella Foenum-graceum, commonly known as Fenugreek, is an herbaceous plant of the leguminous family.

Fenugreek seeds contain a high percentage of mucilage (a natural gummy substance present in the coatings of many seeds). Although it does not dissolve in water, mucilage forms

a viscous tacky mass when exposed to fluids. Like other mucilage- containing substances, fenugreek seeds swell up 82 and become slick when they are exposed to fluids .

The mucilage derived from the seeds of fenugreek, was investigated for use in matrix formulations containing propranolol hydrochloride. Methocel® K4M was used as a standard controlled release polymer for comparison purposes. A reduction in the release rate of propranolol hydrochloride was observed with increase in concentration of the mucilage in comparison to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug: mucilage ratio. Fenugreek mucilage at a concentration of about 66% w/w was found to be a better release retardant compared to hypomellose at equivalent content .

Fenugreek gum thicken ingested food to form a gel in stomach trapping fat, sugars and starch hydrolyzing, amylase enzymes to slow down sugar absorption. Thus, it is good for obese and diabetic persons. The gel, which appears like 'fat' inside the body, signals the gall bladder to empty bile into the stomach. The gel then irreversibly traps lipid-emulsifying bile salts and prevents their reabsorption. Thus, emulsification and absorption of lipids including cholesterol results in lowering of blood lipid. This in turn reduces hypertension and chance of heart attack[13][7].

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Pectin:
Pectin is a structural heteropolysaccharide contained in the primary cell walls of terrestrial plants. It was first isolated and described in 1825 by Henri Braconnot. It is produced commercially as a white to light brown powder, mainly extracted from citrus fruits, and is used in food as a gelling agent particularly in jams and jellies.

In plant cells, pectin consists of a complex set of polysaccharides that are present in most primary cell walls and are particularly abundant in the non-woody parts of terrestrial plants. Pectin is present not only throughout primary cell walls but also in the middle lamella between plant cells, where it helps to bind cells together. In human digestion, pectin binds to cholesterol in the gastrointestinal tract and slows glucose absorption by trapping carbohydrates. Pectin is thus a soluble dietary fiber.

Biopolymers have been used extensively in the pharmaceutical field. Pectin, a biopolymer, has several unique properties that enable it to be used as an excipient or carrier for oral drug delivery systems. Accordingly, several investigators have identified the benefits of pectin-based delivery systems for oral drug administration. This review first describes the chemical structure, source and production, degree of esterification and gel formation properties of pectin. The application of pectin in various oral drug delivery platforms is also discussed, that is, controlled release systems, gastro-retentive systems, colon-specific delivery systems and mucoadhesive delivery systems.

Pectin from different sources provides different gelling abilities, due to variations in molecular size and chemical composition. Like other natural polymers, a major problem with pectin is inconsistency in reproducibility between samples, which may result in poor reproducibility in delivery characteristics. Scintigraphic studies and in vivo studies, in both animals and human volunteers, demonstrate the successful development of a pectin-based colon-specific drug delivery system. Pectin-based controlled release systems, gastro-retentive systems and mucoadhesive systems present promising approaches for increasing the bioavailability of drugs, but are in their infancy.[5]

EVALUATION OF MUCOADHESIVE POLYMERS
Mucoadhesive polymers can be evaluated by testing their adhesion strength by both in vitro and in vivo tests.
In vitro tests / exvivo
The importance is layed on the elucidation of the exact mechanisms of bioadhesion. These methods are,
* methods determining tensile strength
* methods determining shear stress
* adhesion weight method
* fluorescent probe method
* flow channel method
* mechanical spectroscopic method
* falling liquid film method
* colloidal gold staining method
* viscometer method
* thumb method
* adhesion number
* electrical conductance
* swelling properties
* in vitro drug release studies
* mucoretentability studies

In vivo methods
* use of radioisotopes
* use of gamma scintigraphy
* use of pharmacoscintigraphy
* use of electron paramagnetic
* resonance(EPR) oximetry
* X ray studies
* Isolated loop technique[5][6]

CONCLUSION
Mucoadhesive drug delivery systems, are gaining popularity day by day in the global pharma industry and research and development. Extensive research efforts throughout the world have resulted in significant advances in understanding the various aspects of mucoadhesion. The various sites where mucoadhesive polymers have played an important role include buccal cavity, nasal cavity, rectal lumen, vaginal lumen and gastrointestinal tract.

REFERENCES:
[1] Vimal Kumar Yadav1 ABG, Raj Kumar1, Jaideep S. Yadav1, Brajesh Kumar2: Mucoadhesive Polymers: Means of Improving the Mucoadhesive Properties of Drug Delivery System J. Chem. Pharm. Res., ( 2010, ) 2(5):418-432
[2] Girish K Jania DPS, *, Vipul D Prajapatia, Vineet C Jainb: Gums and mucilages: versatile excipients for pharmaceutical formulations. asian Journal of Pharmaceutical Sciences (2009) 4(5):309-323.
[3] Dhachinamoorthi D, Chandra Sekhar K B, Sriram N: A REVIEW ON POLYMERS USED IN MUCOADHESIVE DRUG DELIVERY SYSTEM. Int. J. Pharm & Ind. Res (2011) Vol - 01(ssue - 02):122-126
[4]G.S. Asane, mucoadhesive gastro intestinal drug delivery system an overview,vol. 5 issue 6,(2007). http// www.pharmainfo.net.
[5] Squier, C.A.and Wertz, P.W., Structure and Function of the Oral Mucosa and Implications for Drug Delivery, in, M.J. Rathbone, Eds; Oral Mucosal Drug Delivery, (1996),Marcel Dekker, Inc., New York,1-26.
[6] Gandhi, R.E. and Robinson, J.R., Bioadhesion in drug delivery, Ind. J. Pharm. Sci., 50, 1988, 145-152.
[7] Harris, D. and Robinson, J.R., Drug delivery via the mucous membranes of the oral cavity, J. Pharm. Sci., 81, 1992, 1-10. (1992).
[8] Wertz, P.W. and Squier, C.A., Cellular and molecular basis of barrier function in oral epithelium, Crit. Rev. Ther. Drug Carr. Sys, 8, 1991, 237-269.
[9] Squier, C.A., Cox, P., and Wertz, P.W., Lipid content and water permeability of skin and oral mucosa, The J. Invest. Dermat, 96, 1991,123-126.
[10] Zhang, J., Niu, S., Ebert, C., and Stanley, T.H., An in vivo dog model for studying recovery kinetics of the buccal mucosa permeation barrier after exposure to permeation enhancers: apparent evidence of effective enhancement without tissue damage, Int. J. Pharm.,101, 1994, 15-22.
[11]Squier, C.A.and Wertz, P.W., Structure and Function of the Oral Mucosa and Implications for Drug Delivery, in, M.J. Rathbone, Eds; Oral Mucosal Drug Delivery, (1996 platforms for controlled drug delivery, Eur. J. Pharm. Biopharm,71,2009,505-518.
[12]Chowdary K.P., Srinivas L.M., Mucoadhesive drug delivery systems: A review of current status, Indian Drugs, 2000,37(9), 400-406.
[13]Gandhi R.B., Robinson J.R., Bioadhesion in drug delivery. Ind. J. Pharm. Sci., 1988,50(3), 145-152.
[14] Yang X, Robinson JR. In : Okano T, ed. Biorelated functional polymers and gels : controlled release and applications in biomedical engineering, San Diego: Academic Press, 1998, 135.
[15] Chen J.L., Cyr. G.N., Composition producing adhesion through hydration, In mainly R.S., ed., Adhesion in biological system. New York; Academic Press, 163-181.
[16] Ch’ng H.S., Park H., Kelly P., Robinson J.R.,Bioadhesive polymers as platform for oral controlled drug delivery., II: Synthesis and evaluation of some swelling water insoluble bioadhesive polymers Ind. J. Pharm. Sci., 1988,50(2), 175-182.

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