Roge A B e.t al. / JPBMS, 2011, 5 (25)

Available online at www.jpbms.info ISSN NO- 2230 - 7885 Review Article

JPBMS

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

Bioadhesive Polymer: Review A B Roge*, S N Firke, S B Gaikwad, V N Gunjkar, Dr. S M Vadvalkar Pharmaceutical Chemistry Department, Nanded Pharmacy College, Shyam Nagar, Nanded

Abstract: Bioadhesion is the relatively new and emerging concept in drug delivery, Bioadhesion keeps the delivery system adhering to the mucus membrane. Transmucosal drug delivery systems show various merits over conventional drug delivery systems. Bioadhesive polymers facilitate the bioadhesion by their specific properties. In transmucosal drug delivery system, bioadhesive polymer plays major role along with active ingredients. Bioadhesive polymers that adhere to the mucin epithelial surface are effective and lead to significant improvement in drug delivery system. Improvements are also expected for other mucus-covered sites of drug administration. Bioadhesive polymers find application in the eye, nose, and vaginal cavity as well as in the GI tract, including the buccal cavity and rectum. This review focus on Bioadhesion, Important Factors of Bioadhesion, Ideal Characteristics, Classification, Description and Application of bioadhesive polymer.

Keywords : Bioadhesion, Mucin, Rectum, Transmucosal drug delivery systems,

Introduction: Muco/bioadhesion: Bioadhesion is the phenomenon between two materials, 4.Formation of secondary chemical bonds between the which are held together for extended periods of time by polymer chains and mucin molecules. interfacial forces [1]. It is generally referred as bioadhesion when interaction occurs between polymer and epithelial Important factors of mucoadhesion: surface. High molecular weight (up to 100,000) , High viscosity (up Mucoadhesion when occurs with the mucus layer covering to an optimum), Long chain polymers, Optimum a tissue. Generally bioadhesion is deeper than the concentration of polymeric adhesive, Flexibility of mucoadhesion. However, these two terms seem to be used polymer chain, Spatial confirmation, Optimum cross- interchangeably. It is interesting that the interaction linked density of polymer, Charge and degree of ionization between the layers adsorbed from whole saliva resembles of polymer (anion >cation the one previously reported between layers of adsorbed >unionized), Optimum medium pH, Optimum hydration of gastric mucins, which points to a strong contribution to the polymer, High applied strength and duration of its the interaction of high molecular weight glycoprotein. application and High initial contact time, are some basic properties which a polymer must have to show a good Steps involved in the process of mucoadhesive profile [2]. Besides the above factors, some physiological factors, like bio/mucoadhesion: mucin turnover and disease status also affect the 1.Spreading, wetting, swelling and dissolution of mucoadhesion. The mucin turnover is expected to limit the bio/mucoadhesive polymer at the interface, initiates residence time of the mucoadhesives on the mucus layer. intimate molecular contact at the interface between the No matter, how high the mucoadhesive strength, polymer and the epithelial/mucus layer. mucoadhesives are detached from the surface due to 2.Interdiffusion and interpenetration between the chains mucin turnover. of the adhesive polymer and the mucus/epithelial surface The physiochemical properties of the mucus are known to resulting physical cross links or mechanical interlocking. change during diseases conditions such as common cold, 3.Adsorption: The orientation of the polymers at the gastric ulcers, ulcerative colitis, cystic fibrosis, bacterial interface so that adhesive bonding across the interface is and fungal infections of the female reproductive tract and possible. inflammatory conditions of the eye, thereby changing the degree of mucoadhesion. *Corresponding Author A B Roge* Pharmaceutical Chemistry Department, Buccal adhesive polymers: Nanded Pharmacy College, Polymer is a generic term used to describe a very long Shyam Nagar, Nanded molecule consisting of structural units and repeating units Mob. No. 09561221340 connected by covalent chemical bonds. The term is Fax. No. 254445 derived from the Greek words: polys meaning many, and E-mail: [email protected] meros meaning parts [3]. The key feature that distinguishes polymers from other molecules is the repetition of many 1 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 05, Issue 05 Roge A B e.t al. / JPBMS, 2011, 5 (25) identical, similar, or complementary molecular subunits in Ideal characteristics [5] these chains. These subunits, the monomers, are small
Polymer and its degradation products should be non- molecules of low to moderate molecular weight, and are toxic,non-irritant and free from leachable impurities. linked to each other during a chemical reaction called
It Should have good spreadability, wetting, swelling polymerization. Instead of being identical, similar and solubility and biodegradability properties. monomers can have varying chemical substituents. The
pH should be biocompatible and should possess good differences between monomers can affect properties such viscoelastic properties. as solubility, flexibility, and strength. The term buccal
It should adhere quickly to buccal mucosa and should adhesive polymer covers a large, diverse group of possess sufficient mechanical strength. molecules, including substances from natural origin to
It should possess peel, tensile and shear strengths at biodegradable grafted copolymers and thiolated polymers. the bioadhesive range. Bioadhesive formulations use polymers as the adhesive
Polymer must be easily available and its cost should component. These formulations are often water soluble not be high. and when in a dry form attract water from the biological
It should show bioadhesive properties in both dry and surface and this water transfer leads to a strong liquid state. interaction. These polymers also form viscous liquids
It should demonstrate local enzyme inhibition and when hydrated with water that increases their retention penetration enhancement properties. time over mucosal surfaces and may lead to adhesive
It should demonstrate acceptable shelf life. interactions. Bioadhesive polymers should possess certain
It should have optimum molecular weight. physicochemical features including hydrophilicity,
It should possess adhesively active groups. numerous hydrogen bond-forming groups, flexibility for
It should have required spatial conformation. interpenetration with mucus and epithelial tissue, and
It Should be sufficiently cross-linked but not to the visco-elastic properties [ 4 ]. degree of suppression of bond forming groups.
It should not aid in development of secondary infections such as dental caries. Classification [6] Mucoadhesive polymers in buccal delivery: Criteria Categories Examples Source Semi-natural/natural Agarose, chitosan, gelatin Hyaluronic acid Various gums (guar, hakea, xanthan, gellan, carragenan, pectin, and sodium alginate. Synthetic Cellulose derivatives [CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC, methylhydroxyethylcellulose] Poly(acrylic acid)-based polymers [CP, PC, PAA, polyacrylates, poly(methylvinylether-co- methacrylic acid), poly(2-hydroxyethyl methacrylate), poly(acrylic acid-co- ethylhexylacrylate), poly(methacrylate), poly(alkylcyanoacrylate), poly(isohexylcyanoacrylate), poly(isobutylcyanoacrylate), copolymer of acrylic acid and PEG] Others Poly(N-2-hydroxypropyl methacrylamide) (PHPMAm), polyoxyethylene, PVA, PVP, thiolated polymers Aqueous solubility Water-soluble CP, HEC, HPC (waterb38 8C), HPMC (cold water), PAA, sodium CMC, sodium alginate Water-insoluble Chitosan (soluble in dilute aqueous acids), EC,PC Charge Cationic Aminodextran, chitosan, dimethyl aminoethyl (DEAE)-dextran, trimethylated chitosan Anionic Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, sodium CMC, xanthan gum Non-ionic Hydroxyethyl starch, HPC, poly (ethylene oxide), PVA, PVP, scleroglucan Potential bioadhesive Covalent Cyanoacrylate forces Hydrogen bond Acrylates [hydroxylated methacrylate, poly (methacrylic acid)], CP, PC, PVA Electrostatic interaction Chitosan

2 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 05, Issue 05 Roge A B e.t al. / JPBMS, 2011, 5 (25) Bioadhesive polymers [5] salts will salt out HEC at lower concentrations than Following are mostly used polymer monovalent salts. Shows good viscosity stability over the Polycarbophil (polycyclic acid cross linked pH 2 to pH 12 ranges. Used as suspending or viscosity builder.Binder, film former. with divinyl glycol) Mw is 2.2×105. Viscosity is 2000–22,500 cps (1% aq. soln.). Insoluble in water, but swell to varying degrees in Xanthan gum common organic solvents, strong mineral acids, and Xanthan gum is an anionic polysaccharide derived from bases.it is synthesized by lightly crosslinking of 0.5–1% the fermentation the plant bacteria Xanthamonas w/w divinyl glycol. Swellable depending on pH and ionic campestrisIt is soluble in hot or cold water and gives strength. Swelling increases as pH increases. At pH 1–3, visually hazy, neutral pH solutions.It will dissolve in hot absorbs 15–35 ml of water per gram but absorbs 100 ml glycerin. Solutions are typically in the 1500 to 2500 cps per gram at neutral and alkaline pH.Entangle the polymer range at 1%; They are pseudoplastic and especially shear- with mucus on the surface of the tissue. Hydrogen bonding thinning. In the presence of small amounts of salt, between the nonionized carboxylic acid and mucin. solutions shows good viscosity stability at elevated temperatures. Solutions possess excellent yield value. Xanthan gum is more tolerant of electrolytes, acids and Carbopol/carbomer (carboxy polymethylene) bases than most other organic gums. It can, nevertheless, Empirical formula: (C 3H4O2)x (C 3H5–Sucrose) . be gelled or precipitated with certain polyvalent metal Pharmaceutical grades: 934 P, 940 P, 971 P and 974 P. Mw cations under specific circumstances. Solutions show very is1×10 6–4×10 6.Viscosity is 29,400–39,400 cps at 25 °C good viscosity stability over the pH 2 to 12 range and good with 0.5% neutralized aqueous solution. Density is 5 tolerance of watermiscible solvents. It is more compatible g/cm3 in bulk, 1.4 g/cm3 tapped. pH 2.5–3.0. Soluble in with most nonionic and anionic gums, featuring useful water, alcohol, glycerin. It is White, fluffy, acidic, synergism with galactomannans. It is more resistant to hygroscopic powder with a slight characteristic odour. shear, heat, bacterial, enzyme, and UV degradation than Synthesized by cross-linker of allyl sucrose or allyl most gums. pentaerythritol Excellent thickening, emulsifying, suspending, gelling agent. Common component in Guar gum (galactomannan polysaccharide) bioadhesive dosage forms. Gel looses viscosity on Empirical formula: (C 6H12 O6)n consists chiefly of a high exposure to sunlight. Unaffected by temperature molecular weight hydrocolloid polysaccharide composed variations, hydrolysis, oxidation and resistant to bacterial of galactan and mannan units combined through glycosidic growth. It contributes no off-taste and may mask the linkages .It is obtained from the ground endosperms of the undesirable taste of the formulation. Incompatible with seeds of Cyamposis tetyragonolobus (family Phenols, cationic polymers, high concentrations of leguminosae).MW is approx. 220,000. viscosity is 2000– electrolytes and resorcinol. 22500 Cps (1% aqueous solution.).Forms viscous colloidal solution when hydrated in cold water. The optimum rate Hydroxypropylmethyl Cellulose HPMC of hydration is between pH 7.5 and 9.0. It is stable in (cellulose 2-hydroxypropylmethyl ether) solution over a pH range of 1.0–10.5.Prolonged heating Empirical formula: C 8H15 O6–(C 10 H18 O6) –C8H15 O5.Mw is degrades viscosity. Bacteriological stability can be 8.6×104.Viscosity is E15–15 cps, E4M–400 cps and K4M– improved by the addition of mixture of 0.15% methyl 4000 cps (2% aqueous solution.) Soluble in Cold water, paraben or 0.1% benzoic acid. The FDA recognizes guar mixtures of methylene chloride and isopropyl alcohol. gum as a substance added directly to human food and has Insoluble in alcohol, chloroform and ether. Odorless, been affirmed as generally recognized as safe. tasteless, white or creamy white fibrous or granular Incompatible with acetone, tannins, strong acids, and the powder. It is Suspending, viscosity-increasing and film alkalis. Borate ions, if present in the dispersing water, will forming agent. Tablet binder and adhesive ointment prevent hydration of guar. Used as thickener for lotions ingredient E grades are generally suitable as film formers and creams, as tablet binder, and as emulsion stabilizer. while the K grades are used as thickeners. Stable when dry. Solutions are stable at pH 3.0 to 11.0 Incompatible to Hydroxypropyl Guar extreme pH conditions and oxidizing materials. It is non-ionic derivative of guar. Prepared by reacting guar gum with propylene oxide. It is soluble in hot and Hydroxyethyl Cellulose cold water. Gives high viscosity, pseudoplastic solutions It is non-ionic polymer made by swelling cellulose with that show reversible decrease in viscosity at elevated NaOH and treating with ethylene oxide .Available in grades temperatures. Lacks yield value. Compatible with high ranging from2 to 8, 00,000 cps at2%. Light tan or cream to concentration of most salts. Shows good tolerance of white powder, odorless and tasteless. It may contain water miscible solvents. Better compatibility with suitable anticaking agents. pH is 6–8.5 Soluble in hot or minerals than guar gum.Good viscosity stability in the pH cold water and gives a clear, colorless solution. Solutions range of 2 to 13.More resistance to bacterial and are pseudoplastic and show a reversible decrease in enzymatic degradation. viscosity at elevated temperatures. HEC solutions lack yield value. Solutions show only a fair tolerance with Chitosan water miscible solvents (10 to 30% of solution weight). It is a linear polysaccharide composed of randomly Compatible with most water-soluble gums and resins. distributed â-(1-4)-linked D glucosamine (deacetylated Synergistic with CMC and sodium alginate. Susceptible for unit) and N-acetyl-D glucosamine (acetylated unit). bacterial and enzymatic degradation. Polyvalent inorganic

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Prepared from chitin of crabs and lobsters by N Carrageenan: deacetylation with alkali. soluble in dilute acids to produce It is an anionic polysaccharide, extracted from the red a linear polyelectrolyte with a high positive charge density seaweed Chondrus crispus. and forms salts with inorganic and organic acids such as Available in sodium, potassium, magnesium, calcium and glutamic acid, hydrochloric acid, lactic acid, and acetic mixed cation forms. acid. The amino group in chitosan has a pKa value of ~6.5, Three structural types exist: Iota, Kappa, and Lambda, thus, chitosan is positively charged and soluble in acidic to differing in solubility and rheology. The sodium form of all neutral solution with a charge density dependent on pH three types is soluble in both cold and hot water.Other and the %DA-value. Mucoadhesives agent due to either cation forms of kappa and Iota are soluble only hot water. secondary chemical bonds such as hydrogen bonds or All forms of lambda are soluble in cold water. All solutions ionic interactions between the positively charged amino are pseudoplastic with some degree of yield value. Certain groups of chitosan and the negatively charged sialic acid ca-Iota solutions are thixotropic. Lambda is non-gelling, residues of mucus glycoproteins or mucins. Possesses cell- Kappa can produce brittle gels; Iota can produce elastic binding activity due to polymer cationic polyelectrolyte gels. All solutions show a reversible decrease in viscosity structure and to the negative charge of the cell surface. at elevated temperatures. Iota and Lambda carrageenan biocompatible and biodegradable. Excellent gel forming have excellent electrolyte tolerance; kappa's being and film forming ability. Widely used in controlled somewhat less. Electrolytes will however decreases delivery systems such as gels, membranes, microspheres. solution viscosity. The best solution stability occurs in the Chitosans enhance the transport of polar drugs across pH 6 to 10. It is compatible with most nonionic and anionic epithelial surfaces. Purified qualities of chitosans are water soluble thickeners. It is strongly synergistic with available for biomedical applications. Chitosan and its locust bean gum and strongly interactive with proteins. derivatives such as trimethylchitosan (where the amino Solutions are susceptible to shear and heat degradation. group has been trimethylated) have been used in non-viral Excellent thermoreversible properties. Used also for gene delivery. Trimethylchitosan, or quaternised chitosan, microencapsulation. has been shown to transfect breast cancer cells. As the degree of trimethylation increases the cytotoxicity of the derivative increases. At approximately 50% trimethylation Poly (hydroxy butyrate), Poly (e- the derivative is the most efficient at gene delivery. caprolactone) and copolymers Oligomeric derivatives (3–6 kDa) are relatively non-toxic Biodegradable, Properties can be changed by chemical and have good gene delivery properties. modification, copolymerization and blending. Used as a matrix for drug delivery systems, cell Sodium Alginate microencapsulation. It consists chiefly of the alginic acid, a polyuronic acid composed of â-D-mannuronic Poly (ortho esters) acid residues. empirical formula: (C 6H7O6Na)n anionic It is Surface eroding polymers. Application in sustained polysaccharide extracted principally from the giant kelp drug delivery and ophthalmology. Macrocystis Pyrifera as alginic acid and neutralized to sodium salt. Purified carbohydrate product extracted from Application brown seaweed by the use of dilute alkali. Occurs as a 1. The microspheres were prepared by a solvent white or buff powder, which is odorless evaporation method using Eudragit RL or and tasteless. pH is 7.2.Viscoity is 20–400 Cps (1% hydroxypropylcellulose as matrix polymers. In aqueous solution.).Soluble in water, forming a viscous, another study, microspheres with a Eudragit RS colloidal solution. Insoluble in other organic solvents and matrix polymer and different mucoadhesive polymers, acids where the pH of the resulting solution and acids i.e.chitosan hydrogen chloride, sodium salt of where the pH of the resulting solution falls below 3.0. Safe carboxymethyl cellulose and polycarbophil were and nonallergenic. Incompatible with acridine derivatives, prepared and found to be useful as platforms for oral crystal violet, phenyl mercuric nitrate and acetate, calcium peptide delivery, with a high capacity of binding to salts, alcohol in concentrations greater than 5%, and heavy bivalent cations, which are essential cofactors for metals. Stabilizer in emulsion, suspending agent, tablet intestinal proteolytic enzymes [7]. Disintegrant, tablet binder. It is also used as haemostatic 2. Alur, H.H.et al., studied the transmucosal sustained agent in surgical dressings Excellent gel formation delivery of Chlopheniramine maleate in rabbits using properties. Biocompatible, Microstructure and viscosity a novel natural mucoadhesive gum (from Hakea), as are dependent on the chemical composition. Used as an excipient in buccal tablets [8]. It was concluded that immobilization matrices for cells and enzymes, controlled the gum not only sustained the release of drug but release of bioactive substances, injectable microcapsules also provided sufficient mucoadhesion to tablets for for treating neurodegenerative and hormone deficiency clinical application. diseases. Lacks yield value. Solutions show fair to good 3. Mucoadhesive Polymers useful in the enhancement of tolerance of water miscible solvents (10–30% of volatile Immunogenicity of Nasally Administered HIV Peptides solvents; 40–70% of glycols). Compatible with most [9]. water-soluble thickeners and resins. Its solutions are more 4. Mucoadhesive polymers helpfull for the improvement resistant to bacterial and enzymatic degradation than of oral absorption of poorely absorbable drug by many other organic thickeners. conjugation with it [10].

4 Journal of Pharmaceutical and Biomedical Sciences (JPBMS), Vol. 05, Issue 05 Roge A B e.t al. / JPBMS, 2011, 5 (25) Conclusion: Transmucosal drug delivery systems, are gaining popularity day by day in the global pharma industry and a 4. Sudhakar Y., Ketousetuo KK., Bandyopadhyay AK., burning area of further research and development. To Buccal bioadhesive drug delivery — A promising summarize, polymers with certain specific characters like option for orally less efficient drugs, Journal of high molecular weight and viscosity, long chain length, Controlled Release, 2006;114: 15–40. flexibility of chain length etc. are needed for the design of 5. Salamat MN., Chittchang LM., Johnston TP.,.Advanced transmucosal drug delivery systems. Large number of Drug Delivery Reviews 2005; 57: 1666–1691 bioadhesive polymers are available naturally or 6. Chein H., Langer R., Oral Particulate Delivery: Status synthetically , there may be great opportunity in the and Future Trends, development of transmucosal drug delivery system .It may Adv. Drug Deliv. Rev., 1998; 34, 339-50. be helpful for application of drug with various routes 7. Alur HH., Pather SI., Mitra AK. and Johnston TP., along with improvement in bioavailability. Transmucosal Sustained –Delivery of Chlorphenira mine Maleate in Rabbits using a Novel, Natural References : Mucoadhesive gum as an Excipient in Buccal Tablets, 1. Longer MA. Robinson JR., Fundamental aspects of Int. J. Pharm., 1999; 88(1): 1-10. bioadhesion, Pharm. Int. 1986; 7 :114–117. 8. Nordone SK., and Staats HF., Enhanced 2. Allur HH. Johnston TP., Mitra AK., Swarbrick J. and Immunogenicity of Nasally Administered HIV Peptides Boylan JC., Encyclopedia of Pharmaceutical Using Mucoadhesives Polymers, Conf Retroviruses Technology, Marcel Dekker; New York:1990. Vol Opportunistic Infect 2002 Feb 24-28; 9: abstract no. 20(3), p.193-218. 291-W 3. http://en.wikipedia.org/wiki/Bioadhesive 9. Matsumoto T., Sakuma S., Yamashita S., Wang Y., Lu Z- Batchelor H. Novel bioadhesive formulations in drug R. Conjugation of poorly absorptive drugs with delivery, The Drug Delivery Companies Report mucoadhesives polymers for the improvement of oral Autumn/Winter, Pharma Ventures Ltd.2004. absorption of drugs, Journal of Controlled Release., 2007;123(3):195-202

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