Polymers Used in Mucoadhesive Drug Delivery:

Cellulose and Its Derivatives:

Cellulose is thought to be the most abundant organic compound on the planet. It's a linearly connected polysaccharide made up of 3000–14,000 glucose molecules.⁵ In water and most organic solvents, pure and unaltered cellulose is insoluble. The hydroxyl groups of the primary backbone are esterified or etherified to promote solubility and swelling characteristics. Semisynthetic cellulose derivatives are a broad and diverse collection of chemicals with a wide range of properties. In terms of polarity, water solubility, and swelling properties, as well as potential pharmacological and biological applications.⁶ Microcrystalline cellulose (MCC), methylcellulose (MC), ethylcellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), and sodium carboxymethyl cellulose are the most prevalent cellulose derivatives (Na-CMC).⁷ Depending on how they interact with water, celluloses can be utilised as disintegrants, matrix-forming components, or coating agents to alter drug release. They can also be utilised as thickeners and stabilisers in liquid and semisolid dosage forms due to their swelling capabilities. Semisynthetic celluloses are frequently researched as components of vaginal drug delivery systems, especially in gels or viscous liquids, but also in tablets and micro- or nanoparticulate formulations, because to their mucoadhesive qualities.⁸

Pectin:

Pectin is a broad and very complex group of oligosaccharides and polysaccharides found in large quantities in plant cell walls. The esterified D-galacturonic chain is the major component.⁹ The acid groups in natural pectin are esterified with methoxy residues. Free hydroxyl groups can also be acetylated, and the galacturonic acid main chain can be replaced with rhamnose groups.¹⁰ It is noteworthy that this model may vary significantly in terms of particular domains, e.g., chain length, sugar composition, and the degree of methylation or acetylation Pectin's acid resistance is one of its most essential properties, and it's very useful in oral medication delivery with a modified release in the lower gastrointestinal tract. The methylation degree of the polymer's major linear structural feature has a significant impact on the gelation mechanism. When there is a large concentration of methoxyl groups, a gel forms at pH 3.5, usually in the presence of another material (e.g., sucrose), which reduces the activity of water molecules.¹¹ Pectin’s are used as mucoadhesive components in diverse formulations in vaginal medication delivery studies. Their pH dependent behavior can also strongly influence the drug release mechanism.¹²

Starch:

Starch is one of the most abundant plant polysaccharides and the main carbohydrate in the human diet.¹³ It is made up of two compounds: linear amylose (25%) and branched amylopectin (75%), both of which are made up of multiple -D-glucose units. The structural elements in the first are linked by -1,4 bonds, whereas the structural elements in the second are linked by -1,4, -1,3, and -1,6 links.^14,15 Starch and its derivatives are mostly researched as components of tablets, micro- or nanoparticles, gels, and other vaginal drug delivery systems.^16,17

Alginates:

Alginates are anionic polysaccharides that occur naturally in brown seaweeds and are biocompatible and biodegradable (Phaeophyceae).¹⁸ Alginic acid is a copolymer made up of D-mannuronic and L-guluronic acids that are structured in blocks separated by random sequences of the same units. The compound's specific composition is determined by its source of origin. Due to their hydrophilic nature, alginates have a high water binding capability.¹⁹ The qualities of the resulting gel are mostly determined by the polymer's composition. The gel strength of substances with a higher guluronic acid concentration is higher.²⁰ Alginates can be applied as thickeners and stabilizers in liquid and semisolid pharmaceutical formulations. They are also investigated as binders and hydrophilic matrix-forming agents in prolonged-release solid dosage forms.²¹

Chitosan:

Chitosan is made by deacetylating chitin, which is a natural component of many invertebrate exoskeletons. The reaction is normally carried out in the presence of concentrated NaOH, but it can also be carried out with the help of a chitin deacetylase.²²^,²³ Chitosan is a group of linear copolymers consisting of glucosamine and N-acetyl glucosamine connected with -1,4 bonds.²⁴ In terms of solubility, chitosan is very different from its substrate. Due to the presence of free amine groups in the molecule, chitosan is soluble in acidic solutions. The majority of amine groups in chitin are acetylated, rendering the polymer essentially insoluble in an acidic to slightly alkaline environment.²⁵ Because of its interesting properties, chitosan is extensively investigated both as an active ingredient and as an excipient.²⁶ Because it is non-toxic, biodegradable, and biocompatible, it can be used safely in pharmaceutical formulations.²⁷^,²⁸ Chitosan, when taken orally, can effectively lower serum cholesterol levels, making it useful for hypercholesterolemia treatment and arteriosclerosis prevention. The polymer also has good mucoadhesive characteristics.²⁹ Another intriguing attribute of chitosan, which is connected to its mucoadhesive properties, is its ability to speed up wound healing. This feature is linked to chitosan's slow depolymerization. The products of this interaction increase the structure of new collagen fibres and boost hyaluronic acid synthesis.³⁰

Xanthan Gum:

Xanthan gum is a microbial polysaccharide obtained in a fermentation process of cabbage plant bacterium Xanthomonas campestris. The FDA approved the biopolymer as a food ingredient in the late 1960s, after it had been manufactured industrially since 1964. It's used in a variety of industries, including food, cosmetics, and pharmaceuticals. It can be employed as a thickening ingredient in topical medicinal dosage forms and cosmetics, as well as a structure-enhancing addition in food products, due to its outstanding swelling characteristics and shearthinning behaviour.³¹ the most important structural constituent of the xanthan molecule is a backbone made up of glucose moieties linked by -1, 4-glycosidic linkages, which are also seen in cellulose molecules. The cellulose backbone is coupled to two mannose and one glucuronic acid moiety side chains. The side chains are joined to the primary structural unit by -1, 3-glycosidic linkages, and some of them have pyruvic acid residues at the end. Furthermore, acetic acid can be used to esterify the hydroxyl group in position 6 of one or both mannose moieties. The temperature affects the conformation of xanthan molecules.³²

Gelatin:

Gelatin is a natural biopolymer obtained from animal cartilage and bones as a result of collagen hydrolysis. The properties of the obtained product depend on the technological process employed to pretreat the animal material before collagen extraction. In alkaline conditions, amide groups of asparagine and glutamine are transformed into free carboxylic groups, while in the acidic process, these groups remain intact. As a result, products revealing different electrical properties are obtained. Gelatin produced at alkaline conditions contains more acidic groups that may undergo an ionization process in solution. When compared to the product generated in acidic conditions, negative charge localized along the polymer chain lowers the isoelectric point.^33,27 It is also widely used as a stabilizer in live attenuated viral vaccines; however, allergic reactions related to gelatin presence have been reported.³⁴

Vaginal Mucoadhesive Polymers:

Chitosan:

Chitosan is a natural polycationic copolymer made up of glucosamine and N-acetylglucosamine units, unlike poly (acrylates). Deacetylation of chitin generated from crustacean exoskeletons is the most common method of obtaining it. Because it is biocompatible, biodegradable, and non-toxic, chitosan offers valuable features as a biomaterial.³⁵ It is an appealing biopolymer for various biological and pharmacological applications due to its cationic nature and possible functional groups. Chitosan has been utilised in powders, pills, emulsions, and gels as a medicinal excipient. A controlled release of integrated medications can also be ensured.^36,37 At physiological pHs, it shows promise as a bioadhesive material. Hydrogen bonding can occur due to the presence of OH and NH2 groups in this polymer. These properties are considered essential for mucoadhesion.³⁸ Furthermore, chitosan is well-suited to recurrent adhesion since it did not become inactivated after the initial contact and there was no reduction in mucoadhesion. The persistent release behaviour of chitosan at a concentration of 50% of tablet weight is a general observation.³⁹ Polymer blends can combine the benefits of various polymers to provide a higher-quality dosage form. Furthermore, chitosan's polyionic interaction with anionic polymers will allow for a significant drop in chitosan concentration in tablets.⁴⁰ Because chitosan has antibacterial properties, the chitosan-TGA conjugate would be suitable as a matrix for cationic antimycotics used to treat mycotic infections in the vaginal area. Infection with Candida albicans is a common microbiological issue in the vulvovaginal tract.⁴¹ Approximately 75% of women will have a vaginal infection with a Candida strain at some point in their lives, with 40–50% of them suffering a second infection and a tiny number developing a chronic course.⁴² The cohesive characteristics of the polymeric carrier matrix were much improved due to the immobilisation of thiol groups, preventing an unpleasant vaginal secretion of degraded polymer fragments. The regulated release of clotrimazole was demonstrated to be dependent on the amount of covalently linked thiol groups. Tablets containing chitosan-TGA conjugates, in combination with the controlled release of clotrimazole, have increased bioadhesive and cohesive qualities, making them suitable carriers for vaginal dosage forms in the treatment of genitourinary infections. In addition, chitosan-4-thio-butyl amidin-conjugates (chitosan-TBA) may be beneficial for mucoadhesive vaginal delivery systems.⁴³

Cellulose derivatives:

Many research have compared cellulose derivatives to poly (acrylates) and concluded that they are almost equal. El-Kamel et al. investigated the dissolving rates of metronidazole vaginal tablets made from sodium carboxy methyl cellulose (NaCMC), methyl cellulose (MC), hydroxyl propyl methyl cellulose (HPMC) and HPMC/NaCMC mixes, as well as Carbopol 934, in various ratios. Swelling studies indicated an increase in swelling and mucoadhesion and gave the same rank order. Adhesion behavior of tablets prepared from NaCMC/HPMC (2:1) was intermediate between that of NaCMC and HPMC tablets. Generally, the presence of drug increased the adhesiveness of the formulation.⁴⁴ Bioadhesive polymers (polycarbophil, HPMC, and sodium hyaluronate) were incorporated with semisynthetic solid triglyceride pessaries to create new dosage forms for the antimycotic clotrimazole.

These polymers keep the delivery systems in the vaginal tract for a few days without causing any toxicity or significant physiological changes, extending the drug's stay on the vaginal mucosa. The inclusion of the polymers had no effect on the features of the pessaries, according to the technical controls. An increase in pessary adhesion with increased concentration of mucoadhesive polymers, on the other hand, might be assessed in an in vitro test. The mucoadhesive changed the medication dispersion along the simulated application site, affecting drug persistence. Finally, the creation of novel formulations revealed good technical and adhesion qualities, as well as sufficient dosage form adhesive power on the target site. Polycarbophil, at its maximum concentration, demonstrated the best performance among the bioadhesive polymers used in the test.⁴⁵

Hyaluronic acid and derivatives:

For systemic distribution of calcitonin via the vaginal channel, hyaluronic acid microspheres as vaginal drug delivery devices are recommended.⁴⁶ A further development of such microspheres were based on hyaluronan esters. They've been tested as a novel delivery mechanism for salmon calcitonin vaginal administration. In rats, acute vaginal treatment of hyaluronan-microspheres resulted in severe hypocalcaemia.⁴⁷ Furthermore, in a rat model of osteoporosis, daily dosing for two months prevented bone loss.⁴⁸ Hyaluronic acid can be used in conjunction with Doederlein's bacillus to help regulate bacterial flora. The use of hyaluronic acid in formulations may result in greater Doederlein's bacillus retention and efficacy.⁴⁹

Pectin and Traganth:

A fungicidal/fungistatic medicine, a surfactant as a penetrating agent, and/or a bioadhesive gum such as tragacanth, pectin, dextran, and xanthan to hold the drug to the vaginal wall are all included in one invention. Ketokonazole, pectin, nonyl phenol-9, and polyethylene glycol were thus combined in a solution.⁵⁰ The bioadhesive tablet consisting of a mixture of carbopol 934 and pectin 2:1 had the highest bioadhesive strength, the highest swelling volume, and the lowest pH reduction among sixteen distinct formulations based on bioadhesive polymers for vaginal administration.⁵¹

Poly (ethylene glycol):

The use of poly (ethylene glycol) provides a variety of options for controlled drug release based on physical properties such as molecular weight (3000–8000), specific hydrates, and changing diffusion coefficients of crystalline/rubbery hydrogels, all of which influence drug diffusion through the water swollen matrix and across the polymer bounty. The advantage of starting with a dry, drug impregnated polymer is to obtain the desirable zero order release rate. Drugs have been classified into five groups showing different release profiles. The effects of design and loading on the release profile are described presenting the first clinical results of morphine loaded hydrogel suppositories. A further development for such a PGE2 containing system was a cross linked polymer from PEG 8490, 1, 2, 6-hexanetriol and dicyclo hexyl methane 4,4V-diisocyanate. Vaginal pessaries containing trace levels of radioactive PGE2 were developed for in vitro release tests. The diffusion within the gel and across the gel/water barrier was influenced by a variety of factors including PEG molecular weight, hydrogel preparation, crystallinity, degree of crosslinking, device shape, and drug solubility. Radioimmunoassay showed that PGE2 was stable for >12 months at 4℃ when incorporated into the pessaries.⁵³

Sulfated polysaccharides:

Poly anionic compounds have been shown to impede the reproduction of herpes simplex virus (HSV) and other viruses for almost four decades. However, these findings drew little attention because the antiviral activity of the drugs was thought to be mostly nonspecific. Heparin and other sulfated polysaccharides were discovered to be powerful and selective inhibitors of HIV-1 proliferation in cell culture shortly after the human immunodeficiency virus (HIV) was identified as the causal agent of the acquired immune deficiency syndrome (AIDS) in 1984. Since 1988, the sulfated polysaccharides' action spectrum has been revealed to include viruses that develop as opportunistic infections (e.g., herpes simplex virus (HSV) and cytomegalovirus (CMV) in immune compromised (e.g., AIDS) patients.⁵⁴

Starch:

Insulin was given to sheep vaginally as a lyophilized powder within bioadhesive starch microspheres and as an aqueous solution.⁵⁵ In the sheep, the effect of lysophosphatidylcholine (LPC) on vaginal absorption of insulin from both formulations was investigated. The addition of LPC resulted in a quick rise in plasma insulin and a dramatic fall in plasma glucose levels, despite the fact that vaginal absorption of insulin from insulin solution was negligible. The peptide from the second solution had a 13 percent absolute bioavailability. When compared to insulin solution alone, the hypoglycemic response to vaginally delivered insulin was improved with the microsphere delivery technique, which was further augmented by LPC. The estrous cycle appeared to alter vaginal absorption of insulin from each formulation, and changes in vaginal histology were assumed to be related.⁵⁵ Additional absorption enhancers were used with the drug to increase bioavailability.⁵⁶

Gelatin:

From a historical perspective, the old gelatine-based vaginal forms can be considered the first mucoadhesive systems. To date, gelatine capsules with various medication loadings and extra mucoadhesive polymers have been proposed.^57,58

Sodium Alginate:

The impact of gel pH and osmolarity on the mass transit and bio diffusion of the spermicide nonoxynol-9 (N-9) in bovine cervical mucus was investigated. Alginate crosslinking with calcium chloride containing 3% N-9 was used to create delivery gels with a pH range of 3.4–5.9 and a variable osmolarity. The Double Ended Test was utilised to evaluate bio diffusion, while a UV spectrophotometric approach was employed to estimate mass transfer parameters (diffusion coefficients and total drug loading) (the distance into mucus at which sperm are killed).⁵⁹ The pH of the delivery gel had a substantial impact on the alginate-N-9 system's spermicidal activity; biodiffusion increased as pH decreased. Both the delivery gel pH and osmolarity were found to influence actual N-9 diffusion into mucus. Mass transfer tended to decrease with decreasing pH at the maximum osmolarity at high N-9 concentrations (near the gel/mucus interface). At low concentrations, mass transport tended to decrease as osmolarity increased, while at the highest osmolarity, mass transport tended to decrease as pH increased.⁵⁴

CONCLUSION:

Mucoadhesive polymers are very promising candidates for systemic and local vaginal drug delivery. There is still ongoing research dealing with mucoadhesive vaginal formulations that are capable of delivering the active agent for an extended period at a predictable rate. Although there are limited number of commercially available mucoadhesive vaginal drug delivery systems, in the near future mucoadhesive vaginal drug delivery systems will gain more significance due to the increase in sexually transmitted diseases such as HIV.

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Received on 23.02.2022 Modified on 17.04.2022

Asian J. Pharm. Tech. 2022; 12(3):251-256.

DOI: 10.52711/2231-5713.2022.00041