Bioadhesive/mucoadhesive polymers

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Chapter: Pharmaceutical Drugs and Dosage: Pharmaceutical polymers

A bioadhesive polymer can adhere to a biological substance (usually the surface of an anatomical location) and remain there for an extended period of time, compared with a nonbioadhesive polymer or material.


Bioadhesive/mucoadhesive polymers

A bioadhesive polymer can adhere to a biological substance (usually the surface of an anatomical location) and remain there for an extended period of time, compared with a nonbioadhesive polymer or material. When the adhering surface or the biological substance is a mucous membrane, then the bioadhesive polymer is referred to as a mucoadhesive polymer. All drug delivery systems come in physical contact with an anatomical location of the body. For drugs that are systemically absorbed, the drug passes through that anatomical location into the systemic circulation. Such an anatomical location has been called the site of drug absorption. The duration of time for which a drug delivery system remains in contact with the site of absorp-tion is termed residence time. The rate of drug absorption combined with the residence time of the drug delivery system at the site of drug absorp-tion determines the total amount of drug absorbed. Thus, increasing the residence time of the drug delivery system at the site of drug absorption, through the use of bioadhesive or mucoadhesive polymers, can increase the bioavailability of a drug.

Physiological processes usually limit the residence time of a drug deliv-ery system. For example, bronchiolar cilia and mucosal clearance limit the duration of contact of a foreign material with the bronchiolar tissue due to the ciliary motion and the mucosal clearance rate. Similarly, duration of time for which a drug stays in the gastric compartment is a function of the gastric emptying time.

The residence time of a drug at the site of drug absorption can be increased by the following actions:

·           Altering the physiological processes governing the normal residence time, for example, by slowing down normal mucosal clearance rate/ ciliary motion for bronchiolar drug delivery and increasing the gastric emptying time for gastric drug delivery.

·           Introducing another rate-limiting process that would govern the resi-dence time, for example, by using a gastroretentive drug delivery sys-tem that has lower density and remains in the stomach for a prolonged period of time or by incorporating a bioadhesive or a mucoadhesive polymer in the drug delivery system.

The mucus is a highly viscous aqueous fluid that serves to protect the epithelial cell lining of various organs and organ systems such as respiratory, GI, urogenital, visual, and auditory pathways. The muco-sal fluid, secreted by the cells in the mucosal membranes, is typically rich in glycoproteins and may contain other ingredients such as immu-noglobulins and inorganic salts. Glycoproteins are natural hydrophilic polymers that consist of a protein or polypeptide backbone with cova-lently attached oligosaccharide (i.e., glycan) side chains. This composi-tion of the mucus indicates its high hydrophilicity and polymeric nature. Accordingly, the polymeric materials that have strong hydrogen-bonding groups display mucoadhesive properties. In addition, linear long chains in high-molecular-weight polymers tend to entangle in the glycoproteins, enhancing mucoadhesion. Common hydrogen-bonding groups in poly-mers include hydroxyl, carboxyl, amines, and sulfates. Polymers that exhibit such functional groups, such as several polyacrylic acid and cel-lulose derivatives, are bioadhesive in nature. Examples of polyacrylic acid-based polymers are carbopol, polycarbophil, polyacrylic acid, poly-acrylate, poly(methylvinylether-co-methacrylic acid), poly(2-hydroxyethyl methacrylate), and poly(methacrylate). Cellulose derivatives are exem-plified by CMC, hydroxyethyl cellulose (HEC), HPC, methyl cellulose (MC), and methyl hydroxyethyl cellulose. Some other bioadhesive poly-mers include chitosan, gums, PVP, and PVA.

Advantages of mucoadhesive drug delivery systems

Mucoadhesive drug delivery systems can be utilized for both local and sys-temic drug delivery applications. In the case of local drug delivery, such as vaginal drug delivery, the use of mucoadhesive polymer in the drug delivery system can lead to higher residence time and prolonged duration of local action of the medication. In the case of systemic drug delivery, such as oral administration into the GI tract, localization of the drug delivery system to a particular site (e.g., the site that has a high rate of drug permeability) can lead to (a) more intimate contact between the dosage form and the site of drug absorption, which can increase local drug concentration and the rate of drug absorption or flux and/or (b) higher residence time at the site of drug absorption, leading to an increase in the total amount of drug absorbed (bioavailability).

Mechanism of mucoadhesion

Mucoadhesive polymers interact with a mucosal surface in two stages: (i) contact and (ii) consolidation. The first contact of the mucoadhesive polymer with the mucosal surface leads to surface adhesion due to mul-tiple favorable hydrogen-bond and electrostatic interactions and polymer expansion due to water uptake and plasticization of the drug delivery system. The polymer and the drug delivery system expand and spread on the mucosal surface. The subsequent strong bonding (adhesion) between the polymer and the mucus is a function of polymer chain dif-fusion, hydration and plasticization, and interlocking bond formation. Attractive interactions between the hydrophilic mucoadhesive polymer and the hydrophilic polymeric glycoproteins in the mucus lead to mutual entanglement and interpenetration of the polymeric chains. This facili-tates the formation of more and deeper electrostatic and hydrogen-bond interactions, which promote bioadhesion or mucoadhesion. Thus, muco-adhesion is facilitated by the presence of hydrogen-bond-forming groups in the polymeric chain, flexibility of the polymer chains, and the sur-face activity of the drug delivery system. Mechanical forces at the site of adhesion can help in deeper penetration and mechanical interaction of the polymers.

Quantitation of mucoadhesion

The strength of mucoadhesion, Sm, is the force, F, required to separate two surfaces after adhesion has been established, per unit surface area (A). Thus,

Sm = F/A

The Sm can be calculated in vitro on the isolated mucus immobilized on an artificial surface or ex vivo, using a biological surface, such as an isolated intestinal lumen. In vivo assessment of bioadhesion is usually done by mea-suring the residence time of the dosage form at the site of bioadhesion by an imaging technique.

Sites of application

Mucoadhesive drug delivery systems can be used to deliver a drug to and/or through several anatomical sites in the human physiology, including oral cavity, vagina, nasal cavity, skin (transdermal), conjunctiva of the eye, and the GI tract.

Buccal drug delivery systems seek to deliver drug locally into the oral cavity for local treatment of oral lesions. When used to deliver a drug to the systemic circulation, such as by sublingual administration, bypassing the hepatic first-pass metabolism can contribute to higher bioavailability. Similarly, drug delivery to the nasal mucosa and the vaginal tissue is uti-lized for local drug action or rapid drug absorption in the systemic circula-tion, bypassing the hepatic first-pass metabolism.

Ocular drug delivery using mucoadhesive polymers seeks to address the problem of excessive drainage of the drug via the lachrymal glands before adequate absorption can take place. Prolonged retention of the drug on the cornea reduces precorneal drainage loss of the drug and increases the duration of drug absorption, thus improving ocular bioavailability. Mucoadhesive polymers adhere to the mucin coat covering the conjunctiva and the corneal surface of the eye. Ocular mucoadhesion markedly pro-longs the residence time of a drug in the conjunctival sac, since clearance of a mucoadhesive dosage form is controlled by the much slower rate of mucus turnover rather than the tear turnover rate.

Oral mucoadhesive drug delivery systems have been utilized to effect adhe-sion of particulate insoluble drugs to the GI mucosal surface. Incorporation of mucoadhesive polymers, such as chitosan, poly(acrylic acid), alginate, poly(methacrylic acid), and sodium carboxymethyl cellulose, into the oral solid drug delivery systems can increase the residence time of the drug and adhesion of particulate drug to the mucosal surface, leading to higher local concentration at the site of drug absorption.

Dosage forms

Mucoadhesive dosage forms include tablets, granules, films, patches, solu-tions, gels, and ointments. The selection of dosage form depends on the route of drug administration as well as the desired characteristics of the drug delivery system. For example, while tablet and granules are suitable for administration through the oral route, solutions are more suitable for ocular and nasal drug delivery, patches for transdermal drug delivery, films for buccal drug delivery, and gels and ointments for vaginal drug delivery.

Transdermal patches

Transdermal patches deliver drugs through the skin. Percutaneous absorp-tion of a drug generally results from direct penetration of the drug through the stratum corneum, deeper epidermal tissues, and the dermis. When the drug reaches the vascularized dermal layer, it becomes available for absorp-tion into the general circulation.

Among the factors influencing percutaneous absorption are the physico-chemical properties of the drug, including its molecular weight, solubility, partition coefficient, nature of vehicle, and condition of the skin. Chemical permeation enhancers, iontophoresis, or both are often used to enhance the percutaneous absorption of a drug.

In general, patches are composed of three key compartments: a pro-tective seal that forms the external surface and protects it from dam-age, a compartment that holds the medication itself and has an adhesive backing to hold the entire patch on the skin surface, and a release liner that protects the adhesive layer during storage and is removed just before application.

Most patches belong to one of the two general types—the reservoir system and the matrix system. The reservoir system incorporates the drug in a compartment of the patch, which is separated from the adhe-sion surface. Drug transport from the patch to the skin in channelized and controlled through a rate-limiting surface layer. The matrix system, on the other hand, incorporates the drug uniformly across the patch in a polymer matrix. Diffusion of the drug through the polymer matrix and the bioadhesive properties of the polymer determine the rate of drug absorption.

Marketed transdermal patches are exemplified by Estraderm® (estradiol), Testoderm® (testosterone), Alora® (estradiol), Androderm® (testosterone), and Transderm-Scop® (scopolamine). Transderm® relies on rate-limiting polymeric membranes to control drug release. Nicoderm® is a nicotine patch, which releases nicotine over 16 h, continuously suppressing the smoker’s craving for a cigarette.

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