INTRODUCTION:

In any pharmaceutical formulation, an excipient is one of the ingredients or inactive substances that help in designing the dosage form and improving physiochemical properties such as solubility, absorption and bioavailability of the dosage form¹. Recently, natural polymers have been used as emerging excipients in mucoadhesive drug delivery systems, which have a wider range of applications than synthetics. Natural polysaccharides are available from various origins, e.g., plant origin, animal origin, algal origin, and microorganism origin. They are non-toxic, hydrophilic, biocompatible and low cost². They are capable of chemical modification of thin structures due to the presence of a number of reactive groups such as carboxyl, hydroxyl, sulphate, and amino functional groups.

It has been reported that the chemical modification of polysaccharides improves the functional properties of native gums in different literatures³. The glycocalyx layer of the endothelium is the region where the bioadhesive polymers interact when they come into direct contact with tissue. They facilitate the prolongation of residence time and improve the therapeutic performance of the drugs. The formation of non-covalent bonds and ionic interactions between the mucus layer and natural polymers has been investigated and can be used to overcome physiological barriers in long-term drug delivery⁴. The structural characteristics, such as high molecular weight, chain flexibility, and surface charge properties, also promote the spreading of mucous. Due to their natural origin, polysaccharides are abundant across the earth. As a result, this review aims to give comprehensive information on various mucoadhesive natural polymers, their applications, roles, and future perspective.

MUCOADHESIVE DRUG DELIVERY SYSTEM:

The major challenge and recent progress in pharmaceutical drug delivery systems is the delivery of macromolecular drugs such as proteins, peptides, and oligonucleotides as potential therapeutic agents due to their extensive pre-systemic metabolism and instability in an acidic environment, resulting in inadequate or erratic absorption and bioavailability. For this reason, protein and peptide drugs have to be administered through parenteral routes⁵. However, these formulations are expensive and have low patient compliance. Over the last two decades, pharmaceutical scientists have developed the mucoadhesive drug delivery system to provide a sufficient amount of drug to the site of the body to promptly achieve the desired concentration⁶ In mucoadhesive, the drugs, along with suitable excipients, are attached to the mucous membrane and undergo a complex phenomenon that includes intimate contact, wetting, swelling, and interpenetration of the carrier or excipients⁷. It provides rapid absorption, resulting in improved bioavailability due to the considerable surface area and high blood flow.

Factors affecting mucoadhesion⁸:

The mucoadhesive strength may be affected by following factors shown in Fig.1:

Fig.1: Various factors affecting mucoadhesion.

Mechanism of mucoadhesion:

The mucoadhesion between the bioadhesive polymer and mucus membrane involves two stages: the contact stage and the consolidation stage^9,10. The contact stage is characterised by intimate contact between polymer and mucus membrane. The bioadhesive materials start wetting due to spreading into the mucus surface, which induces swelling and breaks the molecule due to the presence of hydrophilic functional groups linked with mucin by hydrogen bonding and weak van der waals forces¹¹. In the consolidation stage, after the intimate contact between the bioadhesive polymer and mucus layer is established, the molecules penetrate into the crevice of the tissue due to the interpenetration of the chain and the formation of secondary bonds between molecules and mucin glycoprotein¹². This mechanism is shown in Fig. 2.

Fig. 2. Mucoadhesion involves two stages, 1: Contact stage [An intimate contact (wetting and swelling) occurs between the mucus membrane and polymer], 2: Consolidation stage (formation of bond between polymer and mucin).

Mucous layer:

The mucosal surface is the soft tissue that lines various cavities in the body and internal organs including the gastrointestinal tract, the respiratory tract, the ear, and the eye¹³. This surface is responsible for the formation of an adhesive interface in the presence of mucus. Mucus is a translucent and viscid secretion that is a thin, continued gel blanket adherent to the epithelial layer of the mucosal surface¹⁴. The epithelia may be either single-layered, multilayered, or stratified. Single-layered includes the stomach, small intestine, large intestine, and bronchi, while multilayered includes the oesophagus, vagina, and cornea. The goblet cells line the epithelia, or special exocrine glands that secrete mucus. The thickness of the mucous layer varies from 50 to 450um in humans. Major components of the mucus layer are water (95%), glycoproteins and lipids (0.5–5%), mineral salts (1%), and free proteins (0.5–1%). The glycoproteins present in mucous are high-molecular-weight proteins that consist of oligosaccharide units (8–10 monosaccharides). A glycoprotein called mucin has a single-chain amino acid backbone and branching oligosaccharide chains made of galactose, fructose, and N-acetylglucosamine¹⁵.

NATURAL MUCOADHESIVE POLYMERS:

In recent years, natural-origin mucoadhesive polymers have gained more interest in the pharmaceutical industry due to their wide range of advantages over synthetic ones, as they are chemically inert, non-toxic, low-cost, biocompatible, and abundantly available in the biosphere¹⁶. They played numerous roles such as binders, drug release modifiers, film coatings, viscosity enhancers, disintegrants, emulsifiers, and suspending agents. Polymers are not only used as mucoadhesives but also in the advanced technology development of carrier-based drug delivery, entrapment of drugs in the polymeric matrices for controlled drug delivery and nanoparticle formulations. In the novel drug delivery system, polymers are often used in designing dosage forms, especially for target drug delivery to specific sites in the GIT, e.g., the colon target drug delivery system¹⁷.

Cellulose:

The most prevalent natural polymer in the world is cellulose, which is also known as the sugar of plant cell wall. The French chemist Anselme Payen initially identified it in 1838 after isolating it from plant materials and determining that its chemical formula is (C₆H₁₀O₅)n¹. Cellulose is a crucial structural element in the cell walls of higher plants. Cellulose cannot be digested by humans and is not soluble in water¹⁸. β-D-anhydroglucopyranose is cellulose's fundamental monomer unit. The central group of the C4 and C1 carbon atoms provides acetal functions (β-1, 4-glycosidic bonds) that covalently link these units. These β-1,4-glycosidic connections give cellulose its defense against enzymatic and chemical attacks. This linear structure can be expanded to molecules in cellulose chains of polymer with 1000–1500 β-d-glucose monomer units with large numbers of -OH groups. As a result of the abundant -OH groups present throughout the cellulose chain, molecular hydrogen interactions develop across the polymer chain.

a) Cellulose derivatives:

Cellulose is insoluble in water and organic compounds due to its supramolecular structure and high hydrogen bonding structure; therefore, several strategies for cellulose derivatives have been developed to overcome this limitation.

Table 1: Cellulose derivatives.

b) Applications in mucoadhesive drug delivery system:

Mucoadhesive buccal tablets of eplerenone were prepared by using HPMC (hydroxy propyl methyl cellulose) K100M, xanthan gum and sodium CMC (carboxymethyl cellulose) as natural polymers to decrease the drug release time and excellent mucoadhesive time of dosage form¹⁹. Apomorphine, a medication used to control motor responses in Parkinson's disease, was successfully comprised into the formulation of CMC powder, which demonstrated a sustained nasal release starch-based delivery vehicle²⁰. Lysozyme drug delivery by gelatin-CMC mucoadhesive films²¹. HPMC played a major role in mucoadhesion for the formulation of Losartan potassium with natural polysaccharide (Diospyros melonoxylon roxb seeds) extracted from plants and showed the tablet formulation with controlled drug release and a monolithic matrix system²².

Pectin:

Pectin is a non-starch linear heterogeneous polymer that is taken out from apple pomace or citrus peel. It has carboxyl group-containing linear chains of (1-4)-linked α-D-galacturonic acid residues²³. The establishment of an H-bond with mucin and the electrostatic contact between the molecules of pectin and mucin can both be used to explain pectin's mucoadhesion²⁴. Because pectin contains carboxylic acid groups, H bonds can form. Pectin and mucin both have negative charges. As a result, mucin and pectin are more electrostatically attracted to one another when pectin concentration is increased in an aqueous media. In a study, low molecular weight pectin was found to have better mucoadhesion than high molecular weight pectin. According to the author, low molecular weight pectin has an easier time penetrating the mucin layer and forms intermolecular bonds more effectively than high molecular weight pectin²⁵.

a) Modified pectin:

A proposed explanation of modified pectin is that these modified polysaccharides contain structural components that can bind to and inhibit galectin-3 (GAL3), which is supported by emerging evidence associating modified versions of pectic polysaccharides with anti-cancer activity. The process for creating Modified pectin entails depolymerization with enzymatic modification by β-elimination, which splits and de-esterifies the HG backbone to produce oligomers of polygalacturonic acid and rhamnogalacturonan I²⁶.

b) Applications in mucoadhesive drug delivery system:

Formulation and evaluation a pectin-based mucoadhesive buccal disc with carbenoxolone sodium for the treatment of aphthous ulcers²⁷ Synthesis, characterization, and evaluation of the thiolation of pectin showed it to possess superior mucoadhesion than normal pectin²⁸ Mucoadhesive beads of gellan gum/pectin intended to controlled delivery of drugs²⁹. Mucoadhesive buccal patches based on interpolymer complexes of chitosan–pectin for delivery of carvedilol³⁰ Mucoadhesive delivery of novel pectin–liposome nanocomplexes to improve intestinal absorption of calcitonin³¹.

Chitosan:

One of the most popular polysaccharides for mucoadhesive drug delivery is chitosan, which is also the second-most prevalent natural polymer in the world after cellulose³². Numerous scientific papers have been published based on Chitosan mucoadhesive delivery since the early 1980s. N-deacetylation is a process that converts chitin into chitosan. Chitin is a structural polysaccharide comprised of 2-acetamido-2-deoxy-b-D-glucose monomer units joined by β-(1→4) links. In vitro and in vivo studies on chitosan's potential to interact with mucosal epithelia of mucus membranes have been conducted to check their molecular interactions³³. Three reactive functional groups—the NH2 group, the primary -OH group, and the secondary -OH group—are present in chitosan. Chitosan has high mucoadhesive qualities because these reactive groups enable it to create an H-bond with the mucin glycoprotein.

CONCLUSIONS:

Mucoadhesive drug delivery systems indicate to hold an alternative to conventional and injectable medication due to its prolonged contact at the site of administration, minimal enzymatic activity, patient compliance, and improvement of bioavailability. The production of these drug delivery systems requires the development of suitable polymers that have excellent mucosal adhesion properties and biocompatibility. Natural polymers or polysaccharides that have been isolated from plants, animals, and microbes are readily absorbed by the body due to their structural resemblances, chemical adaptability, and biological performance to human extracellular matrix components. Such polysaccharide-based mucoadhesive drug delivery methods improve the efficiency of the medicine being administered. This review has shown that natural polymers and polysaccharides can be an effective replacement for synthetic ones as novel excipients due to their wide range of advantages, such as being biodegradable, non-toxic, low-cost, and readily accessible in the environment. the formulation of the buccal adhesive can also play a significant role in providing an alternative to vaccination and the administration of macromolecule drugs in the future.

CONFLICT OF INTEREST:

All the authors hereby declare that there are no conflicts of interest.

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Received on 02.06.2023 Modified on 08.10.2023

Research J. Pharm. and Tech 2024; 17(2):915-919.

DOI: 10.52711/0974-360X.2024.00142