Expandable-swellable systems

• A dosage form in the stomach will withstand gastric transit if it is bigger than pyloric sphincter. However the dosage form must be small enough to be swallowed, and must not cause gastric obstruction either singly or by accumulation. These systems may be referred to as the ‘plug-type systems’ since they have a tendency to remain lodged near the pyloric sphincter

• Sustained and controlled drug release may be achieved by selecting a polymer with the proper molecular weight and swelling properties. Upon coming in contact with gastric fluid, the polymer imbibes water and swells. The extensive swelling of these polymers is a result of the presence of physical–chemical crosslinks in the hydrophilic polymer network. These cross-links prevent the dissolution of the polymer and thus maintain the physical integrity of the dosage form.

• A balance between the extent and duration of swelling is maintained by the degree of crosslinking between the polymeric chains. A high degree of crosslinking retards the swelling ability of the system and maintains its physical integrity for a prolonged period (see below figure). On the other hand, a low degree of cross-linking results in extensive swelling followed by the rapid dissolution of the polymer. An optimum amount of cross-linking is required to maintain a balance between swelling and dissolution.

Mucuadhesive Systems

• A more specific term than bioadhesion is mucoadhesion. Most mucosal surfaces such as in the gut or nose are covered by a layer of mucus. Adhesion of a matter to this layer is hence called mucoadhesion. It is known that the surface epithelium of the stomach and intestines retains its integrity throughout the course of its life time, despite it is exposed to a high concentration of HCl and powerful digestive enzymes, such as pepsin. This self-protective mechanism is due to the fact that the specialized goblet cells located in the stomach, duodenum, and transverse colon secret a large amount of mucus that remains closely applied to the surface epithelium. Mucus is composed mainly of water (>95%) and mucin, which are glycoprotein’s of exceptionally high molecular weight (2–14 X106 g/mol).

Mucins are a diverse family of densely glycosylated proteins. Mucin domains within the protein core are rich in threonine, serine and hydroxyproline enabling post-translational O-glycosylation. The highly glycosylated properties of mucins make them resistant to proteolysis and able to hold water, giving them the gel-like properties found in mucosal barriers. Mucins also contain cysteine-rich regions that participate in intermolecular cross-linking and are typically secreted as large aggregates. Furthermore, pendant sialicacid (pKa = 2.6) and sulphate groups located on the glycoprotein molecules result in mucin behaving as an anionic polyelectrolyte at neutral pH.

Mucoadhesive polymers

Mucoadhesive agents are usually polymers containing hydrogen bonding groups that can be used in wet formulations or in dry powders for drug delivery purposes. The mechanisms behind mucoadhesion have not yet been fully elucidated, but a generally accepted theory is that close contact must first be established between the mucoadhesive agent and the mucus, followed by interpenetration of the mucoadhesive polymer and the mucin and finishing with the formation of entanglements and chemical bonds between the macromolecules. In the case of a dry polymer powder, the initial adhesion is most likely achieved by water movement from the mucosa into the formulation, which has also been shown to lead to dehydration and strengthening of the mucus layer. The subsequent formation of van der Waals, hydrogen and, in the case of a positively charged polymer, electrostatic bonds between the mucins and the hydrated polymer promotes prolonged adhesion

An ideal mucoadhesive polymer has the following characteristics:

• The polymer and its degradation products should be nontoxic and should be nonabsorbable from the gastrointestinal tract.

• It should be nonirritant to the mucous membrane.• It should preferably form a strong non-covalent bond with the

mucin epithelial cell surfaces.• It should have many strong hydrogen bonding groups (-OH, -

COOH).• It should have many strong anionic groups.• Sufficient flexibility to penetrate the mucus network • Surface tension characteristics suitable for wetting mucus/

mucosal tissue surface.• High molecular weight.Although an anionic nature is preferable for a goodmucoadhesive, a range of nonionic molecules (e.g.,Cellulose derivatives) and some cationic (e.g.,Chitosan) can be successfully used.

Factors Affecting Mucoadhesion1 .Hydrophilicity

Bioadhesive polymers possess numerous hydrophilic functional groups, such as hydroxyl and carboxyl. These groups allow hydrogen bonding with the substrate, swelling in aqueous media, thereby allowing maximal exposure of potential anchor sites. In addition, swollen polymers have the maximum distance between their chains leading to increased chain flexibility and efficient penetration of the substrate.

2 .Molecular Weight

The interpenetration of polymer molecules is favored by low-molecular-weight polymers, whereas entanglements are favored at higher molecular weights. The optimum molecular weight for the maximum mucoadhesion depends on the type of polymer, with bioadhesive forces increasing with the molecular weight of the polymer up to 100,000. Beyond this level, there is no further gain.

3 .Cross-linking and SwellingCross-link density is inversely proportional to the degree of swelling. The lower the cross-link density, the higher the flexibility and hydration rate; the larger the surface area of the polymer, the better the mucoadhesion. To achieve a high degree of swelling, a lightly cross-linked polymer

is favored .

4 .Spatial ConformationBesides molecular weight or chain length, spatial conformation of a polymer is also important. Despite a high molecular weight of 19,500,000 for dextrans, they have adhesive strength similar to that of polyethylene glycol (PEG), with a molecular weight of 200,000. The helical conformation of dextran may shield many adhesively active groups, primarily responsible for adhesion, unlike PEG polymers, which have a linear conformation.

5 .pHThe pH at the bioadhesive to substrate interface can influence the adhesion of bioadhesives possessing ionizable groups. Many bioadhesives used in drug delivery are polyanions possessing carboxylic acid functionalities. If the local pH is above the pKa of the polymer, it will be largely ionized; if the pH is below the pKa of the polymer, it will be largely unionized. The approximate pKa for the poly(acrylic acid) family of polymers is between 4 and 5. The maximum adhesive strength of these polymers is observed around pH 4–5 and decreases gradually above a pH of 6. A systematic investigation of the mechanisms of mucoadhesion clearly showed that the protonated carboxyl groups, rather than the ionized carboxyl groups, react with mucin molecules, presumably by the simultaneous formation of numerous hydrogen bonds.

5. Concentration of Active Polymer There is an optimum concentration of polymer

corresponding to the best mucoadhesion. In highly concentrated systems, beyond the optimum concentration the adhesive strength drops significantly. In concentrated solutions, the coiled molecules become solvent-poor and the chains available for interpenetration are not numerous. This result seems to be of interest only for more or less liquid mucoadhesive formulations.

Mucuadhesive polymers

Polymers that adhere to biological surfaces can be divided into three broad categories:

1 Polymers that adhere through nonspecific, noncovalent interactions which are primarily electrostatic in nature

2 Polymers possessing hydrophilic functional groups that hydrogen bond with similar groups on biological substrates

3 Polymers that bind to specific receptor sites on the cell or mucus surface

Non-covalent specific linking

Lectins are generally defined as proteins or glycoprotein complexes of nonimmune origin that are able to bind sugars selectively in a noncovalent manner. Lectins are capable of attaching themselves to carbohydrates on the mucus or epithelial cell surface and have been extensively studied, notably for drug-targeting applications. These second-generation bioadhesives not only provide for cellular binding, but also for subsequent endo- and transcytosis.

Transcytosis is the process by which various macromolecules are transported across the interior of a cell. Macromolecules are captured in vesicles on one side of the cell, drawn across the cell, and ejected on the other side. Blood capillaries are a well-known site

for transcytosis as in blood brain barrier .

Covalent specific linkingThiolated polymers, also designated thiomers, are hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone. The presence of thiol groups in the polymer allows the formation of stable covalents bonds with cysteine-rich subdomains of mucus glycoproteins leading to increased residence time and improved bioavailability.

An example for thiolated polymers is thiolated chitosan

Mucoadhesive properties of thiolated polymers include improved tensile strength, rapid swelling, and water

uptake behavior .

Formulation and drug incorporation:

Several approaches have been investigated for the incorporation of drug into mucoadhesive polymers

1 Coating: An immediate release core is coated with the mucoadhesive polymer. In this case, the duration of retention is controlled by the dissolution rate of the polymer. Cross-linking can retard this, however, it also reduce the rate of hydration, which negatively affect mucoadhesion. Dose dumping (premature drug release) can result when the coat separate.

2 Matrix type: The drug is dispersed in a matrix of the

mucoadhesive polymer.

3 Hybrid: Matrix coated with a polymer.

Limitations:

• According to in vivo results obtained in animals and in humans, it does not seem that mucoadhesive polymers are able to control and slow down significantly the GI transit of solid delivery systems. The continuous production of mucous by the gastric mucosa to replace the mucous that is lost through peristaltic contractions and the dilution of the stomach content also seems to limit the potential of mucoadhesion as a gastroretentive force

• Attention should be also paid to possible occurrence of local

ulcerous side effects due to the intimate contact of the system with mucosa for prolonged periods of time.

Raft-Forming Systems

• Raft-forming antireflux preparations act by forming a viscous gelatinous barrier on the top of the stomach contents, which for a maximum time remains located at the lower esophageal sphincter and prevents the acidic gastric content from getting refluxed into the esophagus

• This system is used as anti-reflux formulation and for delivery of antacids and drug delivery for treatment of gastrointestinal infections and disorders.

• The raft-forming property of this class is attributed to the agents (raft-forming agent), which have an ability to form a gelatinous viscous layer on contact with the acidic gastric content or which can maintain their viscous structure in presence of acidic gastric content.

• These are the polymers producing viscous solutions in aqueous medium. Alginic acid and alginates are the most commonly employed raft-forming agents in antireflux preparations. In the acid environment of the stomach, both alginate salts and alginic acids precipitate to form a viscous gel. The gel forms rapidly on exposure to gastric acid, occurring within seconds or minutes. Other agents have been investigated for their applicability as raft-forming agents, which include guar gum, locust bean gum, carrageenan, pectin, and isapghula.

• An equally important feature of a raft is its floatation on the stomach content, which helps it to attain a desired position i.e., at the lower esophageal sphincter, to exhibit its barrier function. It is achieved by including nontoxic gas (carbon dioxide) producing agents in the formulation These are mainly bicarbonates, which react with gastric acid to liberate carbon dioxide gas, which gets entrapped within the viscous polymer layer converting it into foam, thus imparting buoyancy to the polymer layer formed.

• Formulations also typically contain some antacids (aluminium salts like aluminium hydroxide, calcium or magnesium salts) to maintain the pH of the raft on neutral or alkaline side