Drug Delivery And Recent Advances Biology Essay

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The buccal mucosa always serves as the most suitable site for systemic drug delivery of drugs. The factors which add to the acceptability are the easy approachability, rich blood supply, bypass of first pass metabolism and thus the resultant drug loss. The advantages and disadvantages of buccal drug delivery are discussed. Mucoadhesion is defined as a state of two components being in contact for extended periods of time, where one component is of biological origin. Most of the buccal dosage forms are formulated based on the principle of mucoadhesive interaction of polymer with buccal membrane. The mechanisms governing the mucoadhesion are discussed in the paper. The properties of polymers influencing the bioadhesion and the resultant drug release are studied. The methods available for evaluating the delivery systems have been looked upon. Moreover the recent applications of polymers on the drug delivery under discussion have also been discussed. The mucoadhesive buccal delivery systems serve to be a promising delivery system for drugs susceptible to first pass metabolism.

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Keywords: Buccal mucosa, Bioadhesion , First pass metabolism, Polymers, Drug delivery, Mucoadhesion.

Introduction 1, 2, 3

Buccal route of drug delivery is a good alternative, amongst the various routes of drug delivery. Oral route is perhaps the most preferred for the patients. Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. However, oral administration of drugs has disadvantages such as hepatic first pass metabolism and enzymatic degradation within the GI tract, that prohibit oral administration of certain classes of drugs especially peptides and proteins. Buccal routes of drug delivery offer distinct advantages over oral administration for systemic drug delivery. These advantages include possible bypass of first pass effect, avoidance of pre-systemic elimination within the GI tract, these factors make the oral mucosal cavity a very attractive and feasible site for systemic drug delivery. Considering the low patient compliance of rectal, vaginal, sublingual and nasal drug delivery for controlled release, the buccal mucosa has rich blood supply and it is relatively permeable. The buccal mucosa lines the inner cheek and buccal formulations are placed in the mouth between the upper gingival (gums) and cheek to treat local and systemic conditions. The buccal route provides one of the potential routes for typically large, hydrophilic and unstable proteins, oligonucleotides and polysaccharides, as well as conventional small drug molecules. Buccal route of drug delivery is a good alternative, amongst the various routes of drug delivery. Oral route is perhaps the most preferred for the patients. Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery.

Advantages of buccal drug delivery 4,5,6,7

Bypass of the gastrointestinal tract and hepatic portal system, increasing the bioavailability of orally administered drugs that otherwise undergo hepatic first-pass metabolism. Improved patient compliance due to the elimination of associated pain with injections.

Sustained drug delivery.

A relatively rapid onset of action can be achieved relative to the oral route and the formulation can be removed if therapy is required to be discontinued.

Increased ease of drug administration

The large contact surface of the oral cavity contributes to rapid and extensive drug absorption

Extent of perfusion is more therefore quick and effective absorption.

Nausea and vomiting are greatly avoided.

Used in case of unconscious and less cooperative patients.

Drugs, which show poor bioavailability via the oral route, can be administered conveniently.

Ex; Drugs, which are unstable in the acidic environment of the stomach are destroyed by the enzymatic or alkaline environment of the intestine.

Limitations of buccal drug delivery 8 ,9

Drugs which irritate oral mucosa or have bitter taste, or cause allergic reactions, discoloration of teeth cannot be formulated. If formulation contains antimicrobial agents, affects the natural microbes in the buccal cavity.

The patient cannot eat/drink/speak.

Only those drugs which are absorbed by passive diffusion can be administered by this route.

Drugs which are unstable at buccal pH cannot be administered by this route.

Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug.

Low permeability of the buccal membrane, specifically when compared to the sublingual membrane.

Structure of Buccal mucosa10,11, 12

Oral mucosa:

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Within the oral mucosal cavity, the buccal region offers an attractive route of administration for systemic drug delivery. The mucosa has a rich blood supply and it is relatively permeable.

Oral histology:

The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium .The epithelium of the buccal mucosa is about 40-50 cell layers thick, while that of the sublingual epithelium contains somewhat fewer. The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The turnover time for the buccal epithelium has been estimated at 5-6 days, and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 μm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue, and the gingivae measure at about 100-200 μm. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosae of areas subject to mechanical stress (the gingivae and hard palate) are keratinized similar to the epidermis. The mucosae of the soft palate, the sublingual, and the buccal regions, however, are not keratinized .The keratinized epithelia contain neutral lipids like ceramides and acylceramides which have been associated with the barrier function. These epithelia are relatively impermeable to water. In contrast, non-keratinized epithelia, such as the floor of the mouth and the buccal epithelia, do not contain acylceramides and only have small amounts of ceramide. They also contain small amounts of neutral but polar lipids, mainly cholesterol sulfate and glucosyl ceramides. These epithelia have been found to be considerably more permeable to water than keratinized epithelia.

Barriers to penetration across buccal mucosa:

Membrane coating granules: The membrane coating granules found in non‐keratinizing epithelia are spherical in shape, membrane bounded and measured about 0.2 μm in diameter. Such granules have been observed in a variety of other human nonkeratinized epithelia, including uterine cervix and esophagus. Basement membrane: Although the superficial layers of the oral epithelium represent the primary barrier to the entry of substances from the exterior, it is evident that the basement membrane also plays a role in limiting the passage of materials across the junction between epithelium and connective tissue. A similar mechanism appears to operate in the opposite direction. The charge on the constituents of the basal lamina may limit the rate of penetration of lipophilic compounds that can traverse the superficial epithelial barrier relatively easily.

Mucus

The epithelial cells of buccal mucosa are surrounded by the intercellular ground substance called mucus with the thickness varies from 40 μm to 300 μm. Though the sublingual glands and minor salivary glands contribute only about 10% of all saliva, together they produce the majority of mucus and are critical in maintaining the mucin layer over the oral mucosa. It serves as an effective delivery vehicle by acting as a lubricant allowing cells to move relative to one another and is believed to play a major role in adhesion of mucoadhesive drug delivery systems. At buccal pH, mucus can form a strongly cohesive gel structure that binds to the epithelial cell surface as a gelatinous layer. Mucus molecules are able to join together to make polymers or an extended three‐dimensional network. Different types of mucus are produced, for example G, L, S, P and F mucus, which form different network of gels. Other substances such as ions, protein chains, and enzymes are also able to modify the interaction of the mucus molecules and, as a consequence, their biophysical properties10. Mucus is composed chiefly of mucins and inorganic salts suspended in water. Mucins are a family of large, heavily glycosylated proteins composed of oligosaccharide chains attached to a protein core. Three quarters of the protein core are heavily glycosylated and impart a gel like characteristic tomucus. Mucins contain approximately 70-80% carbohydrate, 12-25% protein and up to 5% ester sulphate. The dense sugar coating of mucins gives them considerable waterholding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers. Mucins are secreted as massive aggregates by prostaglandins with molecular masses of roughly 1 to 10 million Da. Within these aggregates, monomers are linked to one another mostly by noncovalent interactions, although intermolecular disulphide bonds also play a role in this process. Oligosaccharide side chains contain an average of about 8-10 monosaccharide residues of five different types namely L‐fucose, D‐galactose, N‐acetyl‐D‐glucosamine, N‐acetyl‐D-galactosamine and sialic acid. Amino acids present are serine, threonine and proline11. Because of the presence of sialic acids and ester sulfates, mucus is negatively charged at physiological salivary pH of 5.8-7.4.

Saliva

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The mucosal surface has a salivary coating estimated to be 70 μm thick, which act as unstirred layer. Within the saliva there is a high molecular weight mucin named MG1 that can bind to the surface of the oral mucosa so as to maintain hydration, provide lubrication, concentrate protective molecules such as secretory immunoglobulins, and limit the attachment of microorganisms. Several independent lines of evidence suggest that saliva and salivary mucin contribute to the barrier properties of oral mucosa. The major salivary glands consist of lobules of cells that secrete saliva; parotids through salivary ducts near the upper teeth, submandibular under the tongue, and the sublingual through many ducts in the floor of the mouth. Besides these glands, there are 600- 1000 tiny glands called minor salivary glands located in the lips, inner cheek area (buccal mucosa), and extensively in other linings of the mouth and throat. Total output from the major and minor salivary glands is termed as whole saliva, which at normal conditions has flow rate of 1-2 ml/min12. Saliva is composed of 99.5% water in addition to proteins, glycoproteins and electrolytes. It is high in potassium (7Ã-plasma), bicarbonate (3Ã-plasma), calcium, phosphorous, chloride, thiocyanate and urea and low in sodium(1/10Ã-plasma). Saliva serves multiple important functions. It moistens the mouth, initiates digestion and protects the teeth from decay. It also controls bacterial flora of the oral cavity. Because saliva is high in calcium and phosphate, it plays a role in mineralization of new teeth repair and precarious enamel lesions. It protects the teeth by forming "protective pellicle". This signifies a saliva protein coat on the teeth, which contains antibacterial compounds. Thus, problems with the salivary glands generally result in rampant dental caries. A constant flowing down of saliva within the oral cavity makes it very difficult for drugs to be retained for a significant amount of time in order to facilitate absorption in this site. Permeabilities between different regions of the oral cavity vary greatly because of the diverse structures and functions. In general, the permeability is based on the relative thickness and degree of keratinization of these tissues in the order of sublingual>buccal> palatal. The permeability of the buccal mucosa was estimated to be 4-4000 times greater than that of the skin.

Routes of drug transport 13

There are two possible routes of drug absorption through the squamous stratified epithelium of the oral mucosa.

1) Trans cellular (intracellular, passing through the cell) and

2) Para cellular (intercellular, passing around the cell).

Permeation across the buccal mucosa has been reported to be mainly by the paracellular route through the intercellular lipids produced by membrane granules. Although passive diffusion is the main mechanism of drug absorption, specialized transport mechanisms have been reported to exist in other oral mucosa (that of the tongue) for a few drugs and nutrients; glucose and cefadroxil were shown to be absorbed in this way. The buccal mucosa is a potential site for the controlled delivery of hydrophilic macromolecular therapeutic agents (biopharmaceuticals) such as peptides, oligonucleotides and polysaccharides. However, these high molecular weight drugs usually have low permeability leading to a low bioavailability, and absorption enhancers may be required to overcome this. The buccal mucosa also contains proteases that may degrade peptide-based drugs. In addition, salivary enzymes may also reduce stability.

Stages of Mucoadhesion

Contact stage

Consolidation stage.

Mechanism of mucoadhesion

The concept of mucoadhesion is one that has the potential to improve the highly variable residence times experienced by drugs and dosage forms at various sites in the gastrointestinal tract, and consequently, to reduce variability and improve efficacy. Intimate contact with the mucosa should enhance absorption. The mechanisms responsible in the formation of bioadhesive bonds are not fully known, however most research has described bioadhesive bond formation as a three step process

Step1: Wetting and swelling of polymer

Step2: Interpenetration between the polymer chains and the mucosal membrane.

Step3: Formation of Chemical bonds between the entangled chains.

Step 1: The wetting and swelling step occurs when the polymer spreads over the surface of the biological substrate or mucosal membrane in order to develop an intimate contact with the substrate. This can be readily achieved for example by placing a bioadhesive formulation such as a tablet or paste within the oral cavity or vagina. Bioadhesives are able to adhere to or bond with biological tissues by the help of the surface tension and forces that exist at the site of adsorption or contact. Swelling of polymers occurs because the components within the polymers have an affinity for water.

Step 2: The surface of mucosal membranes are composed of high molecular weight polymers known as glycoproteins. In this step inter diffusion and interpenetration take place between the chains of mucoadhesive polymers and the mucous gel network creating a great area of contact. The strength of these bonds depends on the degree of penetration between the two polymer groups. In order to form strong adhesive bonds, one polymer group must be soluble in the other and both polymer types must be of similar chemical structure.

Step 3: In this step entanglement and formation of weak chemical bonds as well as secondary bonds between the polymer chains mucin molecule. The types of bonding formed between the chains include primary bonds such as covalent bonds and weaker secondary interactions such as van der Waals Interactions and hydrogen bonds. Both primary and secondary bonds are exploited in the manufacture of bioadhesive formulations in which strong adhesions between polymers are formed.

Polymers in Buccal delivery 10

The key feature that distinguishes polymers from other molecules is the repetition of many identical, similar, or complementary molecular subunits in these chains. These subunits, the monomers, are small molecules of low to moderate molecular weight, and are linked to each other during a chemical reaction called polymerization. Bioadhesive polymers should possess certain physicochemical features including hydrophilicity, numerous hydrogen bond forming groups, flexibility for interpenetration with mucus and epithelial tissue, and viscoelastic properties.

Ideal Mucoadhesive polymer Characteristics 14

A mucoadhesion promoting agent or the polymer is added to the formulation which helps to promote the adhering of the active pharmaceutical ingredient to the oral mucosa. The agent can have such additional properties like swelling so as to promote the disintegration when in contact with the saliva. As understood earlier, that various physical and chemical exchanges can affect the polymer/ mucus adhesion, so as polymer should be carefully selected with the following properties in mind.

Molecular weight - polymer must have a high molecular weight up to 10000 or more this is necessary to promote the adhesiveness between the polymer and mucus.

Polymer length - long chain polymers-chain length must be long enough to promote the interpenetration and it should not be too long that diffusion becomes a problem.

High viscosity

4) Degree of cross linking- It influences chain mobility and resistance to dissolution. Highly cross linked polymers swell in presence of water and retain their structure. Swelling favors controlled release of the drug and increases the polymer/mucus interpenetration. But as the cross linking increases, the chain mobility decreases which reduces the mucoadhesive strength.

Spatial conformation

Flexibility of polymer chain- this promotes the interpenetration of the polymer within the mucus network.

6) Concentration of the polymer- an optimum concentration is required to promote the mucoadhesive strength. It depends however, on the dosage form. For solid dosage form the adhesive strength increases with increase in the polymer concentration. But in case of semi solid dosage forms an optimum concentration as essential beyond which the adhesive strength decreases.

7) Charge and degree of ionization- various chemical Entities were attached to chitosan and the mucoadhesive strength was evaluated. Cationic chitosan hcl showed marked adhesiveness when compared to the control. The attachment of EDTA an anionic group increased the mucoadhesive strength significantly. PA/chitosan system exhibited lower mucoadhesive strength than cationic chitosan and anionic EDTA chitosan complexes because of low charge. Hence the mucoadhesive trength can be attributed as anionic>cationic>nonionic.

8) Optimum hydration- excessive hydration leads to decreased mucoadhesive strength due to formation of a slippery mucilage.

9) Optimum Ph - mucoadhesion is optimum at low pH conditions but at higher pH values a change in the conformation occurs into a rod like structure making them more available for inter diffusion and interpenetration. At at very elevated pH values, positively charged polymers like chitosan form polyelectrolyte complexes with mucus and exhibit strong mucoadhesive forces.

10) High applied strength and initial contact time

11) It should nontoxic , economic ,biocompatible preferably biodegradable

Few facts about polymers:

Cationic and anionic polymers bind more effectively than neutral polymers.

Anionic polymers with sulphate groups bind more effectively than those with carboxylic groups.

Polyanions are better than polycations in terms of binding potential and toxicity.

Water-insoluble polymers give greater flexibility in dosage form design compared to rapidly or slowly dissolving water-soluble polymers.

Degree of binding is proportional to the charge density on the polymer.

Some representative Polymers:

Hydrogels 15

Often called as "wet" adhesives because they require moisture to exhibit the adhesive property.

They are usually considered to be cross linked water swollen polymers having water content ranging from 30% to 40% depending on the polymer used.

They swell in the presence of saliva which may also act as dissolution medium for them.

They are structured in such a manner that the cross linking fibers present in their matrix effectively prevent them from being dissolved and thus help them in retaining water.

When drugs are loaded into these hydrogels, as water is absorbed into the matrix, chain relaxation occurs and drug molecules are released through the spaces or channels within the hydrogel network.

Ex: Polyacrylates (carbopol and polycarbophil), ethylene vinyl alcohol, polyethylene oxide, poly vinyl alcohol, poly(N-acryloylpyrrolidine), polyoxyethy lenes, self-cross linked gelatin, sodium alginate. Natural gums like guar gum, karaya gum, xanthan gum, locus t bean gum and cellulose ethers like methyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose etc.

Novel second-generation mucoadhesive polymers

Copolymers 16

Copolymerization with two or more different monomers results in chains with varied proper- ties.

A block copolymer is formed when the react ion is carried out in a stepwise manner, leading to a structure with long sequences or b locks of one monomer alternating with long sequences of the other.

These networks when composed of hydrophilic and hydrophobic monomers are called polymer micelle. These micelles are suitable for enclosing individual drug molecules.

Their hydrophilic outer shell s help to protect the cores and their contents from chemical attack by aqueous medium.

Most micelle-based systems are formed from poly(ethylene oxide)-b-polypropylene-b-poly(ethylene oxide) triblock network.

Graft copolymers:

In this type entire chains of one kind (e.g., polystyrene) are made to grow out of the sides of chains of another kind (e.g., polybutadiene), resulting in a product that is less brittle and more impact resistant.

Lectins:

Bacteria use some proteins for biological recognition of host cells while attachment during their infection. Enhancement of mucosal delivery may be obtained through the use of appropriate cytoadhesives that can bind to mucosal surfaces. Lectins belong to a group of structurally diverse proteins and glycoproteins that can bind reversibly to specific carbohydrate residues. After initial mucosal cell binding, lectins can either remain on the cell surface or in the case of receptor-mediated adhesion possibly become interna-lised via a process of endocytosis.

So these platforms could not only allow targeted specific attachment but additionally offer a method of controlled drug delivery of macromolecular pharmaceuticals via active cell-mediated drug uptake.

Bacterial Mucoadhesion:

The ability of bacteria to adhere to a specific target is rooted from particular cell-surface components or appendages, known as fimbriae, that facilitate adhesion to other cells or inanimate surfaces. Bacterial fimbriae which are extracellular long thread like protein polymers adhere to the binding moiety of specific receptors. The attractiveness of this approach lies in the potential increase in the residence time of the drug on the mucus and its receptor-specific interaction, similar to those of the plant lectins. However, the potential of bacterial adhesion and invasion in buccal drug delivery is yet to be realized. In light of current biotechnological advances, such as cloning and expression of bacterial adhesion factors, the goal of targeted buccal drug delivery by this system does not appear all that distant.

Multifunctional Polymers

These are the bioadhesive polymers having multiple functions. In addition to the possession of bioadhesive properties, these polymers will also serve several other functions such as enzyme inhibition, permeation enhancing effect etc. Examples are polyacrylates, polycarbophil, chitosan etc.

Thiolated polymers 17

These are the special class of multifunctional polymers also called thiomers. These are hydrophilic macromolecules exhibiting free thiol groups on the polymeric backbone. Due to these functional groups various features of well-established polymeric excipients such as poly (acrylic acid) and chitosan were strongly improved. Thiolatedpolymers designated thiomers are capable of forming disulphide bonds with cysteine-rich subdomains of mucus glycoproteins covering mucosal membranes.

Some of the properties and characteristics of some representative bioadhesive polymers were listed in Table 1

Classification of Buccal Mucoadhesive polymers were listed in Table 2 based on their source, solubility and charge.

Table 1: Properties and characteristics of some representative bioadhesive polymers 18

Bioadhesives

Properties

Characteristics

Hydroxypropylmethyl Cellulose

empirical formula:

C8H15O6-(C10H18O6)n-C8H15O5

Methocel E5, E15, E50, E4M, F50, F4M, K100, K4M,K15M, K100M.

Mw 8.6Ã-104.

η E15-15 cps, E4M-400 cps and K4M-4000 cps (2% aqueous solution).

Insoluble in alcohol, chloroform and ether.

Suspending,viscosity increasing agent.

Film forming agent

Adhesive ointment ingredient

Tablet binder

Hydroxyethyl Cellulose

non-ionic polymer made by swelling cellulose with NaOH and treating with ethylene oxide.

Available in grades ranging from2 to 8,00,000 cps at2%.

Light tan or cream to white powder, odorless and tasteless.

d= 0.6 g/mL

pH 6-8.5 miscible solvents (10 to 30% of solution weight).

Polyvalent inorganic salts will salt out HEC at lower concentrations than monovalent salts.

Shows good viscosity stability over the pH 2 to pH 12 ranges.

Binder, film former

Sodium Alginate

consists chiefly of the alginic acid,a polyuronic acid composed of â-D-mannuronic acid residues.

anionic polysaccharide extracted principally from the giant kelp Macrocystis Pyrifera as alginic acid and neutralized to sodium salt.

Purified carbohydrate product extracted from brown seaweed by the use of dilute alkali.

Occurs as a white or buff powder, which is odorless and tasteless.

pH 7.2

ç 20-400 Cps (1% aqueous solution.)

Excellent gel formation property

pH of the resulting solution and acids where the pH of the resulting solution falls below 3.0.

Safe and nonallergenic

Incompatible with acridine derivatives, crystal violet, phenyl mercuric nitrate and acetate, calcium salts, alcohol in concentrations greater than 5%.

Microstructure and viscosity are dependent on the

Chemicalcomposition

Chitosan

a linear polysaccharide composed of randomly distributed â-(1-4)-linked D-glucosamine (de-acetylated unit) and N-acetyl-D-glucosamine (acetylated unit).

Prepared from chitin of crabs and lobsters by Ndeacetylationwith alkali.

The amino group in chitosan has a pKa value of <<6.5 ,thus, chitosan is positively charged and soluble in acidic to neutral solution with a charge density dependent on pH.

Mucoadhesive agent due to either secondary

chemical bonds such as hydrogen bonds or ionic.

Poly (cyano acrylates)

Biodegradable depending on the length of the alkyl chain

Used as surgical adhesives and glues.

Polyphosphazenes

Can be tailored with versatile side chain functionality

Can be made into films and hydrogels.

Poly (vinyl alcohol)

Biocompatible

Gels and blended membranes are used in drug delivery and cell immobilization.

Poly (ethylene oxide)

Highly Biocompatible

Its derivatives and copolymers are used in various biomedical applications.

Poly(hydroxytheyl methacrylate)

Biocompatible

Hydrogels have been used as soft contact lenses.

Poly(ethyleneoxide-b-propylene oxide)

Surfactants with amphiphilic properties

Used in protein delivery and skin treatments.

Table 2: Classification of Polymers9

Property used for classification

Natural and modified natural polymers

Synthetic polymers

Source

Agarose,

Chitosan,

Gelatin,

Hyaluronic acid,

Carrageenan,

Pectin,

Sodium alginate.

Cellulose derivatives

CMC,

thiolated CMC,

Na CMC,

hydroxyethylcellulose,

HPC, HPMC, methylcellulose,

Methylhydroxyethylcellulose.

Carbopol,

Polycarbophil,

Polyacrylic acid,

Polyacrylates,

Copolymer of acrylic acid and

PEG,

Copolymer of methylvinyl ether and

Methacrylic acid,

Poly-2-hydroxyethylmethacrylate, Copolymer of acrylic acid and

Ethylhexylacrylate,

Polymethacrylate, Polyalkylcyanoacrylates:-

Polyisobutylcyanoacrylate,

Polyisohexylcyanoacrylate.

Water soluble

Water insoluble

Solubility in water

Cellulose derivatives

CMC,

Thiolated CMC,

Na CMC,

Hydroxyethylcellulose,

HPC, HPMC,

Methylcellulose, Methylhydroxyethylcel-lulose

Others

Poly-N-2-hydroxypropylmethacrylamide

PVA, PVP,

Thiolated polymers.

Ethylcellulose, polycarbophil

Carbopol,

Polycarbophil,

Polyacrylic acid,

Polyacrylates,

Copolymer of acrylic acid

PEG,

Copolymer of methylvinyl ether

Methacrylic acid,

Ethylhexylacrylate,

Polymethacrylate, Polyalkylcyanoacrylates:-

Polyisobutylcyanoacrylate,

Cationic/anionic

Uncharged

Charge

Aminodextran,

Dimethylaminoethyldex-tran,

chitosan,

Chitosan-EDTA,

Hydroxyethylated starch, HPC, PEG, PVA, PVP

Possible mechanism

Covalent Hydrogen bonds Electrostatic interactions

Cyanoacrylate Acrylates, carbopol, polycarbophil, PVA Chitosan

Theories of mucoadhesion 19

1. Electronic Theory: The adhesive polymer and mucus typically have different electronic characteristics. When these two surfaces come in contact, a double layer of electrical charge forms at the interface, and then adhesion develops due to the attractive force from electron transfer across the electrical double layer.

2. Adsorption Theory: The adsorption theory of bioadhesion proposes that adhesion of a polymer to a biological tissue results from: (i) primary chemical bonds that are somewhat permanent and therefore undesirable in bioadhesion (ii) van der Waals, hydrogen, hydrophobic and electrostatic forces, which form secondary chemical bonds.

3. Wetting Theory: Primary application to liquid bioadhesive system, the wetting theory emphasizes the intimate contact between the adhesive and mucus. Thus, a wetting surface is controlled by structural similarity, degree of cross linking of the adhesive polymer, or use of a surfactant. The work of adhesion [expressed in terms of surface and interfacial tension (Y) being defined as energy per cm2 released when an interface is formed.] According to Dupres equation work of adhesion is given by Wa = YA + YB - YAB Where A & B refer to the biological membranes and the bioadhesive formulation respectively. The work of cohesion is given by: Wc = 2YA or YB. For a bioadhesive material B spreading on a biological substrate, the spreading coefficient is given by: SB/A = YA - (YB+YAB) SB/A should be positive for a bioadhesive material to adhere to a biological membrane.

4. Diffusion Theory: The essence of this theory is that chains of the adhesive and the substrate interpenetrate one another to a sufficient depth to create a semi permanent adhesive bond. The penetration rate depends on the diffusion coefficient of both interacting polymers, and the diffusion co-efficient is known to depend on molecular weight and cross-linking density. In addition, segment mobility, flexibility of the bioadhesive polymer, mucus glycoprotein, and the expanded nature of both network are important parameters that need to be considered.

5. Fracture: Fracture theory of adhesion is related to separation of two surfaces after adhesion. The fracture strength is equivalent to adhesive strength as given by G = (Eε. /L) ½ Where: E- Young's modules of elasticity ε- Fracture energy L- Critical crack length when two surfaces are separated.

Forces involved in mucoadhesion 20

Vander waal's forces

Hydrogen bonding

Disulphide bridging

Hydration force

Electrostatic double layer forces

Steric force

Colavent bonds

Factors Affecting Mucoadhesion 21, 22

Polymer related Factors:

1. Molecular weight:

Low-molecular-weight polymers penetrate the mucus layer better.

High molecular weight promotes physical entangling.

The optimum molecular weight is between 104 and 4 Ã- 106 Dal. Polymers with higher molecular weights will not moisten quickly to expose free groups for interaction with the substrate, while polymers with low molecular weights will form loose gels or will dissolve quickly.

For linear polymers, the mucoadhesion strength increases with increases in molecular weight, for exam-ple, mucoadhesive properties in a series of polyeth ylene glycols increased in the order: 2 Ã- 104 <2 Ã- 105 <4 Ã- 105

2. Polymer chain flexibility:

Required for diffusion of chains and their entanglement with mucin.

For polymers with high levels of linkage, the mobilities of the individual polymer chains decrease, leading to decreases in mucoadhesion strength.

3. Ability to form hy-drogen bonds: Presence of functional groups able to form hydrogen bonds (COOH, OH, etc.).

4. Concentration: Affects the availability for penetration of long polymer chains into the mucus layer; important mainly for liquid and viscous Drug delivery systems(DDS).

5. Extent of swelling of polymer or DDS: Swelling of the polymer allows mechanical entangling because of the exposure of polymer chains and subsequent formation of hydrogen bonds and/or electrostatic interactions between the polymer and components of the mucosa.

Environmental factors:

1. pH: Changes in pH lead to differences in the extent of dissociation of functional groups in carbohydrate sequences or polypeptide amino acid sequences, as well as in the polymer.

2. Pressure applied to the system for attachment: Affects the depth of diffusion of chains. Cannot be controlled for systems used in the GIT.

3. Duration of initial contact: Determines the extent of swelling and diffusion of polymer chains

4. Moistening: Moistening is required to allow the mucoadhesive polymer to spread over the surface and create a "macromolecular network" of sufficient size for the interpenetration of polymer and mucin molecules and to increase the mobility of polymer chains.

5. Presence of metal ions: Interaction with charged groups of polymers and/or mucus can decrease the number of interaction sites and the tightness of mucoadhesive bonding.

Methods of Evaluation 23, 24

Mucoadhesive polymers can be evaluated by testing their adhesion strength by both in vitro and in vivo tests.

In vitro tests / ex vivo

methods determining tensile strength

methods determining shear stress

adhesion weight method

fluorescent probe method

flow channel method

mechanical spectroscopic method

falling liquid film method

colloidal gold staining method

viscometer method

thumb method

adhesion number

electrical conductance

swelling properties

In vivo methods:

use of radioisotopes

use of gamma scintigraphy

use of pharmacoscintigraphy

use of electron paramagnetic resonance(EPR) oximetry

Isolated loop technique

Recent applications in buccal mucoadhesive drug delivery 25

Oral mucoadhesive drug delivery has widespread applications for many drugs which on oral administration result in poor bioavailability and are rapidly degraded by the oral mucoadhesive drug delivery provides advantages of high accessibility and low enzymatic activity. Earlier the hydrophilic polymers like SCMC, HPC and polycarbophil were used for the treatment of periodontal diseases, but now the trend is shifting towards the effective utilization of these systems to the delivery of peptides, proteins and polysaccharides. The buccal cavity has additional advantages of high patient compliance. Orabase, a first generation mucoadhesive paste has been used as barrier system for mouth ulcers. Semisolids offer more ease in administration, but tablets have also been formulated. Tablets include matrix devices or multilayered systems containing a mucoadhesive agent. The tablet is kept under the upper lip to avoid clearance mechanism of the salivary gland. Recent advances in Buccal drug delivery systems mentioned in Table 3.

Table 3: Recent advances in Mucoadhesive polymer drug delivery systems

S No

Description

Polymers used

Application

1

Design and evaluation of Tartarate systems containing Metoprolol mucoadhesive buccal delivery

Carbopo934, HPMC,

HEC, SCMC

Prolong the duration

of action

2

Ionic gelation controlled drug delivery system for gastric mucoadhesive microparticles of Captopril

Alginate, chitosan,

carbopol-934p, CAP,

HPMC

Control the drug

release for a longer

duration of time

3

Formulation and characterization of mucoadhesive buccal films of

glipizide

SCMC, HPMC,

carbopol-934p,

eudragitrl-100

Films exhibited

controlled release

for more tha 6 hours

4

Prepration and evaluation of Sodium alginate, Double layer buccoadhesive films of atenolol

Carbopol 934p, ethyl Cellulose

Provide drug delivery in a unidirectional manner to the mucosa

5

Formulation and evaluation of nitredipine buccal films

HPMC K100, HPC,

SCMC, sodium

alginate, polyvinyl alcohol, carbopol934p

Moderate drug

release for extended

duration

6

Prepration and evaluation of mucoadhesive buccal films of clotrimazole for oral candida infections

HPC-M,

Carbopol 934p

Intended for local delivery.

Concentration

maintiained above

MIC for 4 hours

7

Design, evaluation and pharmacokinetic study of

mucoadhesive buccal tablets of

nicotine by smoking cessation

HPMC, sodiumalginate, Carbopol

Chitosan

Peak plasma

concentration of

16.78+-2.27mg was

obtained in 2 hours

8

Studies on buccoadhesive tablets of terbutaline sulphate

Carbopol934p, Methocel K4M.

Methocel K15M,

SCMC

--

9

Double layered mucoadhesive tablets by HPMC and carbomer

HPMC, Carbomer

--

Conclusion:

The phenomenon of mucoadhesion can be used as a model for the controlled drug delivery approaches for a number of drug candidates. Various advantages and disadvantages were discussed. The factors which are determinant in the overall success of the mucoadhesive drug delivery are the polymer physicochemical properties and the in vivo factors such as the mucin turnover rate, mucin flow. Various ways in which the polymers can be classified was elaborately discussed which would be of great help while selecting a polymer in the formulation of certain drugs. Theories of mucoadhesion and forces of mucoadhesion were also discussed effectively by which one could easily understand the probable mechanism a particular polymer will follow and select it for a formulation. Recent applications of some polymers in preparation of various types of buccal dosage forms were discussed to give upto date knowledge of the recent trends followed in the selection of them.