A Seminar On

Bioadhesive Pharmaceutical formulations

Keyur Vasava

Introduction
Bioadhesion may be defined as the state in which two materials, at least one of which is biological in nature, are held together for extended periods of time by interfacial forces. In the pharmaceutical sciences, when the adhesive attachment is to mucus or a mucous membrane, the phenomenon is referred to as mucoadhesion. Mucoadhesion has been widely promoted as a way of achieve in site-specic drug delivery through the incorporation of mucoadhesive hydrophilic polymers within pharmaceutical formulations along with the active pharmaceutical ingredient (API). The rationale being that the formulation will be held on a biological surface for localized drug delivery. The API will be released close to the site of action with a consequent enhancement of bioavailability. Whilst mucoadhesive drug delivery systems provide a means of enhancing retention at defined sites, if systemic uptake occurs the use of mucoadhesive polymers will not prevent a wider distribution of the API. Undoubtedly as a means of localizing APIs to sites throughout the body (e.g. within the gastrointestinal tract) or systemic delivery, by retaining a formulation in intimate contact with the absorption site (e.g. the nasal cavity) The need to deliver challenging molecules such as biopharmaceuticals (proteins and oligonucleotides) has increased interest in this area. Mucoadhesives materials could also be used as therapeutic agents in their own right, to coat and protect damaged tissues (gastric ulcers or lesions of the oral mucosa) or to act as lubricating agents (in the oral cavity, eye and vagina). There are several advantages in using bio/mucoadhesive drug delivery systems: (1) As a result of adhesion and intimate contact, the formulation stays longer at the delivery site improving API bioavailability using lower API concentrations for disease treatment. (2) The use of specific bioadhesive molecules allows for possible targeting of particular sites or tissues, for example the gastrointestinal (GI) tract. (3) Increased residence time combined with controlled API release may lead to lower administration frequency. (4) The avoidance of first-pass metabolism. (5) Additionally significant cost reductions may be achieved and dose-related side effects may be reduced due to API localization at the disease site. The following drug delivery systems are used as mucoadhesive drug delivery systems. Oral drug delivery system Buccal drug delivery system Vaginal drug delivery system Rectal drug delivery system
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Nasal drug delivery system Ocular drug delivery system Gastro intestinal drug delivery system

Theories of bioadhesion:
Mucoadhesion is a complex process and numerous theories have been presented to explain the mechanisms involved. These theories include mechanical-interlocking, electrostatic, diffusioninterpenetration, adsorption and fracture processes. Whilst undoubtedly the most widely accepted theories are founded surface energy thermodynamics and interpenetration/diffusion. These numerous theories should be considered as supplementary processes involved in the different stages of the mucus/substrate interaction, rather than individual and alternative theories. Wetting theory

The wettability theory is mainly applicable to liquid or low viscosity mucoadhesive systems and is essentially a measure of the spreadability of the API delivery system across the biological substrate. This theory postulates that the adhesive component penetrates surface irregularities, hardens and anchors itself to the surface. The adhesive performance of such elastoviscous liquids may be defined using wettability and spreadability; critical parameters that can be determined from solid surface contact angle measurements. This process defines the energy required to counter the surface tension at the interface between the two materials allowing for a good mucoadhesive spreading and coverage of the biological substrate. Diffusion theory

The diffusion theory describes interpenetration of the mucoadhesive (polymer) and substrate (mucin) to a sufficient depth and creation of semipermenent adhesive bond. In bioadhesion, the polymer first brought into intimate contact with the mucous, and over time, the concentration gradient across the interface causes the diffusion of the chains of the bioadhesive into the mucous layer and also the diffusion of glycoprotein chains of the mucous into the bioadhesive polymer. The rate of diffusion is independent on the chemical potential gradient and the diffusion coefficient of a macromolecule through a cross linked network. The chains that have diffused across the interface serve as anchors to aid in securing semi-permanently the bioadhesive device in place. An appropriate interpenetration distance is necessary for good bioadhesion that approximately equals to end to end distance of the macromolecular chains.

Electronic theory

The mucin glycoprotein and mucoadhesive polymers possess different electronic structures, therefore electronic transfer is likely to occur when contact is made. This electron transfer results in formation of an electrical double layer at the adhesive interface with subsequent adhesion. Hence, the adhesive/mucin interface can be treated as capacitor, which tends to be charged when the two surfaces are in close contact and discharged when they are separated. Adsorption theory

In this instance, adhesion is defined as being the result of various surface interactions (primary and secondary bonding) between the adhesive polymer and mucus substrate. Primary bonds due to chemisorptions result in adhesion due to ionic, covalent and metallic bonding, which is generally undesirable due to their permanency. Secondary bonds arise mainly due to van der Waals forces, hydrophobic interactions and hydrogen bonding. Whilst these interactions require less energy to break they are the most prominent form of surface interaction in mucoadhesion processes as they have the advantage of being semi-permanent bonds.

Fracture theory

According to this theory, the adhesive bond between systems is related to the force required to separate both surfaces from one another. This fracture theory relates the force for polymer detachment from the mucus to the strength of their adhesive bond. The work fracture has been found to be greater when the polymer network strands are longer or if the degree of cross-linking within such as system is reduced. This theory allows the determination of fracture strength () following the separation of two surfaces via its relationship to Young s modulus of elasticity (E), the fracture energy (e) and the critical crack length (L) through the following equation:

1/2

Mechanism of bioadhesion
The process involved in the formation of bioadhesive bonds has been described in three steps Wetting and swelling of polymer to permit intimate contact with biological tissue. Interpenetration of bioadhesive polymer chain and entanglement of polymer and mucin chains. Formation of weak chemical bonds between entangled chain

Two basic steps have been identified for mucoadhesion.

(1)Contact stage:-An intimate contact is formed between the mucoadhesive and mucous membrane.

(2) Consolidation stage :-

It has been proposed that if strong or prolonged adhesion is required, with larger formulations exposed to stresses such as blinking or mouth movements, then a second consolidation stage is required. The mucoadhesive, the mucosa, and the interfacial region, consisting of mucous.

Factors affecting mucoadhesion

(1) Polymer Related Factors:1) Molecular weight: There is certain molecular weight at which bioadhesion is at a maximum. The interpenetration of polymer molecules is favorable for low molecular weight polymers, whereas entanglements are favored for high molecular weight polymers. In general, it has been shown that the bioadhesive strength of a polymer increases with molecular weights above 100,000.

2) Flexibility of polymer chain Bioadhesion starts with the diffusion of the polymer chains in the interfacial region. Therefore it is important that the polymer chains contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus. In general, mobility and flexibility of polymer can be related to their viscosity and diffusion coefficients, where higher flexibility of a polymer causes greater diffusion into the mucus network.

3) Hydrogen bonding capacity Hydrogen bonding is another important factor in mucoadhesion of a polymer. In order for mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds.

4) Cross linking density The average pore size, the number average molecular weight of the cross linked polymers, and the density of crosslinkning are three important and interrelated structural parameters of a polymer network. Therefore it seems reasonable that with increasing density of crosslinking, diffusion of water into the polymer network occurs at a lower rate which in turn causes an insufficient swelling of the polymer and decreased rate interpenetration between polymer and mucin. The degree of swelling at equilibrium has an inverse relationship with the degree of cross linking of a polymer.

5) Charge on polymer Nonionic polymer appears to undergo a smaller degree of adhesion compared to anionic polymers. It has been shown that some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium chitosan, have shown to posses good adhesive properties due to electroststic attraction between positively charged D-glucosamine residue of chitosan and negatively charged sialic acid residue of mucosal surface.

6) Concentration of active polymer When the concentration of active polymer is too low, the number of penetrating polymer chains per unit volume of mucus is small, and the interaction between polymer and mucus is unstable. In general, the more concentrated polymer would results in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration, above which the polymer produces an unpertubed state due to a significantly coiled structure. As a result, the accessibility of the solvent to the polymer decreases and chain penetration of polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improved and, in some cases, actually diminish mucoadhesive properties.

7) Hydration Hydration is required for mucoadhesive polymer to expand and create a proper macromolecular mesh of a sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin.

2) Environment related factors 1) pH pH was found to have a significant effect on mucoadhesion. pH influences the charge on the surface of both mucus and the polymers. Mucus will have a different charge density depending on the pH because of the difference in the dissociation of the functional groups on the carbohydrate moiety and amino acids of the polypeptide backbone. Robinson et al. Observed that the pH of the medium is critical for the degree of hydration of highly cross linked polyacrylic acid polymers, increasing between pH 4 to pH 5, continuing to increase slightly at pH 6- pH 7, and decreasing at more alkaline levels. This behavior was attributed to difference in the charge density at the different pH levels.

2) Applied strength To place a solid bioadhesive system, it is necessary to apply a defined strength. The adhesion strength increases with the applied strength or with the duration of its application, up to an optimum level.

3) Initial contact time The initial contact time between the mucoadhesives and the mucus layer determines the extent of swelling and the interpenetration of the polymer chains. The mucoadhesive strength increases as the initial contact time increases.

3) Physiological factors (1) Mucin turnover The natural turnover of the mucin molecules from the mucus layer is important for at least two reasons The mucin turn over is expected to limit the residence time of mucoadhesive dosage form on the mucus layer. Mucin turnover results in substantial amount of soluble mucin molecules. These mucin molecules interact with mucoadhesive before they have a chance to interact with the mucus layer.

(2) Disease states The physiological properties of the mucus are known to change during disease conditions such as the common cold, gastric ulcers etc. The exact structural changes taking place in mucus under these conditions are not yet clearly understood.

Bioadhesive polymers
They are water soluble and water insoluble polymers which are swellable networks joined by crosslinking agents. Characteristics of an ideal polymer Degradation products should be non toxic and non absorbable from GIT Should have good spreadability, wetting, swelling, solubility and biodegradability properties pH should be biocompatible Should have optimum molecular weight Should non irritant to mucous membrane Should form a strong non covalent bond with mucin epithelial cell surfaces Should adhere quickly to moist tissue and should possess site specificity Allow easy incorporation of the drug and offer no hindrance to its release Polymer must not decompose on storage or during shelf life of dosage form Should have bioadhesive properties in both dry and liquid state Should be cost effective

Classification of bioadhesive polymers Property used for classification Examples Natural and modified Synthetic natural polymers Agarose Chitosan Gelatin Carbopol Hyaluronic acid Polycarbophil Carrageenan Polyacrylic acid Pectin Polyacrylates Sodium alginate Carboxy Methacrylic acid Methyl Cellulose Poly Vinyl Alcohol Thiolated CMC Poly Vinyl Pyrollidine Sodium CMC Ethylhexaacrylate HEC Thiolated polymer HPC HPMC Methylhydroxyethylcellulose

Source

Solubility in water

Charge

Water soluble CMC Thiolated CMC Sodium CMC HEC HPC HPMC MC HPMC Poly vinyl alcohol Poly vinyl pyrollidine Cationic and Anionic Aminodextran Chitosan Chitosan-EDTA Carbopol Polycarbophil Sodium alginate Pectin

Water insoluble Carbopol Polycarbophil Polyacrylic acid Polyacrylates Methacrylic acid PEG

Uncharged Hydroxyethylated starch HPC PEG Poly vinyl alcohol Poly vinyl pyrollidine

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Bioadhesive formulations Route

Oral cavity Nasal Ocular Gastro intestinal Transdermal Vaginal Rectal

Bioadhesive formulation
Tablet, Patch, Gel, Ointment Gel, Microspheres, Dry powders Insert, gel Gel, Tablet, Microspheres, Capsules Patch, liposomes Gel, Microspheres Gel

1) Bioadhesive tablets
Bioadhesive tablets are immobilized drug delivery systems. They can be formulated into monolithic, partially coated or multilayered matrices. Monolithic tablets are easy to manufacture by conventional techniques and provides possibility of loading of large amount of drug. Partial coating of monolithic tablets affords protection of every face of tablet, which is not in contact with mucosa. Such systems allow undirected drug release and avoid drug release in salivary fluid. Multilayered tablets could be of variety of geometrical arrangements. Figure-1 shows the possible designs of buccal bioadhesive drug delivery.

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Figure-1 Possible design of bioadhesive drug delivery Formulation of buccal tablets 1) Active Pharmaceutical ingredient(API): various APIs can be formulated for buccal, oral and vaginal delivery. 2) Mucoadhesive polymer: various mucoadhesive polymers are required as described above for adhesion of bioadhesive tablets. 3) Diluents: diluents are addes to increase bulk of tablet. In case of buccal tablets very low dose drug formulations required diluents. Diluents include lactose, micro crystalline cellulose, mannitol, etc. 4) Lubricants: magnesium stearate, talc, aerosil, etc are used as lubricants in buccal tablets. 5) Buffering agent: In case of buccal tablets, buffering agent is required for adjustment of pH of tablet similar to pH of buccal mucosa. Buffering agents includes sodium citrate, sodium benzoate, potassium phosphate, sodium acetate,etc. 6) Permeation enhancers: In case of buccal and vaginal tablets permeation enhancer are required to enhance the absorption of drug through mucosa. Permeation enhancers includes EDTA, citric acid, sodium lauryl sulphate, sodium glycocholete,cyclodextrins,polysorbate 80, menthol,dextran sulphate,etc. 7) Sweetening agents: In case of buccal tablets sweetening agents are added for bitter taste drugs.
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8) Backing layer polymers: Water impermeable polymers are required for backing layer of buccal tablets which resist the release of drug from the back side of tablet. Commonly ethyl cellulose is use for backing layer preparation. Limitation of bioadhesive tablets The small surface of contact with mucosa Their lack of physical flexibility It is difficult to obtain high release rate, which is required for some drugs The extent and frequency may cause irritation following chronic application on the buccal and sublingual mucosa. Example: Emami J.et al. developed a buccoadhesive tablet of verapamil hydrochloride by direct compression method using polymers like carbomer (CP), hydroxypropylmethyl cellulose (HPMC) and sodium carboxymethyl cellulose (NaCMC) in various combination and ratios. The buccoadhesive VPH tablets containing 53% CP and 13.3% HPMC showed suitable release kinetics (n = 0.78, K0 zero order release = 4.11 mg/h, MDT = 5.66 h) and adhesive properties and did not show any interaction between polymers and drug based on DCS scanning. This buccoadhesive system may be useful for buccal administration of VPH. Evaluation of bioadhesive tablets 1) Weight variation 2) Thickness 3) Hardness 4) Friability 5) Drug content 6) Surface pH 7) In vitro drug release 8) In vitro drug permeation 9) Swelling study 10) Adhesive strength determination Three different types of stress, tensile, shear and peel stress are measured A) Tensile strength For simulation of actual application conditions, the ideal substrate would be the tissue to which the mucoadhesive system will be applied and the force required to separate mucoadhesives from mucosal tissue is measured using modified automatic surface tensiometer. The results from measuring tensile strength provides information regarding the effects of charge density, hydrophobicity and experimental conditions such as pH, ionic strength, mucolytic agents and applied pressure on bioadhesion.

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B) Shear and Peel strength The shear stress measures the force that causes mucoadhesive to slide with respect to the mucus layer in a direction parallel to their plane of contact. The shear mucoadhesive strength is measured by flow channel method where force necessary for the detachment of a particle placed on the mucin gel was determined by passing humid air through the flow cell. The peel test involves the application of stress over a fine line at the edge rather than over the entire area of contact sites.

C) Thumb test Here, the adhesiveness is qualitatively measured by the difficulty of pulling the thumb from the adhesive as a function of the pressure and the contact time. It provides useful information on mucoadhesive potential.

2) Gels Gels include bioadhesive gels and in situ forming gels. Bioadhesive gels:
These gels highly viscous semisolids prepared by using mucoadhesive polymers. They retain longer period of time to the site of application and may give controlled release of drug. Bioadhesive gels are formulated for various sites like buccal, nasal, vaginal, rectal,etc.
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 Formulation 1) Active pharmaceutical ingredient 2) Mucoadhesive polymer 3) Permeation enhancer 4) Preservative 5) Solvent Example: Jaleh Varshosaz et al. developed a chitosan bioadhesive gel for nasal delivery of insulin. The gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. The gel of 2% medium molecular weight of chitosan with EDTA caused increase in insulin absorption and reduction of the glucose level by as much as 46% of the intravenous route. In situ forming gels: In situ gels are in solution form and formed gels upon administration to particular site due to phase transition in environment of that site. Gel formation is due to various mechanisms includes, Thermal change pH change change in electrolyte composition combination of any 2 mechanism. Thermo sensitive gel forming system: Thermo sensitive polymer systems have been extensively studied because of their valuable applications in drug delivery system, cell encapsulation and tissue engineering. Thermo sensitive polymer systems are formed from aqueous polymer solutions with temperature changes. Representative thermo sensitive polymers are as follows; copolymers of N-isopropylacrylamide (PNiPAAM), PEOPPO PEO triblock copolymer (Poloxamer) and PLGAPEGPLGA triblock copolymer. pH sensitive gel forming system: pH sensitive gel forming systems, which swell or shrink in response to changes in the pH, has been extensively studied and used as smart materials for various biomedical applications. Carbopol (polyacrylic acid) is mostly used as pH sensitive polymer. Ion Sensitive gel forming system: Ion sensitive gel forming system is new type of gel, in which solution of polymer containing drug triggered to gel form when contact with specific ion at specific site. It is useful type of gel forming system for site specific drug delivery system based on ionic trigger. Representative ion sensitive polymer includes sodium alginate, gellan gum, xyloglucan, and carrageenan. In situ gels sometimes required viscosity enhancing agent which is generally mucoadhesive polymer. It includes hydroxyl propyl methyl cellulose, hydroxyl ethyl cellulose, etc.
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 In situ gels formulate for various sites including nasal, ophthalmic, oral, vaginal, rectal, and injectable. In situ forming system for oral delivery: pectin, xyloglucan, gellan gum are the natural polymers used in in situ forming oral delivery. In forming oral gels are generally stomach specific and they include floating agents for longer retention of drug into stomach. Wataru Kubo et al. formulate oral in situ gel of ambroxol. The solutions contained calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion-controlled release of ambroxol from the gels over a period of 6 hour. In situ forming system for ocular delivery: gellan gum, alginic acid and xyloglucan are used for ocular delivery. Conventional delivery systems often result in poor bioavailability and therapeutic response because high tear fluids turn over and dynamics cause rapid elimination of the drug from the eyes. So, to overcome bioavailability problems, ophthalmic in situ gels were developed. R. C. DOIJAD et al developed an in situ gelling system for sustained ophthalmic delivery of Gatifloxacin. In which they describe that the poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of drug may be overcome by the use of in situ gel-forming systems that are instilled as drops into the eye and undergo a sol-gel transition in the culde-sac. In situ forming system for vaginal and rectal delivery: xyloglucan, pluronic F-127 are used for vaginal and rectal delivery. They are thermosensitive polymers. Miyazaki et al. investigated the use of xyloglucan based thermoreversible gels for rectal delivery of indomethacin. The given formulation shows better bioavailability than commercial suppository of indomethacin. In situ forming injectable delivery: This system gain more interest over last decade. Various drugs are administered using this system and they are pH sensitive and thermosensitive systems. E.J. Riccia et al. formulated lidocaine in situ injectable gel containing polaxamer 407. The use of P407 gels prolongs the residence time of the lidocaine at the injection site, sustains drug release and increases therapeutic efficacy. Evaluation of gels 1) Drug content 2) Viscosity 3) pH 4) In vitro drug release 5) Adhesion properties: Adhesive strength is measured as described in tablets and the other methods are,

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A)Membrane viscosity The interaction between polymers and cell membranes was examined by labeling the cell membranes with fluorescent probes. The lipid bilayer and proteins of cell membranes were labeled with pyrene and fluorescein isothiocyanate. The fluorescence spectrum of pyrene and the fluorescence depolarization of fluorescein isothiocyanate were used to examine the change in membrane viscosity after interaction with polymer. It was assumed in this study that affinity of polymers to cell membranes is linearly related to the increase in membrane viscosity. B)Electrical conductance The adhesion of orabase, carbopol, guar gum, and methyl cellulose to artificial biomembrane in artificial saliva was studied by using a modified rotational viscometer capable of measuring electrical conductance. In presence of adhesive material the conductance was comparatively low. As the adhesive was removed the value increased to final corresponding to conductance of saliva, which indicates the absence of adhesion.

3) Patches:
Patches are designed for buccal delivery and transdermal delivery of drugs. Buccal patches Adhesive patches can be designed either for unidirectional release into the oral mucosa or for bidirectional release into the oral cavity and oral mucosa. The adhesive part of the system can be used as drug carrier or as an adhesive for retention of a drug loaded on the nonadhesive layer. The use of impermeable backing layer will maximize the drug concentration gradient and prolong adhesion because the system is protected from saliva. (fig-2) Backing no backing backing

Unidirectional release

multidirectional release

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Matrix system

Reservoir system

Figure-2 Typically size of such polymeric patches would be 1-3 cm2 but may have dimensions as large as 10-15 cm2 depending on the site of administration. Formulation of bioadhesive buccal patch 1) API 2) Mucoadhesive polymers: The first step in the development of a buccal patch is the selection and characterization of an appropriate bioadhesive in the formulation. The polymers used are described earlier. 3) Supportive materials: application of impermeable backing layer on buccal patches has been considered to prevent drug loss and for patient s convenience. Guo and cooklock have found that ethylcellulose, a hydrophobic polymer, has very low water permeability and moderate flexibility, therefore it is good candidate for backing layer application. The polymer patches that have higher amount of ethylcellulose had a lower hydration rate. As an alternative backing materials, polyvinylpyrrolidone and cellulose acetate mixture were also studied. Poly(ethyleneco-vinyl acetate) is another material that has been studied for backing layer application. 4) Plasticizer 5) Buffering Agent 6) Sweetening agent 7) Flavoring Agent Example: Surya Adhikari et al developed Buccal patches for the delivery of atenolol using sodium alginate with various hydrophilic polymers like carbopol 934 P, sodium carboxymethyl cellulose, and hydroxypropyl methylcellulose in various proportions and combinations by solvent casting technique. All these fabricated patches were sustained for 24 h and obeyed first-order release kinetics. Evaluation of buccal patch 1) Thickness uniformity 2) Folding endurance 3) Uniformity of weight 4) Drug content uniformity 5) Swelling study
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6) Surface pH 7) In vitro release study 8) Adhesive strength: Adhesive strength is measured as described in bioadhesive tablets. Transdermal Patches Transdermal patch is a medicated adhesive placed on the skin to deliver a specific dose of medication through the skin and into bloodstream. Transdermal patches offer added advantages such as maintenance of constant and prolonged drug level, reduced frequency of dosing, minimization of inter- and intrapatient variability, self administration, and easy termination of medication, leading to patient compliance. Formulation of transdermal patch 1) API 2) Mucoadhesive polymer 3) Supporting material 4) Plasticizer Evaluation of transdermal patch 1) Thickness uniformity 2) Moisture content 3) Uniformity of weight 4) Drug content uniformity 5) Flatness study 6) Surface pH 7) In vitro release study 8) Adhesive strength: Adhesive strength is measured as described in bioadhesive tablets

4) Chewing gums
Chewing gums are mobile drug delivery systems. The main target mucosa for drug absorption is sublingual mucosa. However drug is release into saliva and its subsequent spreading may cause the drug to be absorbed across other mucosa of the oral cavity. Chewing gum can be used as a convenient modified-release drug delivery system. Commercially available medicated chewing gums are currently available for pain relief, smoking cessation, travel illness, and freshening of breath. In addition, a large number of chewing gums intended for prevention of caries, xerostomia alleviation, and vitamin/mineral supplementation are currently available. Medicated chewing gum offers advantages in comparison to conventional oral mucosal and oral dosage forms both for (a) local treatment of mouth diseases and (b) systemic effect after absorption through the buccal and sublingual mucosa or from the gastrointestinal tract. First, chewing gum can be retained in the oral cavity for long periods. Second, if the drug is readily absorbed across oral mucosa, chewing gum can provide a fast onset time for a
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systemic effect and the potential for avoidance of gastrointestinal and hepatic first-pass metabolism of susceptible drugs. Finally, chewing gum can be formulated to deliver drugs to the gastrointestinal tract to provide less irritation to the stomach owing to the drug already being dissolved or suspended in saliva when reaching the stomach Components of chewing gum Medicated chewing gum has a core consisting of the components given in Table 1. The core normally weighs approximately 1 g. A coating can then be applied to the gum either as a film of polymer, wax, or bulk sweetener or as a thicker layer of sugar/ sugar alcohol. The gum base consists of elastomers, resins, fats, emulsifiers, fillers, and possibly antioxidants. Table-1 components of chewing gum Component Drug Gum base Bulk sweeteners Softeners Flavoring agents Coloring agents Concentration (%) Max. approximately 50 2040 30-75 0-10 1-5 1

Manufacturing process of chewing gum Chewing gum can be manufactured in different ways. The most common method comprises mixing the gum base with the other ingredients in a mixer with Z formed blades. The gum base can either be added in a solid form and softened through heating from the jacket of the mixer or from the frictional heat generated during the mixing process, or it can be added in a melted form. The fact that the texture of the chewing gum has a semi fluid dough-like texture during the mixing process and is hardened to a solid unchangeable form after the manufacturing process makes it easy to obtain good homogeneity and there are no segregation problems. Another manufacturing method comprises a continuous production process where the components are added at fixed places in the mixer. Chewing gum can also be manufactured by compression of powders or granulates on a conventional tablet machine (compression technique). The compression technique has the advantage that it is easier to keep different components in the product separated and thereby avoid any potential unwanted chemical interactions. Drug release from chewing gum formulations is generally rapid but not as immediate as in case of fast dissolving tablets. The release period can be extended by associating the drug into ion exchange resin.
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 The drawbacks of chewing gum includes: The release into saliva and disappears rapidly from the oral cavity because of involuntary swallowing. The concentration drug in the oral cavity always tends to decrease as a result of salivary dilution. The drug is not protected from the environment found in oral cavity Drug release from chewable formulations has been shown to be strongly influenced by the way the patient chews the formulation Administration of such dosage form is restricted to short time periods because the delivery system in the oral cavity causes disturbance in drinking, eating and speaking. Despite these limitations chewing gum formulations afford extended delivery periods compared to solutions and fast dissolving tablets.

5) Films
Films are used for buccal bioadhesive drug delivery. Both degradable and non-degradable forms of films have been developed. The major method of polymeric film manufacture is the solvent evaporation process, in which the polymeric material, with or without plasticizer, is dissolved in a solvent or solvent mixture and into which the active constituent is dissolved or dispersed. This solution is then cast onto a suitable substrate and the solvent is allowed to evaporate, leaving a solid polymeric film containing the drug (Jones & Medlicott, 1995). However, other techniques have also been used. Hot-melt extrusion technology has been proposed as a promising technique for films, resulting in shorter and more efficient processing times to a final product, environmental advantages due to elimination of solvents in processing, and increased efficiency of drug delivery to the patient. Formulation of film 1) API 2) Mucoadhesive polymer 3) Plasticizer Evaluation of film 1) Weight uniformity 2) Thickness 3) Swelling study 4) folding endurance 5) Drug content uniformity 6) Surface pH 7) In vitro drug release 8) Mucoadhesion study: As described in tablets.

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 Example: Alagusundaram M. et al developed mucoadhesive buccal films of ranitidine by solvent casting technique using polymers like Hydroxy Propyl Methyl Cellulose-15 cps and Poly Vinyl Pyrrolidone. The formulation was found to be right and suitable candidate for the formulation of ranitidine buccal film for therapeutic use.

6) Ocular inserts
Solid ophthalmic delivery devices (inserts) are thin disks or small cylinders made with appropriate polymeric materials and fitting into the lower or upper conjuctival sac. Their long persistence in the perocular area can result in a greater drug bioavailability with respect to liquid and semisolid formulations. Some inserts, such as now classical Occusert, can release the drug at a slow, constant rate for at least 1 week. Mucoadhesive polymers can be profitably used as constituents of inserts to achieve prolonged contact with the conjuctival tissue and to alleviate the risk of explusion from the cul-de-sac. These polymers can be the exclusive constituents of inserts, can be present as components of a polymeric mixture, or else can be used to coat a hydrophobic insert body. Example: Gilhotra RA et al. developed Piroxicam Bioadhesive Ocular Inserts using film forming polymer, PVP and bioadhesive polymers, HPMC, CMC, and carbopol by film casting method. The physicochemical, bioadhesive, and swelling properties of films were found to vary significantly depending on the type of the polymers and their combination. The above properties were found to be optimum for all films; however, formulation containing carbopol 0.5% and HPMC 1% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable drug release (99% at 12 hr).

7) Hollow fibers
This is an alternative approach for chewing gum formulations. The design of microporous hollow fiber of polysulphone intended for the delivery of histerelin, a LHRH agonist was reported. ( Burnside et al) This fiber is intended to be placed in the buccal cavity for oral mucosal drug delivery. Prelimenery experiments showed that peptide delivery rates could be adjusted and prolonged for up to 6 hours. However, the lack of intimate contact of the delivery system with the mucosa may determine to peptide absorption while the delivery system that does not afford projection of the drug from the environment of oral cavity may subject to degradation of drug in saliva. The fiber may also prepare for periodontal application.

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8) Multi particulate systems 8.1) Microspheres

Bioadhesive microspheres include microparticles and microcapsules (having a core of the drug) of 11000m in diameter and consisting either entirely of a bioadhesive polymer or having an outer coating of it, respectively. Microspheres, in general, have the potential to be used for targeted and controlled release drug delivery; but coupling of bioadhesive properties to microspheres has additional advantages, Efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio A much more intimate contact with the mucus layer Specific targeting of drugs to the absorption site achieved by anchoring plant lectins, bacterial adhesins and antibodies, etc. on the surface of the microspheres. Formulation 1) API 2) Mucoadhesive polymer Bioadhesive microspheres can be tailored to adhere to any mucosal tissue including those found in eye, nasal cavity, urinary and gastrointestinal tract, thus offering the possibilities of localised as well as systemic controlled release of drugs. Application of bioadhesive microspheres to the mucosal tissues of ocular cavity, gastric and colonic epithelium is used for administration of drugs for localised action. Prolonged release of drugs and a reduction in frequency of drug administration to the ocular cavity can highly improve the patient compliance. Microspheres prepared with bioadhesive and bioerodible polymers undergo selective uptake by the M cells of Peyer patches in gastrointestinal (GI) mucosa. This uptake mechanism has been used for the delivery of protein and peptide drugs, antigens for vaccination and plasmid DNA for gene therapy. Example: Patel JK et al developed Mucoadhesive Glipizide Microspheres containing chitosan by simple emulsification phase separation technique using glutaraldehyde as a cross-linking agent. The microspheres exhibited good mucoadhesive property in the in vitro wash-off test and also showed high percentage drug entrapment efficiency. Evaluation 1) Drug entrapment efficiency 2) Particle size analysis 3) In vitro release study

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4) Mucoadhesion study In microspheres adhesion number is determined which is as follows. The adhesion number (Na) is, Na = (N/No)*100 Where, No = total no. of applied particles N = no. of particles attached to the substrate. Measurement methods o Falling liquid film method Small intestinal segments from rats were placed at an inclination on a tygon tube. The adhesion of particles to this surface is measured by passing the particle suspension over the surface and by comparing the fraction of particles adhered to the tissue; the adhesion strength of different polymers can be determined.

o Mucin gold staining Mucin gold staining is used to quantitate the mucoadhesive properties of various hydrogels. In this technique, colloid gold particles, which are red in solution, are stabilized by mucin molecules. The interaction between mucin and hydrogel is monitored by appearance of red color on hydrogel surface.

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8.2) Liposomes
Liposomes are vesicles composed of phospholipid membrane enclosing an aqueous volume. These liposomes are coated with mucoadhesive polymers and remain for longer period of time and improved the drug therapy. Ocular route is widely used for mucoadhesive liposomal preparation.

8.3) Nanoparticles
As microspheres, nanoparticles prepared for mucoadhesive drug delivery by either consisting entirely of a bioadhesive polymer or having an outer coating of it.

S-DBMP-T(Slowly Disintegrating Buccal Mucoadhesive Plain-Tablet)

S-DBMP-T

is prepared by incorporating a relatively large amount of hydroxypropylcellulose in a tablet formulation. An example of a typical composition is a tablet composed of 20 mg of drug, 20 mg of hydroxypropylcellulose, 20 mg of carboxymethylcellulose (ECG-505, disintegrating agent), and 60 mg of lactose. These components are mixed, and then compressed into a tablet with a flat faced die that is 8 mm in diameter. The S-DBMP-T technology was originally developed for increasing the bioavailability of oxendolone (a steroidal antiandrogen). This compound undergoes rapid presystemic elimination when administered orally. It should be noted that the presystemic elimination of oxendolone is unlike that of propranolol, which also undergoes rapid presystemic elimination. However, control of the disintegration time over very extended time periods for the purpose of prolonged release may be limited with this technology.

BCTS (Buccal Covered-Tablet System)

To maintain the tablet shape for as long as possible, Iga et al. developed a method to restrict disintegration from the sides of the tablets. The method involved sandwiching an S-DBMP-T tablet between two polyethylene sheets. The upper sheet contained a hole that allowed the tablet to absorb water and disintegrate only through the hole. The lower sheet contained adhesives to allow the delivery system to adhere to the gingiva for a long time. Iga et al. investigated a hole diameter of 5 mm or 7 mm (when the tablet diameter was 8 mm).

VagiSiteTM Bioadhesive Technology

VagiSiteTM is one of several bioadhesive technologies for different routes of administration that have been developed by KV Pharmaceutical Company, St. Louis, Missouri, U.S.A.
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 The VagiSiteTM technology comprises a high-internal-phase-ratio, water-in-oil emulsion. As such, the internal phase of the emulsion acts as the carrier of the active drug. The drug-laden internal-dispersed phase globules serve a dual purpose for both the sequestering and the controlled release of the active agent, butoconazole nitrate. The high-internal-phase-ratio emulsion containing dispersed phase globules develops a high affinity for surfaces, especially mucosal tissues. After introduction of the drug-containing emulsion to a mucosal surface, in this case the vaginal mucosa, a thin bioadhesive film of contiguous drug-laden internal-phase globules forms on the mucosal surface. This tenacious, bioadhesive film then act as a drug delivery platform providing a controlled release of butoconazole nitrate into the lumen of the vaginal canal.

References
1. Rathbone MJ et al., Modified Release Drug Delivery Technology, Marcel Dekker, Inc., 2002, 349-81, 801-6 2. Vyas SP, Khar RK., Controlled Drug Delivery: Concepts and Advances, Vallabh Prakashan, First Edition: 2002, 257-314 3. Methiowitz E et al., Bioadhesive Drug Delivery System, Marcel Dekker, Inc., 1999, 5513, 621-31 4. Andrews GP et al., Mucoadhesive polymeric platforms for controlled drug delivery, European Journal of Pharmaceutics and Biopharmaceutics 71 (2009) 50518 5. Salamat-Miller N et al., The use of mucoadhesive polymers in buccal drug delivery, Advanced Drug Delivery Reviews 57 (2005) 1666 91

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