Mucoadhesive polymers used in the oral cavity

Desired characteristics / Polymer-related factors Molecular weight

Flexibility Hydrogen bonding capacity Cross-linking density Charge Concentration Hydration (swelling) Environmental factors

Molecular weight

Bioadhesive strength of a polymer increases with molecular weights above 100,000 Eg . polyoxyethylene polymers

Flexibility

Bioadhesion starts with the diffusion of the polymer chains in the interfacial region Mobility and flexibility of polymers can be related to their viscosities and diffusion coefficients, where higher flexibility of a polymer causes greater diffusion into the mucus network Eg poly(ethylene glycol)poly(acrylic acid)

Hydrogen bonding capacity

For mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds Flexibility of the polymer is important to improve this hydrogen bonding potential Eg. poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylic acid)

Cross-linking density

With increasing density of cross-linking, diffusion of water into the polymer network occurs at a lower rate which, in turn, causes an insufficient swelling of the polymer and a decreased rate of interpenetration between polymer and mucin The degree of swelling at equilibrium has an inverse relationship with the degree of cross-linking of a polymer.

Charge

Nonionic polymers appear to undergo a smaller degree of adhesion compared to anionic polymers Strong anionic charge on the polymer is one of the required characteristics for mucoadhesion Some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or

Concentration

The importance of this factor lies in the development of a strong adhesive bond with the mucus depends on chain length. When the concentration of the polymer is too low, the interaction between polymer and mucus is unstable In general, the more concentrated polymer would result in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration, above which the polymer produces an unperturbed state due to a significantly coiled structure. High concentrations of flexible polymeric films based on polyvinylpyrrolidone or poly(vinyl alcohol) as film-forming polymers did not further enhance the mucoadhesive properties of the polymer

Hydration (swelling)

Hydration is required for a mucoadhesive polymer for

to expand and create a proper macromolecular mesh of sufficient size, to induce mobility in the polymer chains in order to enhance the interpenetration permits a mechanical entanglement

Environmental factors

Saliva flow rate The pH of the microenvironment Mucin turnover rate Movement of the buccal tissues while eating, drinking, and talking

Classification

Adhesive polymers can be classified as

synthetic vs. natural water-soluble vs. water-insoluble charged vs. uncharged polymers

(chitosan and polycarbophil vs. HPC)

Criteria Source

Categories

Examples

Seminatural / Agarose, chitosan, gelatin Natural Various gums (guar, hakea, xanthan, gellan, carragenan, pectin, and sodium alginate) Synthetic Cellulose derivatives [CMC, SCMC, HEC, HPC, HPMC, MC,] Poly(acrylic acid)-based polymers : Polyacrylates poly(methacrylate), Others polyoxyethylene, PVA, PVP

Criteria

Categories

Examples

Aqueous Water-soluble HEC, HPC (water < 38 C ) solubility HPMC (cold water), SCMC, sodium alginate Waterinsoluble Chitosan (soluble in dilute aqueous acids), EC

Criteria

Categories Examples Aminodextran, chitosan CMC, pectin PAA, sodium alginate, sodium CMC, xanthan gum Hydroxyethyl starch , HPC, PVA, PVP

Charge Cationic

Anionic

Non-ionic

Criteria

Categories Examples Cyanoacrylate

Potential Covalent bioadhesiv e forces Hydrogen bond

Acrylates [hydroxylated methacrylate, poly(methacrylic acid]

Electrostati Chitosan c interaction

New generation of mucoadhesive polymers

Thiolated mucoadhesive polymers Target-specific, lectin-mediated bioadhesive polymers Bacterial adhesion As enzyme inhibitors and permeation enhancers

Mucoadhesive dosage forms for buccal administration

General considerations in dosage form design :

Physiological aspects Pathological aspects Pharmacological aspects Pharmaceutical aspects

Physiological aspects

The buccal mucosa is a very suitable region for bioadhesive system In general, a buccal delivery device that is 13 cm2 in size and a drug with a daily dose requirement of 25 mg or less would be preferred Advantages and disadvantages related to mucosa

Pathological aspects

Many diseases can affect the thickness of the epithelium, resulting in alteration of the barrier property of the mucosa.

Some diseases or treatments may also influence the secretion and properties of the mucus as well as the saliva

Pharmacological aspects

A buccal dosage form may be designed to deliver a drug to the systemic circulation, or merely indicated for local therapy of the oral mucosa. Selection of dosage forms is affected by the intended application, target site of action, drug characteristics, and the site to be treated (periodontal pockets, gingival, teeth, buccal mucosa, or systemic).

Pharmaceutical aspects

Poor drug solubility in saliva could significantly retard drug release from the dosage form Organoleptic properties or the delivery device should also be considered Some excipients Permeability characteristics of the buccal mucosa may be continually changed by the rapid turnover of the buccal epithelium (38 days compared to about 30 days for the skin Even though the enzyme activity in the buccal mucosa is relatively low and, as a result, drug inactivation is slower and less extensive than in other mucosal routes passive diffusion pH A formulation may be evaluated both in vitro and in vivo

Buccal mucoadhesive dosage forms

Desired characteristics

High drug loading capacity Controlled drug release (preferably unidirectional release), Good bioadhesive properties, Smooth surface Tastelessness Convenient application.

Classification

Categorized into three types based on their geometry. Type I is a single layer device with multidirectional drug release

Type II devices, an impermeable backing layer Type III is a unidirectional Buccal dosage forms can also be classified as either a reservoir or matrix type

Buccal tablets

Buccal tablets are small, flat, and oval, with a diameter of approximately 58 mm Unlike conventional tablets, buccal mucoadhesive tablets allow for drinking and speaking without major discomfort These tablets can be applied to different sites in the oral cavity, including the palate, the mucosa lining the cheek, as well as between the lip and the gum

Buccal Tablet

Some investigated buccal mucoadhesive tablets

Active ingredient Carbamazepine Chlorpheniramine maleate Polymers used HPMC and CP Hakea gum from Hakea gibbosa

Cyanocobalamin Diltiazem HCl Insulin

Polyoxyethylene CP 934P and HPMC CP 934 with HPC or HPMC

Metronidazole

HPMC, sodium CMC, and CP 934P

Bioadhesive tablets are usually prepared by direct compression, but wet granulation techniques can also be used In order to achieve unidirectional release, every face of the tablet, except the one that is in contact with the buccal mucosa, can be coated with water impermeable materials, such as ethylcellulose If necessary, the drug may be formulated in certain physical states microspheres, newer approaches use tablets that melt at body temperatures

Buccal patches

Patches are laminates consisting of : an impermeable backing layer

drug-containing reservoir layer a bioadhesive surface for mucosal attachment

Methods : solvent casting

direct milling

Fentanyl patch.

Buccal patches

Some investigated buccal mucoadhesive patches

Active ingredient Acyclovir Melatonin Metoprolol tartrate Polymers used acrylic acid and PEG CP 934P and polyisobutylene Eudragit NE40D with HPMC, sodium CMC or CP CP 974P CP 934, CP 971, HPMC, HEC,

Oxytocin Terbutaline sulfate

Buccal films

An ideal film should be : flexible, elastic, soft, adequately strong Possess good bioadhesive strength Relatively short residence time of oral gels on the mucosa Manufactured by a solvent casting method

Buccal films

Some investigated buccal mucoadhesive films

Active ingredient Acyclovir Chlorhexidine digluconate Insulin Lidocaine Nifedipine Polymers used Chitosan HCl and PAA sodium salt Chitosan Gelatin and CP 934P HPC Sodium alginate, MC, PVP, and PEG

Tetracycline

Atelocollagen

Buccal gels and ointments

Have the advantage of easy dispersion throughout the oral mucosa. Dosing from semisolid dosage forms may not be as accurate. Certain bioadhesive polymers undergo a phase change reaction Eg SCMC, Carbopol, Xanthan gum. They are formed from hydrated in an aqueous environment physically entrapment of drug molecules

Some investigated buccal mucoadhesive gels

Active ingredient Chlorhexidine Diclofenac sodium Polymers used Collagen Hydroxyethyl methacrylate (HEMA )

Ergotamine tartrate Tetracycline

PVA HEC, PVP, and PC

Marketed preparations

Striant is a testosterone buccal system (tablet-like gum patch) recently approved by the United States Food and Drug Administration (FDA). Another commercially available product is the nitroglycerin buccal extended-release tablet (Nitrogard).