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AbstractBuccal delivery of drugs provides an attractive alternative to the oral route of drug administration, particularly in overcoming deficiencies associated with the latter mode of administration. Problems such as high first-pass metabolism and drug degradation in the harsh gastrointestinal environment can be circumvented by administering the drug via the buccal route. Moreover, buccal drug absorption can be promptly terminated in case of toxicity by removing the dosage form from the buccal cavity. It is also possible to administer drugs to patients who cannot be dosed orally to prevent accidental swallowing. Therefore adhesive mucosal dosage forms were suggested for oral delivery, which included adhesive tablets, adhesive gels and adhesive patches. 185, and many other dosage forms with various combinations of polymers, absorption enhancers were tried and evaluated. In addition to this studies have been conducted on the development of controlled or slow release delivery systems for systemic and local therapy of diseases in the oral cavity.(1,13,14) Keywords- buccal patches, buccal tablets, permeation enhancers, mucoadhesive polymers
Contents 1. Introduction Overview of the oral mucosae 1.2 Routes of drug absorption 1.3 Buccal mucosa as a site for drug delivery 1.3.1 Factors affecting drug delivery via buccul route
2. Buccal drug delivery system 2.1 Structure and Design of buccul dosage forms 2.1.1 Matrix based 2.1.2 Reservior based 2.2 Related researches on mucoadhesive polymers and delivery systems 3. Conclusion Introduction Buccal delivery of drugs provides an attractive alternate to the oral route of drug administration, particularly in over coming deficiencies associated with the latter mode of dosing. Problems such as high first - pass metabolism and drug degradation in the harsh gastrointestinal environment can be circumvented by administering the drug via
the buccal route. Moreover, buccal drug absorption can be promptly terminated in case of toxicity by removing the dosage form from the buccal cavity. It is also possible to administer drugs to patients who cannot be dosed orally. Therefore, adhesive mucosal dosage forms were suggested for oral delivery that included adhesive tablets adhesive gels and adhesive patches.
However, buccal films are preferable over adhesive tablets in terms of flexibility and comfort. Overview of the Buccal Mucosa The buccal 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 of the buccal mucosa is about 4050 cell layers thick. The buccal mucosa measures at 500-800 µm in thickness and it is not keratinized,hence 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. It is currently believed that the permeability barrier in the oral mucosa is a result of intercellular material derived from the socalled ‘membrane coating granules’ (MCG). When cells go through differentiation, MCGs start forming and at the apical cell surfaces they fuse with the plasma membrane and their contents are discharged into the intercellular spaces at the upper one third of the epithelium. For non-keratinized epithelia, the major MCG lipid components are cholesterol esters, cholesterol, and glycosphingolipids. Outer epithelium is considered to be the rate limiting step to mucosal penetration. The cells of the oral epithelia are surrounded by mucus, the principle components of which are complexes made up of proteins and carbohydrates. This matrix may actually play a role in cell-cell adhesion, as well as acting as a lubricant. Along the same lines, the mucus is also believed to play a role in bioadhesion of mucoadhesive drug delivery systems. At physiological pH the mucus
network carries a negative charge (due to the sialic acid and sulfate residues) which may play a role in mucoadhesion. At this pH mucus can form a strongly cohesive gel structure that will bind to the epithelial cell surface as a gelatinous layer. The salivary pH ranges from 5.5 to 7 depending on the flow rate. At high flow rates, the sodium and bicarbonate concentrations increase leading to an increase in the pH. The daily salivary volume is between 0.5 to 2 liters and it is this amount of fluid that is available to hydrate oral mucosal dosage forms. A main reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is this water rich environment of the oral cavity.(13) Buccal routes of drug absorption There are two possible routes of drug absorption through the squamous stratified epithelium of the oral mucosa: i. Transcellular (intracellular, passing through the cell) and ii. Paracellular (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-coating granules. 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, the salivary enzymes may also reduce stability. Disease states where the mucosa is damaged would also be expected to increase permeability. This would be particularly true in conditions that result in erosion of the mucosa such as lichen planus, pemphigus, viral infections and allergic reactions. Buccal Mucosa as a Site for Drug Delivery Buccal mucosa is less permeable and is thus not able to give a rapid onset of absorption (i.e., more suitable for a sustained release formulation). It has an expanse of smooth muscle and relatively immobile mucosa which makes it a more desirable region for retentive systems used for oral transmucosal drug delivery. Thus the buccal mucosa is more fitted for sustained delivery applications, delivery of less permeable molecules, and perhaps peptide drugs. One of the major disadvantages associated with buccal drug delivery is the low flux which results in low drug bioavailability. Various compounds have been investigated for their use as buccal penetration enhancers in order to increase the flux of drugs through the mucosa. Drugs investigated for buccal delivery using various permeation/ absorption enhancers range in both molecular weight and physicochemical properties. Small molecules such as butyric acid and butanol, ionizable low molecular weight drugs such as acyclovir, propranolol, and salicylic acid, large molecular weight hydrophilic polymers such as dextrans, and a variety of peptides including octreotide, leutinizing hormone releasing hormone (LHRH), insulin, and a-interferon have all been studied.
A series of studies on buccal permeation of buserelin and fluorescein isothiocyanate (FITC) labelled dextrans reported the enhancing effects of di- and tri-hydroxy bile salts on buccal penetration. Their results showed that in the presence of the bile salts, the permeability of porcine buccal mucosa to FITC increased by a 100-200 fold compared to FITC alone. The mechanism of penetration enhancement of FITC-labelled dextrans by sodium glycocholate (SGC) was shown to be concentration dependent. Below 10 mM SGC, buccal permeation was increased by increasing the intercellular transport and at 10 mM and higher concentrations by opening up a transcellular route. Gandhi and Robinson investigated the mechanisms of penetration enhancement of transbuccal delivery of salicylic acid. They used sodium deoxycholate and sodium lauryl sulfate as penetration enhancers, both of which were found to increase the permeability of salicylic acid across rabbit buccal mucosa.(14) Factors Affecting Drug Delivery Via Buccal Route The rate of absorption of hydrophilic compounds is a function of the molecular size. Smaller molecules (75-100 Da) generally exhibit rapid transport across the mucosa, with permeability decreasing as molecular size increases. For hydrophilic macromolecules such as peptides, absorption enhancers have been used to successfully alter the permeability of the buccal epithelium, causing this route to be more suitable for the delivery of larger molecules. Only the nonionized forms of molecules have the ability to cross-lipoidal membranes in significant amounts. The more lipid soluble a compound is, the higher its permeability. The permeabilities for these compounds are direct functions of their oilwater partition coefficients. The partition
coefficient is a useful tool to determine the absorption potential of a drug. In general, increasing a drug’s polarity by ionization or the addition of hydroxyl, carboxyl, or amino groups, will increase the water solubility of any particular drug and cause a decrease in the lipid-water partition coefficient. Conversely, decreasing the polarity of a drug (e.g. adding methyl or methylene groups) results in an increased partition coefficient and decreased water solubility. The partition coefficient is also affected by pH at the site of drug absorption. With increasing pH, the partition coefficient of acidic drugs decreases, while that of basic drugs increases. The partition coefficient is also an important indicator of drug storage in fat deposits. Obese individuals can store large amounts of lipidsoluble drug in fat stores. These drugs are dissolved in the lipid and are a reservoir of slow release from these fat deposits. The ionization of a drug is directly related to both its pKa and pH at the mucosal surface. Limitations Of Buccal Drug Delivery Depending on whether local or systemic action is required the challenges faced while delivering drug via buccal drug delivery can be enumerated as follows. 1. For local action the rapid elimination of drugs due to the flushing action of saliva or the ingestion of foods stuffs may lead to the requirement for frequent dosing. 2. The non-uniform distribution of drugs within saliva on release from a solid or semisolid delivery system could mean that some areas of the oral cavity may not receive effective levels. 3. For both local and systemic action, patient acceptability in terms of taste, irritancy and ‘mouth feel’ is an issue.
For systemic delivery the relative impermeability of oral cavity mucosa with regard to drug absorption, especially for large hydrophilic biopharmaceuticals, is a major concern.(13,14) BUCCAL DRUG DELIVERY SYSTEM Structure And Design Of Buccal Dosage Form Buccal Dosage form can be of 1. Matrix type: The buccal patch designed in a matrix configuration contains drug, adhesive, and additives mixed together 2. Reserviour type: The buccal patch designed in a reservoir system contains a cavity for the drug and additives separate from the adhesive. An impermeable backing is applied to control the direction of drug delivery; to reduce patch deformation and disintegration while in the mouth; and to prevent drug loss. Additionally, the patch can be constructed to undergo minimal degradation in the mouth, or can be designed to dissolve almost immediately. Transmucosal drug delivery systems can be bi-directional or unidirectional. Bi-directional (Figure 1) patches release drug in both the mucosa and the mouth while, Unidirectional (Figure 2) patches release the drug only into the mucosa. (13)
Figure 1 : Buccal Patch designed for Bidirectional drug release
Figure 2: Buccal Patch designed for Unidirectional drug release
Related research on mucoadhesive polymers and delivery systems
Keiko Tsutsumi studied that buccal administration of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea-pigs. Tmax of ET in plasma of buccal administration was significantly smaller than that of oral administration. For the buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W35 was most effective.(7) Bioavailability enhancement: This can be achieved by using different types of polymers and various other techniques that will help in increasing the permeability. In a study, flexible buccal patches were developed using water soluble polymer, hydroxypropyl methylcellulose (HPMC E 15) and hydroxypropyl cellulose (HPC JF). The bioavailability of carvedilol from buccal patches has increased 2.29 folds when compared to that of oral solution. HPMC E15 LV showed better results.(1) Thiocolchicoside, a muscle-relaxant agent, is administered by the oral, intra-muscular and topical route. After oral administration the extent of bioavailability compared with intra-muscular administration is low, due to a first pass effect. In this paper, the delivery of thiocolchicoside through oral mucosa is studied to improve the bioavailability. Two dosage forms, a bioadhesive disc and a fast dissolving disc for buccal and sublingual administration of thiocolchicoside, respectively, were designed. The fast dissolving (sublingual) form resulted in a
quick uptake of 0.5 mg of thiocolchicoside within 15 min whereas with the adhesive buccal form the same dose can be absorbed over an extended period of time.(8) Optimizing release characteristics for hydrophobic drugs: It has been shown that the incorporation of cyclodextrins in a PEObased hydrophilic matrix intended for the delivery of poorly soluble drugs can be a suitable strategy to optimize the release features of the system while maintaining good bioadhesive properties. Cyclodextrins are responsible for an increase in the erosion rate of the tablet and an improved dissolution of the drug inside the polymeric matrix. This latter effect is the crucial factor, which determines the increase of release rate from the tablets in solution as well as a twenty-fold increase in the amount of carvedilol permeated through porcine buccal mucosa. This systems turns to be of great potential as buccal delivery system in view of the possibility of tailoring release features while maintaining good bioadhesive properties.(2) Improved buccal transport for peptides and proteins: To improve the buccal transport new absorption promoters should be developed to be sufficiently active and at the same time causing no side effects like irritation or unpleasant taste. Many substances can function as absorption promoter, the most popular being detergents such as bile acids salts, sodium lauryl sulfate, etc. But many detergents have some side effects.We have found that lysalbinic acid, a product of the alkaline hydrolysis of egg albumin and a mild detergent, meets those requirements. The preparation and some physicochemical properties of lysalbinic acid are described. Hamster cheek pouch was used as a model for the penetration process studies lysalbinic acid was shown to increase significantly an oral mucosa permeability for _-interferon and insulin. So this substance of the natural
origin can be applied as an absorption enhancer for the buccal delivery of peptide drugs.(3) chitosan–TGA conjugate in combination with glutathione represents a promising candidate for a safe buccal drug delivery system of PACAP with enhanced buccal adhesion and permeation(11). Improved patient compliance: Buccal administration could be an alternative, noninvasive delivery route for many drugs given parenterall, like Naltrexone hydrochloride (NLX).(4) which is being used in opioid dependent patients who have undergone intoxication. The present study done by Jaehwi Lee, Ian W. Kellaway suggest that PEG 200 enhances the action of the lipophilic permeation enhancer oleic acid and that the combination of oleic acid and PEG 200 as a co-enhancer can be a useful tool to improve the membrane permeability in the buccal delivery of peptide drugs using a cubic liquid crystalline phase of glyceryl monooleate and water.(10) Nagai et al. studied the applicability of hydroxypropyl cellulose (HPC) as a mucoadhesive agent, they found this high viscosity grade material to be a suitable adhesive for topical mucus membranes. They reported the combination of HPC and carbopol 934P (CP) to produce a preferable material for mucoadhesive dosage forms. HPC tablets showed a slight adhesion but dissolved easily on the gel bed. On the other hand, CP tablets showed strong adhesion but the swollen CP tablets seemed too hard. The combination of HPC and CP provided the mucoadhesion and adequate softness to prepare the tablets. The adhesive force of the HPC-CP tablet was affected by the mixing ratio of HPC and CP. The adhesion force showed a minimum value at the mixing ratio of 3:2 (HPC:CP) due to the formation of an
inter-polymer complex between HPC and CP in the acidic pH range. Complex formation between CP and HPC seemed to suppress the interaction between molecules of hydrogel and the mucus membrane, and the adhesion force was therefore most reduced at a mixture ratio of 1:4 (HPC/CP). (13) In a study, a bioadhesive tablet formulation for buccal delivery was designed using a mixture of hydroxypropyl methylcellulose and carbomer, incorporated with a penetration enhancer, sodium glycodeoxycholate (GDC). In vitro bioadhesion property of the formulated tablet was examined and histological study was carried out to examine an in vivo interaction between the tablet and tissue. GDC did not affect the adhesiveness of the tablet which makes it an acceptable excipient for a buccal bioadhesive drug delivery system. Histological changes such as loss of upper cell layers and formation of vacuoles as well swelling in the cells were observed in the buccal epithelium, after 4 h contact with the tablets containing GDC.(5) Watanabe et al. reported on hydrogels formed by the combination of natural gums, xantham gum, and locust bean gum, which are applicable in buccal delivery systems. Xantham gum is a natural gum obtained through fermentation of glucose by Xanthamonas campestris. Locust bean gum and xantham gum alone cannot form a hydrogel. However, when a mixture of these gums is dissolved in a neutral medium at 90°C and then cooled with ice for 30 min, a clear, strong hydrogel is formed. The gel strength of the hydrogels was affected by the mixing ratio of the gums, and the addition of sucrose improved the sustained release properties of the hydrogels. The hydrogel consisting of xantham gum and locust bean gum showed only a low mucoadhesion, but
it can be applied to a buccal delivery system because of its safety, gel strength, sustained release properties and good feel in the mouth.(13) This study of silymarin encapsulated liposomes revealed an amelioration in the encapsulation efficiency upon increasing amount of added drug in the preparation. Addition of cholesterol beyond a certain limit produced a decrease in encapsulation efficiency. Studying the effect of certain additives and their interactions using two full 23 factorial designs enabled the determination of certain enhancement or decrease in encapsulation efficiency according to the additive. Addition of stearyl amine as a positively charge inducer was capable of enhancing the encapsulation efficiency. Tween 20, Tween 80 and dicetylphophate in one molar ratio decreased the encapsulation efficiency. Molar ratios of some ingredients were explored to determine best encapsulation efficiency. In vitro permeation study through chicken cheek pouch of hybrid liposomes containing L:Ch:SA:T 20 of 9:1:1:0.5 molar ratio showed superior permeation results compared with neutral or positively charged liposomes.(12) Poly(ethyleneoxide) (PEO) is a biocompatible eroding polymer available in a number of molecular weights, which is receiving growing attention as sustainedrelease bioadhesive platform due to its safety, ease. Depending on the molecular weight of PEO, different dissolution and water swelling rates, viscoelastic behaviour
of the swollen gel as well as extent and duration of bioadhesion can be achieved. PEO has been used in oral sustained-release tablets Proper modulation of drug release rate has been attained by tailoring molecular weight and its distribution.(9) Conclusion The buccal mucosa offers several advantages for controlled drug delivery for extended periods of time. The mucosa is well supplied with both vascular and lymphatic drainage and first-pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract are avoided. The area is well suited for a retentive device and appears to be acceptable to the patient. With the right dosage form design and formulation, the permeability and the local environment of the mucosa can be controlled and manipulated in order to accommodate drug permeation. Buccal drug delivery is a promising area for continued research with the aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. However, the need for safe and effective buccal permeation/absorption enhancers is a crucial component for a prospective future in the area of buccal drug delivery.
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