INTRODUCTION:

The advances and progress made by pharmaceutical industry have greatly contributed in terms of treatment of disease, thereby enhancing the quality of life ^[1]. Over the time, scientists and researchers in the drug development industries are focusing on alternate routes of administration to add to the potential of approved drug products, or to overcome the drawbacks of the oral route. Although oral route is preferred for administration of drugs, it is associated with some restrictions for example: hepatic first pass metabolism, local GI toxicity and enzymatic degradation within the GI tract. One strategy that has been reasonably successful to circumvent such problems is to deliver drugs systemically via an alternate route of administration such

as intranasal (IN), buccal/sublingual, pulmonary, or transdermal (TD) ^[2].

Characteristics of An Ideal Buccal Adhesive System ^[3-6]:

An ideal buccal adhesive system should possess the following characteristics:

1. Quick adherence to the buccal mucosa and sufficient mechanical strength.

2. Drug release in a controlled fashion.

3. Facilitates the rate and extent of drug absorption.

4. Should have good patient compliance.

5. Should not hinder normal functions such as talking, eating and drinking.

6. Should accomplish unidirectional release of drug towards the mucosa.

7. Should not aid in development of secondary infections such as dental caries.

8. Possess a wide margin of safety both locally and systemically.

9. Should have good resistance to the flushing action of saliva.

Advantages of Buccal Drug Delivery System ^[^{7, 8-13]}:

Drug administration via buccal mucosa offers several distinct advantages:

1. The buccal mucosa is relatively permeable with a rich blood supply, robust in comparison to the other mucosal tissues.

2. Bypass the first-pass effect and non-exposure of the drugs to the gastrointestinal fluids.

3. Easy access to the membrane sites so that the delivery system can be applied, localized and removed easily.

4. Improve the performance of many drugs, as they are having prolonged contact time with the mucosa.

5. High patient acceptance compared to other non-oral routes of drug administration.

6. Tolerance (in comparison with the nasal mucosa and skin) to potential sensitizers.

7. Increased residence time combined with controlled API release may lead to lower administration frequency.

8. Additionally, significant cost reductions may be achieved and dose-related side effects may be reduced due to API localization at the disease site.

9. 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.

10. Harsh environmental factors that exist in oral delivery of a drug are circumvented by buccal drug delivery.

11. It offers a passive system of drug absorption and does not require any activation.

12. The presence of saliva ensures relatively large amount of water for drug dissolution unlike in case of rectal or transdermal routes.

13. Provides an alternative route for the administration of various hormones, narcotic analgesics, steroids, enzymes, cardiovascular agents etc.

14. It allows the local modification of tissue permeability, inhibition of protease activity and reduction in immunogenic response. Thus, delivery of therapeutic agents like peptides, proteins and ionized species can be done easily.

Disadvantages of Buccal Drug Delivery System ^{[14, 15]}:

The main challenges of buccal administration are:

1. Limited absorption area- the total surface area of the membranes of the oral cavity available for drug absorption is 170 cm2 of which ~50 cm2 represents non-keratinized tissues, including buccal membrane.

2. Barrier properties of the mucosa.

3. The continuous secretion of the saliva (0.5-2 l/day) leads to subsequent dilution of the drug.

4. The hazard of choking by involuntarily swallowing the delivery system is a concern.

5. Swallowing of saliva can also potentially lead to the loss of dissolved or suspended drug and ultimately the involuntary removal of the dosage form.

Oral Mucosal Sites:

Within the oral mucosal cavity, delivery of drugs is classified in to three categories.

1. Sublingual Delivery:

It is the administration of the drug via the sublingual mucosa (the membrane of the ventral surface of the tongue and the floor of the mouth to the systemic circulation.

2. Buccal Delivery:

It is the administration of drug via the buccal mucosa(the lining of the cheek)to the systemic circulation.

3. Local Delivery:

For the treatment of conditions of the oral cavity, principally ulcers, fungal conditions and periodontal disease. These oral mucosal sites differ greatly from one another in terms of anatomy, permeability to an applied drug and their ability to retain a delivery system for a desired length of time ^{[16, 17]}.

Oral Mucosa:

The oral mucosa is composed of an outermost layer of stratified squamous epithelium (about 40-50 layers thick), a lamina propria followed by the sub mucosa as the innermost layer. The composition of the epithelium varies depending on the site in the oral cavity. The mucosa of the gingival and hard palate are keratinized similar to the epidermis contain neutral lipids like ceramides and acyl ceramides which are relatively impermeable to water. The mucosa of the soft palate, the sublingual, and the buccal regions, however, are not keratinized contain only small amounts of ceramides.

Fig No. 1: Structure of Oral Mucosa.

NOVEL BUCCAL DOSAGE FORMS:

The novel type buccal dosage forms include buccal adhesive tablets, patches, films, semisolids (ointments and gels) and powders.

A. Buccal Mucoadhesive Tablets:

Buccal mucoadhesive tablets are dry dosage forms that have to be moistened prior to placing in contact with buccal mucosa. Example: a double layer tablet, consisting of adhesive matrix layer of HPC and polyacrylic acid with an inner core of cocoa butter containing insulin and a penetration enhancer (sodium glycocholate).

B. Patches and Films:

Buccal patches consists of two laminates, with an aqueous solution of the adhesive polymer being cast onto an impermeable backing sheet, which is then cut into the required oval shape. A novel mucosal adhesive film called “Zilactin” - consisting of an alcoholic solution of HPC and three organic acids. The film which is applied to the oral mucosal can be retained in place for at least 12 hrs even when it is challenged with fluids.

C. Semisolid Preparations (Ointments and Gels):

Bioadhesive gels or ointments have less patient acceptability than solid bioadhesive dosage forms, and most of the dosage forms are used only for localized drug therapy within the oral cavity. One of the original oral mucoadhesive delivery systems -“orabase”- consists of finely ground pectin, gelatin and NaCMC dispersed in a poly (ethylene) and a mineral oil gel base, which can be maintained at its site of application for 15-150 minutes.

D. Powders:

HPC and beclomethasone in powder form when sprayed on to the oral mucosa of rats, a significant increase in the residence time relative to an oral solution is seen, and 2.5% of beclomethasone is retained on buccal mucosa for over 4 hrs^[18].

Structure and Design of Buccal Dosage Form:

Buccal Dosage form can be of the following types:

1. Matrix Type:

The buccal patch designed in a matrix configuration contains drug, adhesive, and additives mixed together.

2. Reservoir 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.

Buccal Absorption:

Buccal absorption leads systemic or local action via buccal mucosa.

Mechanism of Buccal Absorption:

Buccal drug absorption occurs by passive diffusion of the non-ionized species, a process governed primarily by a concentration gradient, through the intercellular spaces of the epithelium. The passive transport of non-ionic species across the lipid membrane of the buccal cavity is the primary transport mechanism.

The buccal mucosa has been said to be a lipoidal barrier to the passage of drugs, as is the case with many other mucosal membrane and the more lipophilic the drug molecule, the more readily it is absorbed^[19].The dynamics of buccal absorption of drugs could be adequately described by first order rate process. Several potential barriers to buccal drug absorption have been identified. Dearden and Tomlison (1971) pointed out that salivary secretion alters the buccal absorption kinetics from drug solution by changing the concentration of drug in the mouth.

-dm KC

------ = --------

Dt Vi Vt

Where,

M - Mass of drug in mouth at time

K - Proportionality constant

C - Concentration of drug in mouth at time

Vi - The volume of solution put into mouth cavity and

Vt - Salivary secretion rate.

FACTORS AFFECTING BUCCAL ABSORPTION:

The oral cavity is a complex environment for drug delivery as there are many interdependent and independent factors which reduce the absorbable concentration at the site of absorption ^[20].

1. Membrane Factors:

This involves degree of keratinization, surface area available for absorption, mucus layer of salivary pellicle, intercellular lipids of epithelium, basement membrane and lamina propria. In addition, the absorptive membrane thickness, blood supply/ lymph drainage, cell renewal and enzyme content will all contribute to reducing the rate and amount of drug entering the systemic circulation.

2. Environmental Factors:

A. Saliva:

The thin film of saliva coats throughout the lining of buccal mucosa and is called salivary pellicle or film. The thickness of salivary film is 0.07 to 0.10 mm. The thickness, composition and movement of this film affect the rate of buccal absorption.

B. Salivary Glands:

The minor salivary glands are located in epithelial or deep epithelial region of buccal mucosa. They constantly secrete mucus on surface of buccal mucosa. Although, mucus helps to retain mucoadhesive dosage forms, it is potential barrier to drug penetration.

C. Movement of Buccal Tissues:

Buccal region of oral cavity shows less active movements. The mucoadhesive polymers are to be incorporated to keep dosage form at buccal region for long periods to withstand tissue movements during talking and if possible during eating food or swallowing.

Methods to Increase Drug Delivery Via Buccal Route:

A. Absorption Enhancers ^[21]:

Absorption enhancers have demonstrated their effectiveness in delivering high molecular weight compounds, such as peptides, that generally exhibit low buccal absorption rates. These may act by a number of mechanisms, such as increasing the fluidity of the cell membrane, extracting inters/intracellular lipids, altering cellular proteins or altering surface mucine. The most common absorption enhancers are azone, fatty acids, bile salts and surfactants such as sodium dodecyl sulfate. Solutions/gels of chitosan were also found to promote the transport of mannitol and fluorescent-labelled dextrans across a tissue culture model of the buccal pithelium while Glyceryl mono oleates were reported to enhance peptide absorption by a co-transport mechanism.

B. Prodrugs ^[21]:

Hussain et al delivered opioid agonists and antagonists in bitterless prodrug forms and found that the drug exhibited low bioavailability as prodrug. Nalbuphine and naloxone bitter drugs when administered to dogs via the buccal mucosa, the caused excess salivation and swallowing. As a result, the drug exhibited low bioavailability. Administration of nalbuphine and naloxone in prodrug form caused no adverse effects, with bioavailability ranging from 35 to 50% showing marked improvement over the oral bioavailability of these compounds, which is generally 5% or less.

C. pH ^[21]:

Shojaei et al evaluated permeability of acyclovir at pH ranges of 3.3 to 8.8, and in the presence of the absorption enhancer, sodium glycocholate. The in vitro permeability of acyclovir was found to be pH dependent with an increase in flux and permeability coefficient at both pH extremes (pH 3.3 and 8.8), as compared to the midrange values (pH 4.1, 5.8, and 7.0).

D. Patch Design ^[21]:

Several in vitro studies have been conducted regarding on the type and amount of backing materials and the drug release profile and it showed that both are interrelated. Also, the drug release pattern was different between single-layered and multi-layered patches.

Table No. 1: Commercially Available Buccal Adhesive Formulations ^[22].

Brand Name	Bioadhesive Polymer	Company	Dosage forms
Buccastem	PVP, Xanthum gum, Locust bean gum	Rickitt Benckiser	Tablet
Suscard	HPMC	Forest	Tablet
Gaviscon Liquid	Sodium alginate	Rickitt Benckiser	Oral liquid
Orabase	Pectin,gelatin	Orabase	Pectin,gelatin
Corcodyl gel	HPMC	Glaxosmithkline	Oromucosal Gel
Corlan pellets	Acacia	Celltech	Oromucosal Pellets
Luborant	Sodium CMC	Antigen	Artificial Saliva
Saliveze	Sodium CMC	Wyvem	Artificial Saliva
Aphtach	Hydroxypropyl cellulose Polyacrylic acid	Tejin Ltd	Tablet
Buccastem buccal	Xanthan gum	Reckitt	Tablet
Oralin – Gencrex	Unknown	Generex Biotechnology (Phase II trials)	Solution
Lauriad (Phase III trials)	Unknown	BioAlliance Pharma	Tablet
Striant SR buccal	Carbomer 934P Hypromellose Polycarbophil	Ardana Bioscience Ltd	Tablet
Suscard buccal	Hypromellose	Forest Laboratories	Tablet

CONCLUSION:

From both a financial and global healthcare perspective, finding ways to administer injectable medications is costly and sometime leads to serious hazardous effects. Hence inexpensive multiple dose formulations with better bioavailability are needed. In the past few decades, research in buccal drug delivery has revealed remarkable growth and advances. The transmucosal route is becoming more and more popular because it does have significant advantages like avoidance of first pass metabolism in the liver and pre-systemic elimination in the gastrointestinal tract. Buccal drug delivery holds a great promise for 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. Moreover, Buccal adhesive systems offering numerable advantages in terms of accessibility, administration and withdrawal, retentivity, low enzymatic activity, economy and high patient compliance, making these categories of drugs to play a major role in the field of pharmaceutical research and therapeutics by providing a good bioavailability.

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Received on 04.08.2017 Modified on 11.09.2017

Res. J. Pharm. Dosage Form. & Tech. 2017; 9(3): 109-113.

DOI: 10.5958/0975-4377.2017.00019.2