buccal patches: novel advancement in mucoadhesive drug ... · mucosal surface.among the various...

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Indo American Journal of Pharmaceutical Research, 2015 ISSN NO: 2231-6876

BUCCAL PATCHES: NOVEL ADVANCEMENT IN MUCOADHESIVE DRUG DELIVERY

SYSTEM

Vyas Kuldeep *, Garg Kumar Shiv Research Scholar, Dept. of Pharmaceutics, Maharishi Arvind College Of Pharmacy, Ambabari, Jaipur, Rajasthan, India.

Corresponding author

Kuldeep Vyas

Research Scholar, Dept. of Pharmaceutics

Maharishi Arvind College of Pharmacy,

Ambabari, Jaipur, Rajasthan, India

[email protected]

+91-8502091092

Copy right © 2015 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical

Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT

Article history

Received 28/01/2015

Available online

28/02/2015

Keywords

Oral-Mucosa,

Bioadhesion,

Mucoadhesive Polymer,

Enzyme Inhibitor,

Buccal Absorption.

For the oral mucosal route of drug administration, various types of dosage forms can be

prepared, such as adhesive tablets, adhesive gels, adhesive patches and many other dosage

forms with various combinations of polymers, absorption enhancers. The duration of

Sublingual Tablet delivery is short owing to the inevitable loss of a large proportion of the

administered dose due to swallowing. To overcome such losses, a patch can be formulated

that is located on the buccal mucosa of the oral cavity, i.e. buccal patches. The buccal region

of the oral cavity is one of the beneficial routes of administration for systemic and local drug

delivery, specifically in overcoming problems associated with the latter mode of

administration, such as high first-pass metabolism and drug degradation in the G.I

environment due to high acidic pH. The phenomenon of buccal drug delivery includes direct

access to the systemic circulation through the internal jugular vein bypasses drugs from the

hepatic first pass metabolism which results in the increase of bioavailability. Moreover, rapid

onset of action can be achieved relative to the oral route and the formulation can also be

removed when therapy is discontinued. It is also possible to administer the drug to patients

who are unconscious and less co-operative. Buccal mucosa has advantages like, rich blood

flow, lesser thickness of the buccal mucosa and high permeability, low enzymatic activity in

the buccal mucosa. In addition, 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.

Please cite this article in press as Kuldeep Vyas et al. Buccal Patches: Novel Advancement In Mucoadhesive Drug Delivery

System. Indo American Journal of Pharm Research.2015:5(02).

mailto:[email protected]

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Vol 5, Issue 02, 2015. Kuldeep Vyas et al. ISSN NO: 2231-6876

INTRODUCTION[1]

Mucoadhesion is commonly defined as the phenomenon of adhesion between two materials, at least one of which is a

mucosal surface.Among the various routes of drug delivery, the oral route is an attractive site for the delivery of drug. The buccal

cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic

drug delivery. Buccal Adhesive drug delivery system prolong the residence time of the dosage form at the site of application or

absorption and facilitate an intimate contact of the dosage form with the absorption surface and thus contribute to improved

therapeutic performance of the drug. Over the decades mucoadhesion has become popular for its potential to optimize localized drug

delivery, by retaining a dosage form at the site of action (e.g. within the gastrointestinal tract) or systemic delivery by retaining the

formulation in intimate contact with the absorption site (e.g. buccal cavity). Bioadhesion is the ability of a material (synthetic or

biological) to adhere to a biological tissue for an extended period of time.

The biological surface can be epithelial tissue or it can be the mucus coat on the surface of a tissue. If adhesion is to a mucous

coat, the phenomenon is referred to as mucoadhesion. The use of mucoadhesive polymers in buccal drug delivery has a greater

application. Various mucoadhesive devices, including tablets, films, patches, disks, strips, ointments and gels, have recently been

developed. However, buccal patch offer greater flexibility and comfort than the other devices. In addition, a patch can bypass the

problem of the relatively short residence time of oral gels on mucosa, since the gels are easily washed away by saliva. It provides

direct entry of drug molecules into the systemic circulation, and avoids hepatic first pass metabolism and gastrointestinal drug

degradation. The term bio adhesion has been used to define the attachment of a synthetic natural macromolecule to a biological tissue

for an extended period of time. When a substrate is a mucosal system adheres and interacts primarily with the mucus layer, this

phenomenon being referred to as mucoadhesion.

ORAL CAVITY: ANATOMIC AND PHYSIOLOGIC FEATURES [2,3]

Light microscopy reveals several distinct patterns of maturation in the epithelium of the human oral mucosa based on various

regions of the oral cavity. Three distinctive layers of the oral mucosa are the epithelium, basement membrane, and connective tissues.

The oral cavity is lined with the epithelium, below which lies the supporting basement membrane which in turn is supported by

connective tissues. The epithelium, as a protective layer for the tissues beneath, is divided into (a) non-keratinized surface in the

mucosal lining of the soft palate, the ventral surface of the tongue, the floor of the mouth, alveolar mucosa, vestibule, lips, and cheeks,

and (b) keratinized epithelium which is found in the hard palate and non-flexible regions of the oral cavity. The epithelial cells,

originating from the basal cells, mature, change their shapes, and are increased in size while moving towards the surface. The buccal

epithelium is classified as a non-keratinized tissue. The thickness of buccal epithelium in humans, dogs and rabbits has been

determined to be approximately 500800-μ. The term „buccal‟, even if is used wrongly to indicate the mucosa of the total oral cavity,

refers to the lining of the cheek and the upper and lower lips, which represent one-third of the total oral mucosal surface.

Fig. 1: Structure of Oral Cavity.

Fig.2. Schematic diagram of buccal mucosa.

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Tissue homeostasis requires differentiation followed by migration and desquamation of the superficial cells. The prickle cells

(intermediate layer) accumulate lipids and cytokeratins with low molecular weight that do not aggregate to form filaments. The buccal

epithelium lack tight junctions common to intestinal and nasal mucosa and is endowed with gap junctions, desmosomes and

hemidesmosomes, which are loose intercellular links.

DELIVERY OF DRUGS WITHIN THE ORAL MUCOSAL CAVITY [4,5,6]

It is classified into three categories

1) Sublingual delivery: Is the administration of drug via sublingual mucosa (membrane of the ventral surface of the tongue and floor of the mouth) to

systemic circulation. The sublingual mucosa is relatively permeable, giving rapid absorption and acceptable bioavailability of many

drugs, and is convenient, accessible, and generally well accepted. The sublingual route is by far the most widely studied of these

routes. Sublingual dosage forms are most often one of two designs: those composed of rapidly disintegrating tablets and those

consisting of soft gelatin capsules filled with liquid drug. Such systems create a very high drug concentration in the sublingual region

before they are systemically absorbed across the mucosa.

2) Buccal delivery:

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

considerably less permeable than sublingual area, and is generally not able to provide rapid absorption and good bioavailability seen

with sublingual administration.

3) Local delivery: For the treatment of conditions of 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. Even though sublingual mucosa is relatively more permeable than buccal mucosa, it is not suitable

for a retentive oral transmucosal delivery system. The sublingual region lacks an expanse of smooth and immobile mucosa and is

constantly washed by a considerable amount of saliva, making device placement difficult. The preferred site for retentive oral

transmucosal delivery systems and for sustained and controlled-release delivery devices is the buccal mucosa, mainly because of

differences in permeability characteristics between the two regions and the buccal mucosa‟s expanse of smooth and relatively

immobile mucosa.

BUCCAL MUCOSA ENVIRONMENT [5,7,8]

The oral cavity is marked by presence of saliva produced by salivary glands and mucus which is secreted by major and minor

salivary glands as part of saliva.

ROLE OF SALIVA:

• Protective fluid for all tissues of oral cavity.

• Continuous mineralization / demineralization of tooth enamel.

• To hydrate oral mucosal dosage forms.

ROLE OF MUCUS:

• Made up of proteins and carbohydrates

• Cell-cell adhesion

• Lubrication

• Bioadhesion of mucoadhesive drug delivery systems.

BARRIERS TO PENETRATION ACROSS BUCCAL MUCOSA [9,10,11]

The barriers such as saliva, mucus, membrane coating granules, basement membrane etc retard the rate and extent of drug

absorption through the buccal mucosa. The main penetration barrier exists in the outermost quarter to one third of the epithelium.

1. Membrane coating granules or cored granules The permeability barrier property of the oral mucosa is predominantly due to intercellular materials derived from the so-

called “membrane coating granules” (MCGs). MCGs are spherical or oval organelles that are 100–300 nm in diameter and found in

both keratinized and non-keratinized epithelia.

2. Saliva 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”. 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. In general, keratinization of these

tissues in the order of sublingual>buccal>palatal.

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3. 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.

4. Mucus The epithelial cells of buccal mucosa are surrounded by the intercellular ground substance called mucus with the thickness

varies from 40-300μm. Mucus is composed of mucins and inorganic salts suspended in water. Mucins are a family of large, heavily

glycosylated proteins composed of oligosaccharide chain attached to a protein core. Three quarters of the protein core are heavily

glycosylated and impart a gel like characteristic to mucus. The dense sugar coating of mucins gives considerable water holding

capacity and also makes resistant to proteolysis.

Fig.3. buccal absorption through differrent routes.

ADVANTAGES OF BUCCAL DRUG DELIVERY SYSTEM [12,13]

Bypass of the gastrointestinal tract and hepatic portal system, increasing the bioavailability of orally administered drugs that

otherwise undergo hepatic first-pass metabolism. In addition the drug is protected from degradation due to pH and digestive enzymes

of the middle gastrointestinal tract.

1) Improved patient compliance due to the elimination of associated pain with injections.

2) A relatively rapid onset of action can be achieved relative to the oral route.

3) The formulation can be removed if therapy is required to be discontinued.

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

5) The residence time of dosage form at the site of absorption is prolong, hence increases the bioavailability.

6) High blood supply and good blood flow rate cause rapid absorption.

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

8) Significant cost reductions may be achieved and dose-related side effects may be reduced due to API localization at the

disease site.

LIMITATIONS OF BUCCAL DRUG ADMINISTRATION[14]

There is certain limitation via drug administered through buccal route

1. Drugs with ample dose are often difficult to be administered.

2. Possibility of the patient to swallow the tablet being forgotten.

3. Eating and drinking may be restricted till the end of drug release.

4. This route is unacceptable for those drugs, which are unstable at pH of buccal environment.

5. This route cannot administer drugs, which irritate the mucosa or have a bitter or unpleasant taste or an obnoxious odour.

6. Limited surface area is available for absorption. Drug absorption is 170 cm2 of which ~50 cm2 represents non-keratinized

tissues, including buccal membrane.

7. Continuous secretion of the saliva(0.5-2 l/day)leads to subsequent dilution of the drug.

FACTORS AFFECTING BUCCAL ABSORPTION [14,15,16]

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.

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

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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.

THEORIES OF BIOADHESION [16,17,18,19]

Bioadhesives are naturally occuring polymeric substances that behave as adhesives. They are mainly designed to

biological tissue. Bio-adhesion is the phenomenon where natural and synthetic materials adhere to biological surfaces.

1) Electronic theory:

According to this theory, electron transfer occurs upon contact of an adhesive polymer with a mucous glycoprotein due to

difference in their electronic structure. This results in formation of electrical double layer at the interface. Adhesion occurs due to

attractive forces across the double layer. It is based on the electronic charges on mucoadhesive and biological materials being

possessing opposite electrical charges. When these materials come into contact, they transfer electrons and finally formed the double

electronic layer at the interface, mucoadhesive strength determined by attractive forces within this layer.

2) Adsorption theory:

According to this theory after an initial contact between two surfaces, the material adheres because of the interatomic surface

forces acting on surface. Vander Waals forces hydrogen bonds, electrostatic attraction or hydrophobic interactions play an important.

By this forces mucoadhesive material adheres to the mucus layer after an initial contact between two surfaces.Two types of chemical

bonds resulting from these forces are:

Primary chemical bonds of covalent nature.

Secondary chemical bonds having many different forces of attraction.

3) Wetting theory:

This theory applies to those liquid systems which present affinity to the surface in order to spread over it. The interfacial

energy is responsible for the contact between the two surfaces and adhesive strength. The wetting theory applies to liquid systems

which present affinity to the surface in order to spread over it. This theory based on measuring contact angle between two surfaces. It

is generally known and accepted that, lower the contact angle greater is the affinity. The contact angle should be appropriate to

provide adequate spreadability. . For the adequate speadability the contact angle must be equal or close to zero.The spreadability

coefficient (SAB) is calculated by the equation:

SAB = γB- γA – γAB

Where: γB is Surface energy and

γA is Interfacial energy

WA = γA + γB – Γab

4) Fracture theory:

It attempts to relate the difficulty of separation of two surfaces after adhesion. This is the most accepted theory on

mucoadhesion. This theory 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 is Young‟s modules of elasticity,

ε is Fracture energy and

L is Critical crack length when two surfaces are separated

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5) Diffusion theory:

Diffusion theory explained that both polymer and mucin chains penetrates each other to a sufficient depth to create a semi-

permanent adhesive bond. The degree of penetration depends on diffusion coefficient, flexibility and nature of the mucoadhesive

chains, mobility and contact time of the polymer chains. This diffusion coefficient, in turn, depends onthe value of molecular weight

between cross-links and decreases significantly as the linking density increases.

6) Mechanical theory

According to mechanical theory adhesion occurs due to the filling of the irregularities on a rough surface by a mucoadhesive

liquid. Such roughness increases the interfacial area available to interactions thereby increasing dissipating energy and is considered

important phenomenon of the process.

MECHANISM OF BUCCAL ABSORPTION [20,21,22]

Absorption of drug through buccal cavity occurs by passive diffusion of the nonionized species 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.

Higher the lipophillic a drug is, the more readily it gets absorbed. The dynamics of buccal absorption could be explained by first order

kinetics. The linear relationship between salivary secretion and time is given as follows:

-dm/dt= KC/ViVt

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.

MUCOADHESIVE POLYMERS[23,24]

Mucoadhesive polymers can be classified as following:

1. Synthetic polymers:

Cellulose derivatives (methylcellulose, ethyl cellulose, hydroxy-ethylcellulose, Hydroxyl propyl cellulose, hydroxyl propyl

methylcellulose, sodium carboxy methylcellulose, Poly (acrylic acid) polymers (carbomers, polycarbophil), Poly (hydroxyethyl

methylacrylate), Poly (ethylene oxide), Poly (vinyl pyrrolidone), Poly (vinyl alcohol), Natural polymers, Tragacanth, Sodium alginate,

Karaya gum, Guar gum, Xanthan gum, Lectin, Soluble starch, Gelatin, Pectin, Chitosan.

2. Hydrophilic Polymers:

These are the water-soluble polymers that swell indefinitely in contact with water and eventually undergo complete

dissolution, e.g. Methyl Cellulose, Hydroxyl Ethyl Cellulose, Hydroxyl Propyl Methyl Cellulose, Sodium Carboxy Methyl Cellulose,

Carbomers, Chitosan and Plant gums.

3. Hydrogels:

These are water swellable materials, usually a cross-link polymer with limited swelling capacity, E.g. poly (acrylic acid co

acrylamide) copolymers, carrageenan, sodium alginate, guar gum and Modified guar gum etc.

4. Thermoplastic Polymers:

These polymers include the non-erodible neutral polystyrene and semi-crystalline bio-erodible polymers, which generate the

carboxylic acid groups as they degrade, e.g. polyanhydrides and polylactic acid. Various synthetic polymers used in mucoadhesive

formulations include polyvinyl alcohol, polyamides, polycarbonates, polyalkylene glycols, polyvinyl ethers, esters and halides,

polymethacrylic acid, polymethylmethacrylic acid, Methyl Cellulose, Hydroxyl Propyl Cellulose, Hydroxyl Propyl Methyl Cellulose,

and Sodium Carboxy Methyl Cellulose. Various biocompatible polymers used in mucoadhesive formulations include cellulose-based

polymers, ethylene glycol polymers and its copolymers, oxyethylene polymers, polyvinyl alcohol, polyvinyl acetate and esters of

hyaluronic acid.

Various biodegradable polymers used in mucoadhesive formulations are poly (lactides), poly (Glycolides), poly (lactides-co-

glycolides), polycaprolactones, and polyalkyl cyanoacrylates. Polyorthoesters, polyphosphoesters, polyanhydrides, polyphosphazenes

are the recent additions to the polymers.

MUCOADHESIVE AGENTS[25,26,27]

PLASTICIZERS

Plasticizer is a vital ingredient of the film formulation. It helps to improve the flexibility of the film and reduces the

brittleness of the film. Plasticizer significantly improves the film properties by reducing the glass transition temperature of the

polymer. The selection of plasticizer will depend upon its compatibility with the polymer and also the type of solvent employed in the

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casting of film. The flow of polymer will get better with the use of plasticizer and enhances the strength of the polymer. Glycerol,

Propylene glycol, low molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate,

Citrate derivatives such as tributyl, triethyl, acetyl citrate, triacetin and castor oil are some of the commonly used plasticizer

excipients. Typically the plasticizers are used in the concentration of 0–20% w/w of dry polymer weight. However inappropriate use

of plasticizer may lead to film cracking, splitting and peeling of the film. It is also reported that the use of certain plasticizers may also

affect the absorption rate of the drug. The Plasticizer employed should impart the permanent flexibility to the film and it depends on

the volatile nature plasticizer and the type of interaction with the polymer. It should be noted that the properties of plasticizer are

important to decrease the glass transition temperature of polymer in the range of 40–600C for non aqueous solvent system and below

750C for aqueous systems. Plasticizer should be compatible with drug as well as other excipients used for preparation of film.

PENETRATION ENHANCERS

Penetration enhancers are also required when a drug has to reach the systemic circulation to exert its action. These must be

non-irritant and have a reversible effect. The epithelium should recover its barrier properties after the drug has been absorbed. The

most common classes of buccal penetration enhancers include fatty acids (that act by disrupting intercellular lipid packing),

surfactants and, among these, bile salts (by extracting membrane protein or lipids, by membrane fluidization, by producing reverse

micellization in the membrane and creating aqueous channels), azone (by creating a region of fluidity in intercellular lipids) and

alcohols (by reorganizing the lipid domains and by changing protein conformation). Recently, chitosan and its derivatives, polymers

already known for their mucoadhesive properties, have been shown to be the potential penetration enhancers for transmucosal

(intestinal, nasal, buccal and vaginal) absorption of drugs. Although the penetration enhancement properties of chitosan through

mucosae (intestinal and nasal) are mainly owing to a transient widening of the tight junctions between the cells, the mechanism of

penetration enhancement through the mucosa of the oral cavity has still to be clarified. A hypothesis that has still to be demonstrated is

that chitosan acts on the intercellular lipid domain, recognized as being the main barrier to drug transport via paracellular pathway in

the buccal mucosa. It must be emphasized that different in vitro and ex vivo methods have been used for characterizing the penetration

enhancement properties of the different materials, but they do not always appropriately simulate the in vivo conditions. The

establishment of standardized biological models alternative to animal studies is needed for the evaluation and comparison of different

materials.

Examples of some penetration enhancers: Aprotinin, Cetyl Pyridinium Chloride, Azone, Benzalkonium Chloride, 2,3-lauryl

ether, Cyclodextrin, Glycol, Lauric Acid, Polysorbate-80, Sodium Salicylate, Phosphatidyl choline etc

ENZYME INHIBITORS The co-administration of a drug with enzyme inhibitors is another strategy for improving the buccal absorption of drugs,

particularly peptides. Enzyme inhibitors, such as aprotinin, bestatin, puromycin and some bile salts stabilize protein drugs by different

mechanisms, including affecting the activities of the enzymes, altering the conformation of the peptides or proteins and/or rendering

the drug less accessible to enzymatic degradation. Some mucoadhesive polymers, such as polyacrylic acid and chitosan derivatives,

have been proved to inhibit enzyme activity even if not in buccal mucosa. In particular, polyacrylic acid (carbomers) is able to bind

the essential enzyme cofactors calcium and zinc, causing a conformational change resulting in enzyme autolysis and loss of enzyme

activity. Moreover, the chemical modification of chitosan (cationic polymer) with ethylene diamine tetra acetic acid (EDTA) produces

polymer conjugate chitosan–EDTA that is a very potent inhibitor of metallopeptidases, such as carboxypeptidase. In recent years, the

polymer derivatization with thiol groups on poly (acrylates) or chitosan has been demonstrated to improve polymer enzyme inhibitory

properties.

TYPES OF BUCCAL DOSAGE FORM[28]

1. Buccal patches and films:

Buccal patches consists of two laminates or multilayered thin film that are round or oval in shape, consisting basically of

adhesive polymeric layer and impermeable backing layer to provide unidirectional flow of drug across buccal mucosa.

2. Lozenges:

Act typically within the mouth including the antimicrobials, corticosteroids, local anaesthetics, antibiotics and antifungal.

3. Bioadhesive liquids:

Dry mouth is treated with artificial saliva solution that is retained on mucosal surfaces to provide lubrication. These solutions

contain bioadhesive polymers including sodium carboxymethyl cellulose.

4. Hollow fibers: a) Burnside et al designed a micro porous hollow fiber of poysulfone, intended for delivery of histrelin.

b) This fiber is intended to be placed in the buccal cavity for oral mucosal drug delivery.

c) The lack of intimate contact of the delivery system with the mucosa may be detrimental to peptide absorption and the delivery

system does not afford protection of the drug.

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5. Buccal Tablets:

Buccal mucoadhesive tablets are dry dosage forms that have to be moistened prior to placing in contact with buccal mucosa.

They can deliver drug multi- directionally into the oral cavity or to the mucosal surface.

6.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.

7. Powders:

Buccal bioadhesive powder dosage forms are a mixture of bioadhesive polymers and the drug and are sprayed onto the buccal mucosa

COMPONENTS OF BUCCAL PATCHES[28,29]

A. Active ingredient:

High dose molecules are difficult to be incorporated in buccal patch due to size limitation of dosage form. Generally 5%w/w

to 30%w/w of active pharmaceutical ingredients can be incorporated in the buccal patches

B. Polymers (adhesive layer):

The polymer hydration and subconsequently the mucus dehydration could cause promote in mucous cohesive properties that

increase in mucoadhesion. Swelling should favor polymer chain flexibility and interpenetration between polymer and mucin chains

.Depending on the type of formulation, polymers with different characteristics have to be considered. Examples: Hydroxy

ethylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, carbopol and other mucoadhesive polymers

C. Diluents:

Lactose DC is selected as diluent for its high aqueous solubility, its flavouring characteristics, and its physico-mechanical

properties, which make it suitable for direct compression, other example : microcrystalline starch and starch.

D. Sweetening agents:

Sucralose, aspartame, mannitol, etc.

E. Flavouring agents:

Menthol, vanillin, clove oil, etc.

F. Backing layer:

Ethyl cellulose, etc.

G. Penetration enhancer: Cyano acrylate, etc.

H. Plasticizers:

PEG-100, 400, propylene glycol, etc.

CHARACTERISTICS OF PATCH[30]

Size of the flexible buccal patch may be as large as 10–15cm2 in area.

Mucoadhesive buccal patches with a surface area of 1–3 cm2 are most acceptable.

It has been estimated that the total amount of drug that can be delivered across the buccal mucosa from a 2-cm2 system in 1 day is

approximately 10–20 mg.

Shape of the delivery system may also vary, although for buccal drug administration, an ellipsoid shape appears to be most

acceptable.

Thickness of the delivery device is usually restricted to only a few millimeters. The location of delivery device also needs to be

considered

Maximal duration of buccal drug retention and absorption is approximately 4–6 h because food and/or liquid intake may require

removal of delivery device.

Physiology of mucus membrane under disease condition need to be accounted (for e.g.: Cancer patients suffer from oral

candidosis).

DESIGNS OF BUCCAL PATCHES[31]

1. Matrix design: (Bi directional)

The buccal patch designed in a matrix configuration containing drug, adhesive, and additives mixed together. Bi-directional

patches release drug in both the mucosa and the mouth.

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Figure.4 : Bi-Directional Buccal Patch.

2. Reservoir design:(Uni direction)

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.

Figure.5. : Unidirectional Buccal Patch.

Basically unidirectional types of buccal patches are used for both local as well as systemic effect.

METHODS OF PREPARATION OF BUCCAL PATCHES[30,31,32,33]

1. Solvent casting

2. Direct milling

3. Solid dispersion extrusion

4. Semisolid casting

5. Hot melt extrusion

1. Solvent casting

In this method of buccal patch preparation, the appropriate mucoadhesive polymers are collected and required quantity of

polymer or polymers is allowed to mix with suitable solvent on a magnetic stirrer to allow proper mixing and thus swelling of polymer

solution. Then weight quantity of plasticizer is added to the mixture and again kept on stirrer. Finally, drug is added to the solution and

the mixture is poured into the pre lubricated petri dishes. These are alowed to dry in oven or at room temperature and finally cut into

desired patches.

2. Direct milling

In this method, there is no use of solvents at any stage of formulation. The active pharmaceutical ingredient and the other

excipients are mixed well together and spread on the liner of roller. The roller compresses and directly formulates the appropriate

patches or films. Films are then collected separately.

3. Solid dispersion extrusion:

In this method no solvent is required,therefore, no residual solvent is left behind after the formulation and so no stability

issues occur in the shelf life of a product. The immiscible solid ingredients are mixed with the active pharmaceutical ingredient and

solid dispersions are prepared for better formulation. Solid dispersion refers to the formulation of two or more non soluble

compounds. The prepared mixture is then poured into dye and collected after drying and cut into appropriate portions.

4. Semisolid casting:

In semisolid casting method, firstly, a solution of water soluble polymers is prepared. Then this solution is added slowly to

the acid insoluble polymer mixture. Now suitable plasticizer is added to the above mixture to form a mixture with gel like consistency.

Finally this gel is poured onto the drum rollers and allowed to dry. Patches are collected after drying.

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5. Hot melt extrusion:

The Hot-melt extrusion (HME) technique is an attractive alternative to traditional processing methods and offers many

advantages over the other pharmaceutical processing techniques. Patches prepared through this method have better content uniformity.

The numbers of processing and time-consuming drying steps are reduced. The intense mixing and agitation imposed by the rotating

screw cause de-aggregation of suspended particles resulting in a more uniform dispersion and the process is continuous and efficient.

In hot melt extrusion method, firstly the drug is mixed with carriers without any use of solvent, in solid form. Then the extruder

consisting of heaters are used to melt the mixture. Finally, the melted mixture is given the shape of films or patches with the help of

dies. Hot-Melt Extrusion processes can be classified as:

(a). Ram extrusion

(b). Screw Extruders are of two types

i). Single Screw Extruder, ii).Twin-Screw Extruders

i). Single Screw Extruder

Fig.6..Hot melt extrusion apparatus.

EVALUATIONS OF BUCCAL PATCH[34,35,36,37]

1. Surface pH

Buccal patches are allowed to swell for 2 hours or more on the surface of an agar plate. The pH is measured by placing pH

paper on the surface of patch or it can also be measured by using combined glass electrode. The electrode can be brought near the

surface of patch and allowed to equillibriate for few minutes for ph measurement.

2. Thickness measurements

The patches from each batch are collected as sample and thickness of each patch can be measured at five different locations

i.e. centre and four corners, using a micrometer and an average of all the samples is reported.

3. Swelling index

The unswollen buccal patches are initially weighed individually,from each batch and allowed to be placed in the agar plate in

gel for some time. This slowly leads to swelling of the patches. Each patch is observed well and checked after an approximate interval

of about half-n-hour or more. The swelling of patches leads to an increase in the weight of patches. This procedure is repeated with all

the patches and variation in initial weight (X1) before swelling and final weight (X2) after swelling of patches is calculated according

to the following formula. This states the amount of water absorption by patches. Swelling of patches also leads to the incresae in area

of patches. This can also be calculated by using a graph paper to observe the variation in initial and final lengh and width of patches.

S.I = X2 - X1/ X1 x100

4. Pallatability test

This test is carried out on the basis of taste of the patches. As these are the buccal patches, so this character for evaluation

plays an important role. The patches are graded according to the criterea of taste wise better formulation. The bitter patches are graded

lowest or poor preparations, while patches with good taste are graded among the very good formulations. Patches should be patient

acceptable, i.e. good at taste so that it is patient friendly.

5. Morphological characterization

Morphological characters can be studied by using scanning electron microscope (SEM). This is carried out bye examination

of the sample of patches from each batch of the formulation for their physical appearance like shape, size, structure, colour, etc. An

average from all the batches is reported and the patches are categorized as good, very good, etc.

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6. Ageing

This criteria of evaluation is carried out under accelerated stability conditions. The patches are stored in petri dish covered

with aluminium foil for about 6 months in an incubator at accelerated temperature and humidity. The patches are observed for any

kind of change in the appearance, release time, resident time, etc. Patches are investigated each month upto 6 months and a report of

average behaviour of each patch is prepared.

7. Ex-vivo bioadhesion test

The fresh sheep mouth separated and washed with phosphate buffer (pH 6.8). A piece of gingival mucosa is tied in the open

mouth of a glass vial, filled with phosphate buffer (pH 6.8). This glass vial is tightly fitted into a glass beaker filled with phosphate

buffer (pH 6.8, 37°C ± 1°C) so it just touched the mucosal surface. The patch is stuck to the lower side of a rubber stopper with cyano

acrylate adhesive. Two pans of the balance are balanced with a 5-g weight. The 5 g weight is removed from the left hand side pan,

which loaded the pan attached with the patch over the mucosa. The balance is kept in this position for 5 minutes of contact time. The

water is added slowly at 100 drops/min to the right-hand side pan until the patch detached from the mucosal surface. The weight, in

grams, required to detach the patch from the mucosal surface provided the measure of mucoadhesive strength.

8. In vitro drug release

The United States Pharmacopeia rotating paddle method is used under sink conditions to study the drug release. The

phosphate buffer with pH 6.8 is used. The evauation is performed at 37°C ± 0.5°C, with a rotation speed of 50 rpm. The buccal patch

is attached to the glass disc.Samples (5 ml each) are withdrawn at predetermined time intervals and replaced with fresh medium. The

samples are filtered via whattman filter paper and studied for drug release content using ultra violet spectrophotometer. This release

study is carried out usually by using franz diffusion cell for buccal patches.

Fig.7. In-vivo drug release apparatus.

10. Ex-vivo mucoadhesion time

The ex-vivo mucoadhesion time performed after application of the buccal patch on freshly cut buccal mucosa (sheep and

rabbit). The fresh buccal mucosa is tied on the glass slide, and a mucoadhesive patch is wetted with 1 drop of phosphate buffer pH 6.8

and pasted to the buccal mucosa by applying a light force with a fingertip for 30 seconds. The glass slide is then put in the beaker,

which is filled with 200 ml of the phosphate buffer pH 6.8, is kept at 37°C ± 1°C. After 2 minutes, a 50-rpm stirring rate is applied to

simulate the buccal cavity environment, and patch adhesion is monitored for 12 hours. The time for changes in colour, shape,

collapsing of the patch, and drug content is noted.

11. Measurement of mechanical properties

Mechanical property includes tensile strength study. Tensile strength states the break at elongation of the patch. The patches

must have good tensile strength so as to avoid breakage or damage while transportation and handling. For this study, small and

appropriate portions of patches are cut from each batch. The cut portions are preobserved for no cuts and defects. Tensile tester is used

for this purpose. The pieces of patches are placed between the two ends of the tester and by keeping one end stationary, another end is

elongated with predetermined force upto a certain distance(about 2cm). Tensile strength (kg/mm2) is the force at break (kg) per initial

cross- sectional area of the specimen (mm2). The force and distance at the point where patch breaks down is reported. Tensile strength

further can be calculated by using the following formula:

T.S. = m x g / b x t kg/mm2

Where,M-mass in gm,

G-acceleration due to gravity 980 cm/sec2

B-breadth of the specimen in cm

T -thickness of specimen in cm.

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Fig.8. Mechanical property measurement apparatus.

12. Folding Endurance

The folding endurance of patches is calculated by collecting samples from each batch and repeatedly folding a patch from the

same point till it breaks down. This procedure is done for the patches of each batch and an average of all is reported as mean folding

endurance for all.

13. Drug- excipient interaction study

Drug and different polymers or excipients used to formulate a buccal patch formulation must be compatible with each other

in order to formulate a successful and appropriate preparation. This can be done by applying different methods like infrared radiation

study, differential scanning calorimetery, thin layer chromatography, etc. Therefore, any change in the behaviour of drug or excipient

or any type of incompatability can be studied and observed by this.

APPLICATIONS[38]

•Multilayer drug film construction is possible, which an emerging area for immediate application. Two or more drugs could be

combined into one format and the layers may be formulated to have the same or various dissolution rates.

• The films can be formulated in such a way that the dissolution rates of the drugs can range from minutes to hours.

.Films acts as gastro retentive dosage forms, in which the dissolution of the films could be triggered by the pH or enzyme secretions of

gastro intestinal tract, and could be potentially used to treat gastro intestinal disorders

CONCLUSION

The buccal mucosa offers several advantages for controlled drug delivery for extended periods of time. Buccal region

provides a convenient route of administration for both local and systemic drug actions. Mucoadhesive buccal patches have

applications from different angles includes avoiding first-pass metabolism in the liver and pre-systemic elimination in the

gastrointestinal tract. 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 in 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 noninvasive delivery of potent peptide and protein drug

molecules.

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