Buccal Drug Delivery System – An Overview

 

*M Alagusundaram1, C Madhusudhana Chetty1, K Umasankari1, P Anitha1, K Gnanprakash1 and D Dhachinamoorthi2

1 Annamacharya College of Pharmacy, Rajampet, Andhra Pradesh, India.

2QIS College of Pharmacy, Ongole, Andhra Pradesh, India.

*Corresponding Author E-mail: alagu_sundaram@rediffmail.com

 

ABSTRACT

The oral cavity has long been a site for mucosal and transmucosal delivery of drugs via Buccal route. However, as Buccal delivery, because of its undeniable advantages, has become popular for systemic drug delivery and prolonged well controlled release has been identified as beneficial, especially for chronic diseases. The buccal mucosa offers an alternative route to conventional, parenteral administration. It associated with buccal drug delivery have rendered this route of administration useful for a variety of drugs. The strategies to overcome the main obstacles that drugs meet when administered via the buccal route include the employment of new materials that, possibly, combine mucoadhesive, enzyme inhibitory and penetration enhancer properties. Buccal mucosa offers innovative drug delivery systems which, besides improving patient compliance, favor a more intimate contact of the drug with the rapid buccal absorption in mucosa. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research. With the right dosage form design, local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution and permeation. Further, these dosage forms are self administrable, cheap and have superior patient compliance.

 

KEYWORDS: Buccal delivery, Transmucosal delivery, Controlled release, Patient compliance.

 

 


INTRODUCTION:

Based on biochemical and physiological aspects of absorption and metabolism of many biotechnologically-produced drugs, they cannot be delivered effectively through the conventional oral route. Difficulties associated with parenteral delivery and poor oral availability provided the impetus for exploring alternative routes for the delivery of such drugs. Various strategies have been implemented to promote the bioavailability of these drugs, including supplemental administration of enzyme inhibitors, use of absorption enhancers, novel formulation strategies, and reversible chemical modifications. Among the various transmucosal routes, buccal mucosa has excellent accessibility, an expanse of smooth muscle and relatively immobile mucosa, hence the buccal region of oral cavity is an attractive target for the delivery of drug of choice1. The mucosal drug administration aims to achieve a site-specific release of drug on the mucosa, where as the trans-mucosal drug administration involves drug absorption through the mucosal barrier to reach the systemic circulation. The main impendent to the use of many hydrophilic macro-molecular drugs as potential therapeutic agents is their inadequate and erratic oral absorption, which are found to be favorable candidates for administration via the buccal route.

 

Advantages:

1.      It is richly vascularised and more accessible for administration and removal of dosage forms.

2.      High patient accessibility.

3.      An expanse of smooth muscle and relatively immobile mucosa, (suitable for administration of retentive dosage forms.

4.      Direct access to systemic circulation through the internal jugular vein bypasses drugs from hepatic first pass metabolism, leading to high bioavailability.

5.      More rapid cellular recovery and achievement of a localized site on smooth surface of buccal mucosa.

6.      Low enzyme activity, suitability for drugs/ excipients that mildly and reversibly damages or irritates the mucosa.

7.      Non-invasive method of drug administration.

8.      Facility to include permeation enhancer or enzyme inhibitor or pH modifier in the formulation.

Disadvantages

1.      Low permeability of buccal membrane.

2.      Small surface area2 (170 cm2).

3.      Subsequent dilution of the drug due to continuous secretion of saliva.

4.      Inconvenience of patient when eating or drinking.

Limitations

1.      Effect of salivary scavenging.

2.      Accidental swallowing of delivery system.

3.      Barrier property of buccal mucosa.


 

Fig.1. Anatomy of the oral mucosa

 


Anatomy of oral mucosa:

Buccal region is that part of the mouth bounded anteriorly and laterally by the lips and the cheeks, posteriorly and medially by the teeth and/or gums, and above and below by the reflections of the mucosa from the lips and cheeks to the gums. The buccal glands are placed between the mucous membrane and buccinator muscle: they are similar in structure to the labial glands, but smaller. Maxillary artery supplies blood to buccal mucosa and blood flow is faster and richer (2.4ml/min/cm2) than that in the sublingual, gingival and palatal regions, thus facilitates passive diffusion of drug molecules across the mucosa3. The thickness of the buccal mucosa is measured to be 500–800 μm and is rough textured, hence suitable for retentive delivery systems4. The turnover time for the buccal epithelium has been estimated at 5–6 days5.

 

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 tissues6. Oral cavity is lined with the epithelium, below which lies the supporting basement membrane. The basement membrane is, in turn, 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

 

b)      Keratinized epithelium which is found in the hard palate and non-flexible regions of the oral cavity7. The basement membrane forms a distinctive layer between the connective tissues and the epithelium. It provides the required adherence between the epithelium and the underlying connective tissues, and functions as a mechanical support for the epithelium. The underlying connective tissues provide many of the mechanical properties of oral mucosa.

 

Drug transport mechanisms:

The main mechanisms responsible for the penetration of various substances include simple diffusion (paracellular and transcellular), carrier-mediated diffusion, active transport and pinocytosis or endocytosis. Passive diffusion is the primary mechanism for the transport of drugs across the buccal mucosa, although carrier-mediated transport has been reported to have a small role6.

 

Rate of penetration varies depending on the physicochemical properties of the molecule and the type of tissue being traversed. This has led to the suggestion that materials uses one or more of the following routes simultaneously to cross the barrier region in the process of absorption, but one route is predominant over the other depending on the physicochemical properties of the diffusant8.

1.      Passive diffusion:

·        Transcellular or intracellular route (crossing the cell membrane and entering the cell)

·        Paracellular or intercellular route (passing between the cells)

2.      Carrier mediated transport:

 

 

3.      Endocytosis:

Depending on the nature of the permeant, i.e. the overall molecular geometry, lipophilicity, and charge, either of the transport pathways across buccal epithelium can be selected. Most compounds diffuse through the buccal mucosa by passive diffusion or simple Fickian diffusion9.

 

The flux of drug through the membrane under sink condition for paracellular route can be written as

         DP ε

JP = ---------- Cd

         hP

Where, Dp is diffusion coefficient of the permeate in the intercellular spaces, hp is the path length of the paracellular route, ε is the area fraction of the paracellular route and Cd is the donor drug concentration.

 

Similarly, flux of drug through the membrane under sink condition for transcellular route can be written as Eq. (2).

          (1- ε) Dc Kc

Jc = ------------------Cd

               hc

Where, Kc is partition coefficient between lipophilic cell membrane and the aqueous phase, Dc is the diffusion coefficient of the drug in the transcellular spaces and hc is the path length of the transcellular route.

 

Some are transported by a carrier mediated process across the buccal mucosa. Glucose9, monocarboxylic acids and salicylic acid10 and nicotinic acid are examples of substances which utilize a carrier-mediated diffusion mechanism for permeation across buccal epithelium. The use of mucoadhesive as enzyme inhibitor agents has been developed to overcome this obstacle in peptide and protein delivery.

 

Barriers to penetration across buccal mucosa:

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 epithelium11.

Ø  Cored granules

Ø  Basement membrane

Ø  Mucus

Ø  Saliva

 

Cored granules:

In nonkeratinized epithelia, the accumulation of lipids and cytokeratins in the keratinocytes is less evident and the change in morphology is far less marked than in keratinized epithelia. The mature cells in the outer portion of nonkeratinized epithelia become large and flat retain nuclei and other organelles and the cytokeratins do not aggregate to form bundles of filaments as seen in keratinizing epithelia.

The membrane-coating granules found in non keratinizing epithelia are spherical in shape, membrane-bounded and measure about 0.2 μm in diameter. Such granules have been observed in a variety of other human nonkeratinized epithelia, including uterine cervix and esophagus. However, current studies employing ruthenium tetroxide as a post-fixative indicate that in addition to cored granules, a small proportion of the granules in nonkeratinized epithelium do contain lamellae, which may be the source of short stacks of lamellar lipid scattered throughout the intercellular spaces in the outer portion of the epithelium.

 

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.

 

Mucus:

The epithelial cells of buccal mucosa are surrounded by the intercellular ground substance called mucus with the thickness varies from 40 μm to 300 μm. Though the sublingual glands and minor salivary glands contribute only about 10% of all saliva, together they produce the majority of mucus and are critical in maintaining the mucin layer over the oral mucosa. It serves as an effective delivery vehicle by acting as a lubricant allowing cells to move relative to one another and is believed to play a major role in adhesion of mucoadhesive drug delivery systems12. At buccal pH mucus can form a strongly cohesive gel structure that binds to the epithelial cell surface as a gelatinous layer11. Mucus molecules are able to join together to make polymers or an extended three-dimensional network. Different types of mucus are produced, for example G, L, S, P and F mucus, which form different network of gels. Other substances such as ions, protein chains, and enzymes are also able to modify the interaction of the mucus molecules and, as a consequence, their biophysical properties13. Mucus is composed chiefly of mucins and inorganic salts suspended in water. Mucins are a family of large, heavily glycosylated proteins composed of oligosaccharide chains attached to a protein core. Three quarters of the protein core are heavily glycosylated and impart a gel like characteristic to mucus. Mucins contain approximately 70–80 % carbohydrate, 12–25 % protein and up to 5 % ester sulphate. The dense sugar coating of mucins gives them considerable water-holding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers.

 

Saliva:

The mucosal surface has a salivary coating estimated to be 70 μm thick14, which act as unstirred layer. Within the saliva there is a high molecular weight mucin named MG115 that can bind to the surface of the oral mucosa so as to maintain hydration, provide lubrication, concentrate protective molecules such as secretory immunoglobulins, and limit the attachment of microorganisms.

 

The major salivary glands consist of lobules of cells that secrete saliva; parotids through salivary ducts near the upper teeth, submandibular under the tongue, and the sublingual through many ducts in the floor of the mouth. Besides these glands, there are 600–1000 tiny glands called minor salivary glands located in the lips, inner cheek area (buccal mucosa), and extensively in other linings of the mouth and throat.

 

Total output from the major and minor salivary glands is termed as whole saliva, which at normal conditions has flow rate of 1–2 ml/min. The normal pH of saliva is 5.6–7. Saliva contains enzymes namely α-amylase (breaks 1–4 glycosidic bonds), lysozyme (protective, digests bacterial cell walls) and lingual lipase (break down the fats)16. Saliva serves multiple important functions. It moistens the mouth, initiates digestion and protects the teeth from decay. It also controls bacterial flora of the oral cavity.

 

Lysozyme, secretory IgA, and salivary peroxidase play important roles in saliva's antibacterial actions. Lysozyme agglutinates bacteria and activates autolysins. IgA interferes with the adherence of microorganisms to host tissue. Peroxidase breaks down salivary thiocyanate, which in turn, oxidizes the enzymes involved in bacterial glycolysis.

 

In general, intercellular spaces pose as the major barrier to permeation of lipophilic compounds, and the cell membrane which is lipophilic in nature acts as the major transport barrier for hydrophilic compounds because it is difficult to permeate through the cell membrane due to a low partition coefficient . Permeabilities between different regions of the oral cavity vary greatly because of the diverse structures and functions. In general, the permeability is based on the relative thickness and degree of keratinization of these tissues in the order of sublingual>buccal>palatal. The permeability of the buccal mucosa was estimated to be 4–4000 times greater than that of the skin17.

 

Muco adhesion:

In 1986, Longer and Robinson defined the termbioadhesion” as the attachment of a synthetic or natural macromolecule to mucus and/or an epithelial surface. The general definition of adherence of a polymeric material to biological surfaces (bioadhesives) or to the mucosal tissue (mucoadhesives) still holds.

 

Factors affecting muco adhesion:

Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. A variety of factors affect the mucoadhesive properties of polymers, such as molecular weight, flexibility, hydrogen bonding capacity, cross-linking density, charge, concentration, and hydration (swelling) of a polymer, which are briefly addressed below.

I. Polymer related factors:

1. Molecular weight:

In general, it has been shown that the bioadhesives strength of a   polymer increases with molecular weights above 100,00018. As one example, the direct correlation between the bioadhesives strength of polyoxyethylene polymers and their molecular weights, in the range of 200,000 to 7,000,000.

 

2. Flexibility:

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. A recent publication demonstrated the use of tethered poly (ethylene glycol)–poly (acrylic acid) hydrogels and their copolymers with improved mucoadhesive properties19. The increased chain interpenetration was attributed to the increased structural flexibility of the polymer upon incorporation of poly (ethylene glycol). In general, 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 network20.

 

3. Hydrogen bonding capacity:

Hydrogen bonding is another important factor in mucoadhesion of a polymer. They have also confirmed that flexibility of the polymer is important to improve this hydrogen bonding potential. Polymers such as poly (vinyl alcohol), hydroxylated methacrylate, and poly (methacrylic acid), as well as all their copolymers, are polymers with good hydrogen bonding capacity21.

 

4. Cross-linking density:

The average pore size, the number average molecular weight of the cross-linked polymers and the density of crosslinking are three important and interrelated structural parameters of a polymer network20. Therefore, it seems reasonable that 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.

 

5. 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 mucoadhesion21. It has been shown that some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium22. Additionally, some cationic high-molecular-weight polymers, such as chitosan, have shown to possess good adhesive properties23.

 

6. Concentration:

The importance of this factor lies in the development of a strong adhesive bond with the mucus, and can be explained by the polymer chain length available for penetration into the mucus layer. When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small, and the interaction between polymer and mucus is unstable21. 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 a bunperturbed state due to a significantly coiled structure. As a result, the accessibility of the solvent to the polymer decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improve and, in somecases, actually diminish mucoadhesive properties.

 

7. Hydration (swelling):

Hydration is required for a mucoadhesive polymer to expand and create a proper macromolecular mesh20 of sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin. Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network. However, a critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and bioadhesion occurs21.

II. Environmental factors:

Saliva, as a dissolution medium, affects the behavior of the polymer. Depending on both the saliva flow rate and method of determination, the pH of this medium has been estimated to be between 6.5 and 7.524. The pH of the microenvironment surrounding the mucoadhesive polymer can alter the ionization state and, therefore, the adhesion properties of a polymer. Mucin turnover rate is another environmental factor. The residence time of dosage forms is limited by the mucin turnover time, which has been calculated to range between 47 and 270 min in rats25 and 12–24 h in humans26. Movement of the buccal tissues while eating, drinking, and talking, is another concern which should be considered when designing a dosage form for the oral cavity. Movements within the oral cavity continue even during sleep, and can potentially lead to the detachment of the dosage form. Therefore, an optimum time span for the administration of the dosage form is necessary in order to avoid many of these interfering factors.

 

Methods for measuring muco adhesion:

These tests are important during the design and development of a mucoadhesive release system to study compatibility, stability, surface analysis and bioadhesive bond strength. These tests are broadly classified in to qualitative methods and quantitative methods.

 

Quantitative methods:

These are also called macroscopic methods. The majority of the quantitative bio and/or mucoadhesion measurement methods found in the literature are based on measuring the force required to break the adhesive bond between the model membrane and the adhesive. Depending on the direction in which the adhesive is being separated from the substrate, peel, shear, and tensile forces can be measured.

 

1.      Determination of peel strength:

The peel adhesion tests are mainly used for buccal and transdermal patches27 .The test is based on the calculation of energy required to detach the dosage form from the substrate material (usually excised buccal mucosa) attached through the bioadhesive material

Fracture Energy (G)

            P (1- Cos θ)

G = --------------------

              W

Where; P is the peel force, w is the peel width

 

Peel work is the sum of the following components

Ø  Surface energy that results from the creation of two free surfaces (energy of dewetting) also referred to as the intrinsic work of adhesion (or cohesion)

Ø  Bulk energy that dissipates into the stripping member

Ø  Strain energy in the newly detached strip

 

Intrinsic work of adhesion (or cohesion) is independent of the following:

§  Peel rate (speed)

§  Peel angle

§  Thickness of the adhesive

§  Thickness of the stripping member

 

Values of intrinsic work of adhesion vary from0.07 J/m squared for hydrocarbon Vanderwaal's interactions, 2 J/m squared for a system with covalent bonding as part of the adhesion. The work of fracture can be several orders of magnitude greater than the intrinsic work of adhesion

 

2.      Determination of shear strength:

Shear stress, τ is the force acting tangentially to a surface divided by the area of the surface. It is the force per unit area required to sustain a constant rate of fluid movement. Mathematically, shear stress can be defined as:

τ = F/A

Where, τ = shear stress, F = force and A = area of the surface subjected to the force.

 

If a fluid is placed between two parallel plates spaced 1.0 cm apart, and a force of 1.0 dyn is applied to each square centimeter of the surface of the upper plate to keep it in motion, the shear stress in the fluid is 1 dyn/cm2 at any point between the two plates3. Shear stress measures the force that requires causing the bioadhesive to slide with respect to the mucus layer in a direction parallel to their plane of contact.

 

3.      Determination of tensile strength:

Tensile stress is also termed Maximum Stress or Ultimate Tensile Stress. The resistance of a material to a force tending to tear it apart, measured as the maximum tension the material can withstand without tearing.

 

Tensile strength can be defined as the strength of material expressed as the greatest longitudinal stress it can bear without tearing apart. As it is the maximum load applied in breaking a tensile test piece divided by the original cross-sectional area of the test piece, it is measured asNewtons/sq.m. Methods using the tensile strength usually measure the force required to break the adhesive bond between a model membrane and the test polymers. Mucoadhesive material is to be tested for its shear stresses by clamping the model mucosal surface between two plates, one having a U-shaped section cut away to expose the test surface28. The tablet was attached to a Perspex disc, and then placed into contact with the exposed mucosa at the base of the U shaped cut.

 

4.      Colloidal gold staining method:

The technique employs red colloidal gold particles, which were adsorbed on mucin molecules to form mucin–gold conjugates, which upon interaction with bioadhesive hydrogels develops a red color on the surface. This can be quantified by measuring at 525 nm either the intensity on the hydrogel surface or the conjugates29.

 

5.      Direct staining method:

It is a novel technique to evaluate polymer adhesion to human buccal cells following exposure to aqueous polymer dispersion, both in vitro and in vivo. Adhering polymer was visualized by staining with 0.1 % w/v of either Alcian blue or Eosin solution; and the uncomplexed dye was removed by washing with 0.25M sucrose. The extent of polymer adhesion was quantified by measuring the relative staining intensity of control and polymer treated cells by image analysis3.

 

Qualitative methods:

These methods are useful for preliminary screening of the respective polymer for its bio or mucoadhesion, compatibility and stability. However, these methods are not useful in measuring the actual bioadhesive strength of the polymers. They are

 

1.      Viscometric method:

A simple viscometric method30 is to quantify mucin–polymer bioadhesive bond strength. Viscosities of 15 % w/w porcine gastric mucin dispersion were measured with Brookfield's viscometer. In absence or presence of selected neutral, anionic and cationic polymer, viscosity components and the forces of bioadhesion were calculated.

 

2.      Analytical ultracentrifuge criteria for muco adhesion

These methods are useful in identifying the material that is able to form complexes with the mucin. The assay can be done for change in molecular mass using sedimentation equilibrium, but this has an upper limit of less than 50 MDa. Since complexes can be very large, a more sensible assay procedure is to use sedimentation velocity with change in sedimentation coefficient, S, as their marker for mucoadhesion. Where mucin is available in only miniscule amounts, a special procedure known as Sedimentation Fingerprinting can be used for assay of the effect on the mucoadhesive. UV absorption optics is used as the optical detection system. However, in this case the mucoadhesive is invisible, but the pig gastric mucin at the concentrations normally employed is visible. The sedimentation ratio (scomplex/smucin), the ratio of the sedimentation coefficient of any complex involving the mucin to that of pure mucin itself, is used as the measure for mucoadhesion31.

 

3.      Atomic force microscopy:

This method is based on the changes in surface topography when the polymer bound on to buccal cell surfaces. Unbound cells shows relatively smooth surface characteristics with many small craters like pits and indentations spread over cell surfaces; while polymer bound cells will loose crater and indentation characteristics and gained a higher surface roughness3.

 

4.      Electrical conductance:

Modified rotational viscometer is used to determine electrical conductance of various semi-solid mucoadhesive ointments and found that the electrical conductance was low in the presence of adhesive material3.

 

5.      Fluorescent probe method:

In this method the membrane lipid bilayered and membrane proteins were labeled with pyrene and fluorescein isothiocyanate, respectively. The cells were mixed with the mucoadhesive agents and changes in fluorescence spectra were monitored. This gave a direct indication of polymer binding and its influence on polymer adhesion32.

 

6.      Lectin binding inhibition technique:

The method involves an avidin–biotin complex and a colorimetric detection system to investigate the binding of bioadhesive polymers to buccal epithelial cells without having to alter their physicochemical properties by the addition of marker entities33.

7.      Thumb test:

This is a very simple test used for the qualitative determination of peel adhesive strength of the polymer and is useful tool in the development of buccal adhesive delivery systems. The adhesiveness is measured by the difficulty of pulling the thumb from the adhesive as a function of the pressure and the contact time. Although the thumb test may not be conclusive, it provides useful information on peel strength of the polymer3.

 

Mucoadhesive polymers:

Polymer is a generic term used to describe a very long molecule consisting of structural units and repeating units connected by covalent chemical bonds. Bioadhesive formulations use polymers as the adhesive component. These formulations are often water soluble and when in a dry form attract water from the biological surface and this water transfer leads to a strong interaction. These polymers also form viscous liquids when hydrated with water that increases their retention time over mucosal surfaces and may lead to adhesive interactions. Bioadhesive polymers should possess certain physicochemical features including hydrophilicity, numerous hydrogen bond-forming groups, flexibility for interpenetration with mucus and epithelial tissue and visco-elastic properties34.

 

Ideal characteristics:3

Polymer and its degradation products should be non-toxic, non-irritant and free from leachable impurities.

1.      Should have good spreadability, wetting, swelling and solubility and biodegradability properties.

2.      pH should be biocompatible and should possess good visco-elastic properties.

3.      Should adhere quickly to buccal mucosa and should possess sufficient mechanical strength.

4.      Should possess peel, tensile and shear strengths at the bioadhesive range.

5.      Polymer must be easily available and its cost should not be high.

6.      Should show bioadhesive properties in both dry and liquid state.

7.      Should demonstrate local enzyme inhibition and penetration enhancement properties.

8.      Should demonstrate acceptable shelf life.

9.      Should have optimum molecular weight.

10.    Should possess adhesively active groups.

11.    Should have required spatial conformation.

12.    Should be sufficiently cross-linked but not to the degree of suppression of bond forming groups.

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

 

CLASSIFICATION:6

Buccal adhesive polymers can be classified as follows based on:

1.      Source:

·   Natural:   e.g. Agarose, chitosan, gelatin, Hyaluronic acid,

Various gums (guar, hakea, xanthan, gellan, carragenan,

Pectin and sodium alginate)

·   Synthetic: e.g. Cellulose derivatives

[CMC, Thiolated CMC, sodium CMC, HEC, HPC, HPMC,

MC, methylhydroxyethylcellulose] Poly (acrylic acid)-based polymers

 

2.      Aqueous solubility:

·   Water soluble: e.g. CP, HEC, HPC (waterb38 8C), HPMC (cold water),  PAA, sodium CMC, sodium alginate

·   Water insoluble: e.g. Chitosan (soluble in dilute aqueous acids), EC, PC

3.      Charge:

Cationic: e.g. Aminodextran, chitosan, dimethylaminoethyl (DEAE)- Dextran, trimethylated chitosan

Anionic : e.g. Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium

alginate, sodium CMC, xanthan gum

Non-ionic: e.g.: Hydroxyethyl starch, HPC, poly(ethylene oxide), PVA PVP, scleroglucan

4.      Potential bio-adhesive forces:

·   Covalent: e.g.: Cyanoacrylate

Hydrogen bond: e.g.: Acrylates [hydroxylated methacrylate, poly(methacrylic acid)], CP, PC, PVA

·   Electro-static interaction : e.g.: Chitosan

 

Factors governing drug release from a polymer:

For a given drug the release kinetics from the polymer matrix could be governed predominantly by the polymer morphology and excipients present in the system. Drug release from a polymeric material takes place either by the diffusion or by polymer degradation or by a combination of the both. Polymer degradation generally takes place by the enzymes or hydrolysis either in the form of bulk erosion or surface erosion

·   Polymer morphology

The polymer matrix could be formulated as macro or nanospheres, gel film or an extruded shape (cylinder, rod etc). Also the shape of the extruded polymer can be important to the drug release kinetics. It has been shown that zero order release kinetics can be achieved using hemispherical polymer form.

·   Excipients:

The main objective of incorporating excipients in the polymer matrix is to modulate polymer degradation kinetics. Studies carried out have shown that by incorporating basic salts as excipients slow down the degradation and increase the stability of protein polymers. Similarly hydrophilic excipients can accelerate the release of drugs although they may also increase the initial burst effect.

 

Formulation design:

Buccal adhesive drug delivery systems with the size 1–3 cm2 and a daily dose of 25 mg or less are preferable. The maximal duration of buccal delivery is approximately 4–6 h35.

 

General considerations in dosage form design:

1.      Pharmaceutical considerations.

2.      Physiological considerations.

3.      Pathological considerations.

4.      Pharmacological considerations.

 

1. Pharmaceutical considerations:

Regardless of dosage form types, the drug must be released from the delivery system and subsequently taken up by the oral mucosa. Poor drug solubility in saliva could significantly retard drug release from the dosage form. Cyclodextrin has been used to solubilize and increase the absorption of poorly water-soluble drugs delivered via the buccal mucosa36. In addition to the physicochemical characteristics required for desirable drug release and absorption, organoleptic properties of the drug or the delivery device should also be considered, since the buccal delivery systems are to be exposed to a highly developed sensory organ. Some excipients may be incorporated to enhance the effectiveness and acceptability of the dosage forms. Selection of formulation excipients is yet another important consideration, since acidic compounds can stimulate the secretion of saliva, which enhances not only drug dissolution, but also drug loss by involuntary swallowing.

 

Permeability of the buccal mucosa can be increased by various penetration enhancers capable of increasing cell membrane fluidity. Extracting the structural intercellular and/or intracellular lipids, altering cellular proteins, or altering mucus structure and rheology37.

 

Susceptible drugs, especially peptides and proteins, can be degraded by the enzymes in saliva and buccal mucosa. Therefore, enzyme inhibitors may be incorporated in the dosage forms to increase drug bioavailability38. It might be desirable to include some pH modifiers in the formulation in order to temporarily modulate the microenvironment at the application site for better drug absorption. It is worth noting that pH can also influence the charge on the surface of the mucus, as well as certain ionizable groups of the polymers, which might affect the strength of mucoadhesion. In addition, it has been shown that the pH of the medium influences the degree of hydration of cross-linked poly (acrylic acid)39, 40.

 

2. Physiological considerations:

Constant flow of saliva and mobility of the involved tissues challenge drug delivery to the oral cavity. The residence time of drugs delivered to the oral cavity is typically short, in the range of <5–10 min41. Buccal mucoadhesive formulations are expected to overcome this problem. Bioadhesive polymers offer a means by which a delivery system is attached to the buccal mucosa, and hence, provide substantially longer retention times at the absorption site. They also provide a means to confine and maintain high local concentrations of the drug and/or excipients to a defined, relatively small region of the mucosa in order to minimize loss to other regions and limit potential side effects.

 

In general, a buccal delivery device that is 1–3 cm2 in size42 and a drug with a daily dose requirement of 25 mg or less43 would be preferred. In addition, an ellipsoid shape appears to be most acceptable44 and the thickness of buccal delivery devices is usually limited to a few millimeters45.

 

The mucus layer covering the buccal mucosa is necessary for bioadhesive systems. Unfortunately, it not only forms a physical barrier to drug permeation, but also prevents long-term bioadhesion and sustained drug release by its short turnover time. Interestingly, the presence of bioadhesive polymers on a mucous membrane might alter the turnover of mucin, since the residence time of mucoadhesives are usually longer than the reported mucin turnover time46. Nevertheless, the maximum duration for buccal drug delivery is usually limited to approximately 4–6 h, since meal intake and/or drinking may require dosage form removal47.

 

3. Pathological considerations:

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 mucus48, as well as the saliva. Changes at the mucosal surface due to these pathological conditions may complicate the application and retention of a bioadhesive delivery device.

 

4. 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 treated6.

 

Ideal properties of buccal drug delivery systems:

1.      Should release the drug in a controlled fashion

2.      Should provide drug release in an unidirectional way toward the mucosa.

3.      Should facilitate the rate and extent of drug absorption.

4.      Should not cause any irritation or inconvenience to the patient.

5.      Should not interfere with the normal functions such as talking, drinking etc.

 

Several approaches of buccal drug delivery system are:

1.      Non-attached drug delivery systems:

·   Fast dissolving tablet dosage forms.

·   Chewing gum formulations.

·   Micro-porous hollow fibres.

2.      Bio-adhesive drug delivery systems:

·   Solid buccal adhesive dosage forms.

·   Semi-solid buccal adhesive dosage forms.

·   Liquid buccal adhesive dosage forms.

3.      Liposome

4.   Delivery of proteins and peptides.

 

1. Non-attached drug delivery system:

Non-attached drug delivery system has many drawbacks due to the local physiological environment, e.g. the presence of saliva and the intake of foods and liquids49.

 

2.   Bio-adhesive drug delivery systems:

2.1. Solid buccal adhesive dosage forms:

Dry formulations achieve bio-adhesion via dehydration of the local mucosal   surface.

 

2.1.1. Tablets:

Buccal tablets are small, flat, and oval, with a diameter of approximately 5–8 mm. Bioadhesive tablets are usually prepared by direct compression, but wet granulation techniques can also be used. Tablets that are placed directly onto the mucosal surface have been demonstrated to be excellent bioadhesive formulations. However, size is a limitation for tablets due to the requirement for the dosage form to have intimate contact with the mucosal surface. These tablets adhere to the buccal mucosa in presence of saliva. They are designed to release the drug either unidirectional targeting buccal mucosa or multidirectional in to the saliva3.

 

2.1.2. Micro-particles:

Bioadhesive micro particles offer the same advantages as tablets but their physical properties enable them to make intimate contact with a lager mucosal surface area. The small size of micro particles compared with tablets means that they are less likely to cause local irritation at the site of adhesion and the uncomfortable sensation of a foreign object within the oral cavity is reduced3.

 

2.1.3. Wafers:

Wafer is a drug delivery system with surface layers possessing adhesive properties, while the bulk layer consists of antimicrobial agents, biodegradable polymers and matrix polymers50.

 

2.1.4. Lozenges:

Conventional lozenges51 produce a high initial release of drug in the oral cavity, which rapidly declines to sub therapeutic levels, thus multiple daily dosing is required. A slow release bioadhesive lozenge offers the potential for prolonged drug release with improved patient compliance.

 

2.2. Semi-solid dosage forms:

2.2.1. Gels:

Gel forming bioadhesive polymers include cross linked polyacyclic acid that has been used to adhere to mucosal surfaces for extended periods of time and provide controlled release of drug at the absorption site. A limitation of gel formulations lies on their inability to deliver a measured dose of drug to the site. They are therefore of limited use for drugs with narrow therapeutic window52.

 

2.2.2. Buccal patches:

Patches are laminates consisting of an impermeable backing layer, a drug-containing reservoir layer from which the drug is released in a controlled manner, and a bioadhesive surface for mucosal attachment6. Two methods used to prepare adhesive Patches include solvent casting and direct milling. In the solvent casting method, the intermediate sheet from which patches are punched is prepared by casting the solution of the drug and polymer(s) onto a backing layer sheet, and subsequently allowing the solvent to evaporate. In the direct milling method, formulation constituents are homogeneously mixed and compressed to the desired thickness, and patches of predetermined size and shape are then cut or punched out. An impermeable backing layer may also be applied to control the direction of drug release, prevent drug loss, and minimize deformation and disintegration of the device during the application period.

 

2.2.3. Buccal films:

Films are the most recently developed dosage form for buccal administration. Buccal films may be preferred over adhesive tablets in terms of flexibility and comfort. In addition, they can circumvent the relatively short residence time of oral gels on the mucosa, which are easily washed away and removed by saliva. Moreover, in the case of local delivery for oral diseases, the films also help protect the wound surface, thus helping to reduce pain and treat the disease more effectively. An ideal film should be flexible, elastic, and soft, yet adequately strong to withstand breakage due to stress from mouth movements. It must also possess good bioadhesive strength in order to be retained in the mouth for the desired duration of action. Swelling of film, if it occurs, should not be too extensive in order to prevent discomfort. They are usually manufactured by a solvent casting method. The drug and polymer(s) are first dissolved in a casting solvent or solvent mixture. The solution is then cast into films, dried, and finally laminated with a backing layer or a release liner. The backing layer helps retard the diffusion of saliva into the drug layer, thus enhancing the adhesion time and reducing drug loss into the oral cavity. The solvent casting method is simple, but suffers from some disadvantages, including long processing time, high cost, and environmental concerns due to the solvents used. These drawbacks can be overcome by the hot-melt extrusion method53.

 

2.3. Liquid dosage forms:

Viscous liquids may be used to coat buccal surface either as protectants or as drug vehicles for delivery to the mucosal surface. Traditionally, pharmaceutically acceptable polymers were used to enhance the viscosity of products to aid their retention in the oral cavity. Dry mouth is treated with artificial saliva solutions that are retained on mucosal surfaces to provide lubrication. These solutions contain sodium CMC as bioadhesive polymer3.

 

3. Liposomes:

Liposome formulations with encapsulated drugs have been investigated for buccal administration54-57. Applications of liposome formulation in buccal delivery resulted in an increase of local, and a decrease of systemic, drug concentration. Peptide entrapment within liposome is also possible58. Liposome limits the transport of hydrophilic substances to the supercial layer of the epithelium. Among the hydrophilic polymers, polymethylmethacrylate was found to be the most appropriate mucoadhesive ointment for local application in the oral cavity since the liposomes were shown to be more stable in this polymer. Incorporation of protease inhibitors is one approach to improving the performance of less effective liposome peptide delivery systems59.

 

4. Delivery of proteins and peptides:

The buccal mucosa represents a potentially important site for controlled delivery of macromolecular therapeutic agents, such as peptides and protein drugs with some unique advantages such as the avoidance of hepatic first-pass metabolism, acidity and protease activity encountered in the gastrointestinal tract. Another interesting advantage is its tolerance (in comparison with the nasal mucosa and skin) to potential sensitizers3.

 

Evaluation:

In addition to the routine evaluation tests such as weight variation, friability, hardness, content uniformity, in vitro dissolution for tablets; tensile strength, film endurance, hygroscopicity etc for films and patches; viscosity, effect of aging etc for gels and ointments; buccal adhesive drug delivery devices are also to be evaluated specifically for their mucoadhesive strength and permeability.

 

I.            Determination of the residence time:

1. In vitro residence time:

It was determined using a modified USP disintegration. The disintegration medium composed of 800 ml isotonic phosphate buffer pH 6.75 maintained at 37 °C. A segment of rabbit intestinal mucosa, 3 cm long, was glued to the surface of a glass slab, vertically attached to the apparatus. The mucoadhesive tablet was hydrated from one surface using 15 ml IPB and then the hydrated surface was brought into contact with the mucosal membrane. The glass slab was vertically fixed to the apparatus and allowed to move up and down so that the tablet was completely immersed in the buffer solution at the lowest point and was out at the highest point. The time necessary for complete erosion or detachment of the tablet from the mucosal surface was recorded60.

 

2. In vivo residence time test:

The experiment was conducted on four human healthy volunteers of 25–50 years old. Plain bioadhesive tablets with optimized properties were selected for the in vivo evaluation. The bioadhesive tablet was placed on the buccal mucosa between the cheek and gingiva in the region of the upper canine and gently pressed onto the mucosa for about 30 s. The tablet and the inner upper lip were carefully moistened with saliva to prevent the sticking of the tablet to the lip. The volunteers were asked to monitor the ease with which the system was retained on the mucosa and note any tendency for detachment. The time necessary for complete erosion of the tablet was simultaneously monitored by carefully observing for residual polymer on the mucosa. In addition, any complaints such as discomfort, bad taste, dry mouth or increase of salivary flux, difficulty in speaking, irritation or mucosal lesions were carefully recorded. Repeated application of the bioadhesive tablets was allowed after a two days period for the same volunteer60

 

II. Permeation studies:

During the preformulation studies, buccal absorption/permeation studies must be conducted to determine the feasibility of this route of administration for the candidate drug and to determine the type of enhancer and its concentration required to control the rate of permeation of drugs. These studies involve methods that would examine in vitro, ex vivo and/or in vivo buccal permeation profile and absorption kinetics of the drug.

 

1. In vitro method:

An apparatus consisting of a water jacket and an internal compartment containing 50 ml of simulated saliva is taken as dissolution medium to study the release of cetylpyridinium chloride tablet by placing in the metal die sealed at the lower end by Paraffin wax to ensure the drug release from one end alone61. The medium was stirred with a rotating stirrer at 250 rpm. A novel dissolution testing system that is capable of characterizing buccal dissolution comprises of a single, stirred, continuous flow-through filtration cell that includes a dip tube designed to remove finely divided solid Particles62. Filtered solution is removed continuously and used to analyze for dissolved drug.

 

2.      Ex vivo methods:

Ex-vivo studies examining drug transport across buccal mucosa uses buccal tissues from animal models. Immediately after sacrificing the animals the buccal mucosal tissue is surgically removed from the oral cavity. The membranes are stored in Krebs buffer at 4 °C until mounted in the diffusion cells for the ex vivo permeation experiments. Preservation of the dissected tissue is an important issue that will affect the studies. There is no standard means by which the viability or the integrity of the dissected tissue can be assessed. The most meaningful method to assess tissue viability is the actual permeation experiment itself, if the drug permeability does not change during the time course of the study under the specific experimental conditions of pH and temperature, then the tissue is considered viable3.

 

3.           In vivo methods:

Selection of animal species:

Small animals including rats and hamsters have been used for performing permeability studies63. But unlike humans, most laboratory animals have totally keratinized oral lining, hence not suitable. The rat has a buccal mucosa with a very thick, keratinized surface layer. The rabbit is the only laboratory rodent that has non-keratinized mucosal lining similar to human tissue. But, the sudden transition to keratinized tissue at the mucosal margins makes it hard to isolate the desired non-keratinized region64. Among the larger experimental animals monkeys are practical models because of the difficulties associated with its maintenance. Dogs65 are easy to maintain and less expensive than monkeys66 and their buccal mucosa is non-keratinized and has a close similarity to that of the human buccal mucosa. Pigs also have non-keratinized buccal mucosa similar to that of human and their inexpensive handling and maintenance costs make them a highly suitable animal model for buccal drug delivery studies. In fact, the oral mucosa of pigs resembles that of human more closely than any other animal in terms of structure and composition67.

 

1.      Buccal absorption test:

Buccal absorption test is carried out by swirling of a 25 ml sample of the test solution for 15 min by human volunteers followed by the expulsion of the solution. The amount of drug remaining in the expelled volume is then determined to assess the amount of drug absorbed. The drawbacks of this method are inability to localize the drug solution within a specific site of the oral cavity, accidental swallowing of a portion of the sample solution and the salivary dilution of the drug.

 

2.           Modified buccal absorption test:

This method is developed for correcting the salivary dilution and accidental swallowing68, but these modifications also suffer from the inability of site localization.

3.           Perfusion system:

A circulating perfusion chamber attached to the upper lip of anesthetized dogs by cyanoacrylate cement and the drug solution is circulated through the device for a predetermined period of time69. Sample fractions are collected from the perfusion chamber and blood samples are drawn at regular intervals.

 

4.      Buccal perfusion cell apparatus:

Buccal perfusion cell apparatus70 provides continuous monitoring of drug loss as a function of time offers larger area for drug transfer and has no leakage problem. He used several methods to study the rate and extent of drug loss from human oral cavity. These include the buccal absorption test, disk methods and perfusion cells. These methods have provided information on the mechanism by which drugs are transported across oral cavity membranes and suggest that passive diffusion or carrier mediated transport systems may be involved.

 

CONCLUSION:

Mucus is a complex aqueous mixture of glycoprotein, lipid, salts and cellular debris covering many epithelial surfaces in the human body. It affords protection for the underlying tissues from various environmental insults and the effects of enzymes or other chemical agents. Hence, the buccal mucosa offers several advantages for controlled drug delivery for extended periods of time and it is well supplied with both vascular and lymphatic drainage. It avoids first pass metabolism and presystemic elimination. Buccal drug delivery can be promptly terminated in cases of toxicity through the removal of dosage form thereby offering a safe and easy method of drug utilization. Buccal drug delivery is a promising area for continued research with aim of systemic delivery of orally inefficient drugs as well as a feasible and attractive alternative for noninvasive delivery.

 

REFERENCES:

1.       Silvia Rossi, Giuseppina Sandri, Carla M. Caramella. Buccal drug delivery:  challenge already won? Drug discovery today: Technologies 2005; 2(1):59-65.

2.       L.M.C. Collins, C. Dawes, The surface area of the adult human mouth and thickness of the salivary film covering the teeth and oral mucosa. J. Dent. Res. 1987; 66:1300– 1302.

3.       Yajaman Sudhakar, Ketousetuo Kuotsu, A.K. Bandyopadhyay, Buccal bioadhesive drug delivery — A promising option for orally less efficient  drugs. Journal of Controlled Release2006; 114: 15–40.

4.       M.J. Rathbone, G. Ponchel, F.A. Ghazali, Systemic and oral mucosal drug delivery and delivery systems. Oral Mucosal Drug Delivery, Marcel Dekker Inc., New York, 1996; 74:241–284.

5.       D. Harris, J.R. Robinson, Drug delivery via the mucous membranes of the oral cavity.    J. Pharm. Sci. 1992; 81: 1–10.

6.       B Nazila Salamat-Miller, Montakarn Chittchang1, Thomas P. Johnston. The use of mucoadhesive polymers in buccal drug delivery. Advanced Drug Delivery Reviews 2005;57: 1666– 1691

7.       S.Y. Chen, C.A. Squier, The ultrastructure of the oral epithelium, in: J. Meyer, C.A. Squier, S.J. Gerson (Eds.). The Structure and Function of Oral Mucosa, Pergamon Press, Oxford, 1984: 7 –30.

8.       J. Hao, P.W.S. Heng, Buccal delivery systems. Drug Dev. Ind. Pharm. 2003; 29 (8) :821–832.

9.       Y. Oyama, H. Yamano, A. Ohkuma, K. Ogawara, K. Higaki, T. Kimura, Carrier-mediated transport systems for glucose in mucosal cells of the human oral cavity. J. Pharm. Sci. 1999; 88: 830–834.

10.     N. Utoguchi, Y. Watanabe, Y. Takase, T. Suzuki, M. Matsumoto, Carrier-mediated absorption of salicylic acid from hamster cheek pouch mucosa. J. Pharm. Sci. 1999; 88:142– 146.

11.     R.B.Gandhi, J.R. Robinson, Bioadhesion in drug delivery. Ind. J. Pharm. Sci. 1988; 50 (3): 145–152.

12.     N.A. Peppas, P.A. Buri, Surface, Interfacial and molecular aspect of polymer bioadhesion on soft tissues. J. Control. Release 1985; 2:257–275.

13.     E. Odeblad, The discovery of different types of cervical mucus. Bull. Ovul. Method Res. Ref. Cent. Aust. 1994; 21: 3–35.

14.     L.M.C. Collins, C. Dawes, The surface area of the adult human mouth and thickness of the salivary film covering the teeth and oral mucosa. J. Dent. Res. 1987; 66:1300–1302.

15.     M.J. Levine, P.C. Jones, R.E. Looms, M.S. Reddy, I. Al-Hashimi, E.J. Bergey, in: I.C. Mackenzie, C.A. Squierv, Dablesteen (Eds.), Oral Mucosal Diseases.  Biology, Etiology and Therapy, Laege-foreningens Folag, Copenhagen, 1987:  7–9.

16.     R.D. Mattes, Physiologic responses to sensory stimulation by food: nutritional implications.  J. Am. Diet. Assoc. 1997; 97: 406–410.

17.     A.R. Silvers, P.M. Som, Salivary glands. Head Neck Imag 1998; 36: 941–966.

18.     M.A. Longer, J.R. Robinson, Fundamental aspects of bioadhesion. Pharm. Int. 1986; 7:114– 117.

19.     D. Tiwari, D. Goldman, R. Sause, P.L. Madan, Evaluation of polyoxyethylene homopolymers for buccal bioadhesive drug delivery device formulations. AAPS PharmSci 1999; 1:13.

20.     Y. Huang, W. Leobandung, A. Foss, N.A. Peppas, Molecular aspects of muco- and bioadhesion: tethered structures and site-specific surfaces. J. Control. Release 2000; 65:63– 71.

21.     J.-M. Gu, J.R. Robinson, S.-H.S. Leung, Binding of acrylic polymers to mucin/epithelial surfaces: structure–property relationships. Crit. Rev. Ther. Drug Carr. Syst. 1998; 5: 21– 67.

22.     N.A. Peppas, P.A. Buri, Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues, J. Control. Release 1985;2: 257–275.

23.     H. Park, M. Amiji, K. Park, Mucoadhesive hydrogels effective at neutral pH, Proc. Int. Symp. Control. Release Bioact. Mater 1989; 16: 217–218.

24.     C.-M. Lehr, J.A. Bouwstra, E.H. Schacht, H.E. Junginger, In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharm 1992; 78: 43– 48.

25.     M.J. Rathbone, B.K. Drummond, I.G. Tucker, The oral cavity as a site for systemic drug delivery.  Adv. Drug Deliv. Rev 1994; 13: 1 –22.

26.     C.-M. Lehr, F.G.J. Poelma, H.E. Junginger, J.J. Tukker, An estimate of turnover time of intestinal mucus gel layer in the rat in situ loop. Int. J. Pharm. 1991; 70: 235– 240.

27.     N.F.H. Ho, C.L. Brushy, P.S. Burton, H.P. Merkle, (D) Routes of delivery: case studies. (3) Mechanistic insights to buccal delivery of proteinaceous substances. Adv. Drug Deliv. Rev 1992; 8: 197– 235.

28.     J.W. Lee, J.H. Park, J.R. Robinson, Bioadhesive based dosage forms: the next generation. J. Pharm. Sci. 2000; 89 (7): 850–866.

29.     C.M. Lehr, F.G.J. Poelma, H.E. Junginger, J.J. Tucker, An estimate of turnover time of intestinal mucus gel layer in the rat intestinal in situ loop.  Int. J. Pharm. 1991; 70: 235–240.

30.     K. Park, H. Park, Test methods of bioadhesion, Int. J. Pharm. 1989;52: 265–270.

31.     E.E. Hassan, J.M. Gallo, Bioadhesive drug delivery system. Pharm.Res 1990; 7: 491.

32.     S.E. Harding, Mucoadhesive interactions. Biochem. Soc. Trans 2003; 31 (5): 1036–1041.

33.     K. Park, J.R. Robinson, Bioadhesive polymers as platforms for oral controlled drug delivery.  Int. J. Pharm 1984; 19: 107–127.

34.     P.K. Nanti, D.J. Cook, D.J. Rogers, J.D. Smart, Lectins for drug delivery within the oral cavity — investigation of lectin binding to oral mucosa. J. Drug Target 1997;5: 45–55.

35.     J.Heller, D.C.Washington, D.W.H. Penhale, Use of bioerodible polymers in self-regulated drug delivery systems, in: P.I. Lee, W.R. Good (Eds.), Controlled Release Technology, Pharmaceutical Applications. Washington DC, ACS Symposium Series 1997; 76:  281–282.

36.     H.H. Alur, T.P. Johnston, A.K. Mitra, Peptides and Proteins: Buccal Absorption. Encyclopedia of Pharmaceutical Technology 2001; 20 (3):193–218.

37.     A.C. Jain, B.J. Aungst, M.C. Adeyeye, Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 h-cyclodextrin (SBE 7) complexes. J. Pharm. Sci. 2002; 91: 1659–1668.

38.     F. Veuillez, Y.N. Kalia, Y. Jacques, J. Deshusses, P. Buri, Factors and strategies for improving buccal absorption of peptides. Eur. J. Pharm. Biopharm. 2001; 51: 93–109.

39.     M.E. de Vries, H.E. Bodde´, J.C. Verhoef, H.E. Junginger, Developments in buccal drug delivery. Crit. Rev. Ther. Drug Carr. Syst. 1991; 8: 271–303.

40.     H.S. Ch’ng, H. Park, P. Kelly, J.R. Robinson, Bioadhesive polymers as platforms for oral controlled drug delivery: II. Synthesis and evaluation of some swelling, water-insoluble bioadhesive polymers. J. Pharm. Sci 1985; 74: 399– 405.

41.     H. Park, J.R. Robinson, Physico-chemical properties of water insoluble polymers important to mucin epithelial adhesion, J. Control. Release 1985; 2: 47–57.

42.     J.W. Lee, J.H. Park, J.R. Robinson, Bioadhesive-based dosage forms: the next  generation.  J. Pharm. Sci. 2000;89: 850– 866.

43.     R. Anders, H.P. Merkle, Evaluation of laminated muco-adhesive patches for buccal drug delivery.  Int. J. Pharm 1989; 49: 231–240.

44.     R.B. Gandhi, J.R. Robinson, Oral cavity as a site for bioadhesive drug delivery. Adv. Drug Deliv. Rev 1994; 13: 43– 74.

45.     M.J. Rathbone, B.K. Drummond, I.G. Tucker, The oral cavity as a site for systemic drug delivery, Adv. Drug Deliv. Rev 1994; 13: 1 –22.

46.     J.W. Lee, J.H. Park, J.R. Robinson, Bioadhesive-based dosage forms: the next generation. J. Pharm. Sci 2000; 89: 850– 866.

47.     A.K. Mitra, H.H. Alur, T.P. Johnston, Peptides and proteins— buccal absorption, in: J. Swarbrick, J.C. Boylan (Eds.).  Encyclopedia of Pharmaceutical Technology, 2nd edn, Marcel Dekker, Inc., New York, 2002: 2081– 2095.

48.     K. Khanvilkar, M.D. Donovan, D.R. Flanagan, Drug transfer through mucus.  Adv. Drug Deliv. Rev 2001; 48: 173– 193.

49.     F. Veuilleza, Y.N. Kaliaa, Y. Jacquesa, J. Deshussesb, P. Buria,c, Factors and strategies for improving buccal absorption of peptides. European Journal of Pharmaceutics and Biopharmaceutics 2001; 51: 93-109.

50.     L.E. Bromberg, D.K. Buxton, P.M. Friden, Novel periodontal drug delivery system for treatment of periodantitis. J. Control. Release 2001; 71: 251–259.

51.     J.E. Codd, P.B. Deasy, Formulation development and invivo evaluation of a novel bioadhesive lozenge containing a synergistic combination of antifungal agents. Int. J. Pharm 1998; 173: 13–24.

52.     H. He, X. Cao, I.J. Lee, Designal of a novel hydrogel-based intelligent system for controlled drug deliveries. J. Control. Release 2004; 95: 391–402.

53.     M.A. Repka, S.L. Repka, J.M. McGinity, Bioadhesive Hot- Melt Extruded Film for  Topical and Mucosal Adhesion Applications and Drug Delivery and Process for Preparation Thereof., US, 2002.

54.     H.G.V. Betageri, S.A. Jenkins, D.L. Parsons, Pharmaceutical applications of liposomes, in: G.V. Betageri, S.A. Jenkins, D.L. Parsons (Eds.). Liposome Drug Delivery Systems, Technomic, Lancaster/ Basel 1993:65-88.

55.     S.J. Sveinsson, W.P. Holbrook, Oral mucosal adhesive ointment containing liposomal corticosteroid.  Int. J. Pharm 1993; 95: 105-109.

56.     F.S. Farshi, A.Y. Ozen, M.T. Ercan, A.A. Hincal, In vivo studies in the treatment of oral ulcers with liposomal dexamethasone phosphate. J. Microencapsul 1996; 13: 537-544.

57.     G. DeGrande, L. Benes, F. HorrieÁre, H. Karsenty, C. Lacoste, R. McQuinn, J.-H. Guo, R. Scherrer, Specialized oral mucosal drug delivery systems: patches, in: M.J. Rathbone (Ed.), Oral Mucosal Drug Delivery, New York, Marcel Dekker, 1996: 285-317.

58.     F. Veuillez, J. Deshusses, P. Buri, Synthesis and characterization of an acylated di-peptide (Myr-Trp-Leu) with modified transmucosal transport properties. Eur. J. Pharm. Biopharm 1999; 48: 21-26.

59.     W. Wang, Oral protein drug delivery.  J. Drug Target 1996; 4: 195-232.

60.     N.A. Nafee, F.A. Ismail, N.A. Boraie, L.M. Mortada, Mucoadhesive delivery systems. I. Evaluation of mucoadhesive polymers for buccal tablet formulation. Drug Dev. Ind. Pharm. 2004; 30 (9): 985–993.

61.     A.E. Collins, P.B. Deasy, Bioadhesive lozenge for the improved delivery of cetylpyridinium chloride, J. Pharm. Sci 1990; 79 (2):116.

62.     D.L. Hughes, A. Gehris, A new method for characterizing the buccal dissolution of   drugs, Rohm and Haas Research laboratories, Spring house, PA, USA.

63.     B.J. Angust, N.J. Rogers, Comparison of the effects of various transmucosal absorption promoters on buccal insulin delivery.  Int. J Pharm 1989; 53: 227–235.

64.     C.A. Squier, P.W. Wertz, in: M.J. Rathbone (Ed.), Structure and Function of the Oral Mucosa and Implications for Drug Delivery, Oral Mucosal Drug Delivery, Marcel Dekker Inc., New York, 1996: 1–26.

65.     C.L. Barsuchn, L.S. Olanoff, D.D. Gleason, E.L. Olanoff, D.D. Gleason, E.L. Adkins, N.F.H. Ho, Human buccal absorption of flubiprofen. Clin. Pharmacol. Ther 1988; 44: 225–231.

66.     M. Mehta, B.W. Kemppainen, R.G. Stafford, In vitro penetration of tritium labeled water (THO) and [3H] Pb Tx-3 (a red tide toxin) through monkey buccal mucosa and skin. Toxicol. Lett 1991; 55:185–194.

67.     C.A. Squier, P. Cox, P.W. Wertz, Lipid content and water permeability of skin and oral mucosa. J. Invest. Dermat 1991; 96: 123–126.

68.     I.Gonzalez-Younes, J.G. Wagner, D.A. Gaines, Absorption of flubriprofen through human buccal mucosa, J. Pharm. Sci. 1991;80: 820–823.

69.     H. Yamahara, V.H. Lee, Drug metabolism in the oral cavity. Adv. Drug Del. Rev 1993; 12: 25–39.

70.     M.J. Rathbone, J. Hadgraft, Absorption of drugs from human oral cavity.  Int. J. Pharm 1991; 74: 9–24.

 

 

 

Received on 24.07.2009       Modified on 27.09.2009

Accepted on 30.10.2009      © RJPT All right reserved

Research J. Pharm. and Tech.2 (4): Oct.-Dec. 2009; Page 653-663