1. Buccal Mucosa As A Route For Systemic Drug Delivery
Drug administration through the mucosal membranes lining the cheeks (buccal mucosa). The mucosa has a rich blood supply and it is relatively permeable.
Structure:
The oral mucosa is composed of an outermost layer of stratified squamous epithelium. Below this lies a basement membrane, a lamina propria followed by the submucosa as the innermost layer. The epithelium has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium
The epithelial cells increase in size and become flatter as they travel from the basal layers to the superficial layers. The epithelium of the buccal mucosa is about cell layers thick, while that of the sublingual epithelium contains somewhat fewer cell layers. The buccal mucosal thick. varies from 500 to 800 µm.

2. The epithelia of buccal mucosa is non keratnized and have been found to be considerably more permeable to water than keratinized epithelia, such as those found in hard palate, which is relatively impermeable to water.
The lamina propria is a thin layer of loose connective tissue, or dense irregular connective tissue, which lies beneath the epithelium and together with the epithelium constitutes the mucosa.
Permeability
The oral mucosa in general is a somewhat leaky epithelia intermediate between that of the epidermis and intestinal mucosa. It is estimated that the permeability of the buccal mucosa is times greater than that of the skin. In general, the permeabilities of the oral mucosa decrease in the order of sublingual greater than buccal, and buccal greater than palatal. This rank order is based on the relative thickness and degree of keratinization of these tissues, with the sublingual mucosa being relatively thin and non-keratinized, the buccal thicker and non-keratinized, and the palatal intermediate in thickness but keratinized.

3. Environment:
In stratified squamous epithelia found elsewhere in the body, mucus is synthesized by specialized mucus secreting cells like the goblet cells, however in the oral mucosa, mucus is secreted by the major and minor salivary glands as part of saliva. Saliva is an aqueous fluid with 1% organic and inorganic materials. The major determinant of the salivary composition is the flow rate which in turn depends upon three factors: the time of day, the type of stimulus, and the degree of stimulation. The salivary pH ranges from 5.5 to 7 depending on the flow rate. At high flow rates, the sodium and bicarbonate concentrations increase leading to an increase in the pH. The daily salivary volume is between 0.5 to 2 liters and it is this amount of fluid that is available to hydrate oral mucosal dosage forms. A main reason behind the selection of hydrophilic polymeric matrices as vehicles for oral transmucosal drug delivery systems is this water rich environment of the oral cavity.

4. Buccal Routes of Drug Absorption:
The are two permeation pathways for passive drug transport across the oral mucosa: paracellular and transcellular routes. Permeants can use these two routes simultaneously, but one route is usually preferred over the other depending on the physicochemical properties of the diffusing. Since the intercellular spaces and cytoplasm are hydrophilic in character, lipophilic compounds would have low solubilities in this environment. The cell membrane, however, is rather lipophilic in nature and hydrophilic solutes will have difficulty permeating through the cell membrane due to a low partition coefficient. Therefore, the intercellular spaces pose as the major barrier to permeation of lipophilic compounds and the cell membrane acts as the major transport barrier for hydrophilic compounds. Since the oral epithelium is stratified, solute permeation may involve a combination of these two routes. The route that predominates, however, is generally the one that provides the least amount of hindrance to passage.

5. Advantages Limitations
Ease of administration and termination of drug action.
Avoidance of hepatic first pass metabolism
Salivary secretion ensure adequate drug dissolution
Suitable for drug prone for acidic degradation
Lack of mucus secretion from goblet cells leads to minimal diffusion hindrance due to mucus buildup beneath the applied dosage form
Ease of administration to unconscious patient
Initial mucuadhesion time can be controlled
Limitations
Not suitable for drug with high doses
Possibility of the patient swallow the tablet being forgotten
Eating and drinking may be restricted
Restricted for some drugs (irritant, with bitter taste or odor, unstable at the salivary pH)
Limited area for drug absorption
Low permeability of the buccal membrane specifically when compared to the sublingual membrane

6. Mechanism of Mucoadhesion
Contact Stage: An intimate contact or wetting occurs between the
mucoadhesive polymer and mucous membrane. These two
Surfaces can be mechanically brought together, i.e placing and
holding a delivery system within the oral cavity.
Consolidation Stage: Various physicochemical interactions occur
to consolidate and strengthen the adhesive joint, leading to
prolonged adhesion. Mucoadhesive materials adhere most
strongly to solid dry surfaces as long as they are activated by the
presence of moisture. Moisture will effectively plasticize the
system allowing mucoadhesive molecules to become free,
conform to the shape of the surface and bond predominantly by
weaker Vander Waal and hydrogen bonding

7. Penetration Enhancers
One of the major disadvantages associated with buccal drug delivery is the low flux which results in low drug bioavailability. Hence, various compounds have been investigated for their use as buccal penetration enhancers in order to increase the flux of drugs through the mucosa classified
Mechanism of permeation enhancers
Increase in the fluidity of lipid bilayer membrane
Action on the components at tight junctions
Overcoming the enzymatic barrier
Some permeation enhancers alter the partition coefficient of the drug there by increase the solubility.

8. Mechanism of action
Examples
Category
Perturbation of intercellular Lipids and protein domain integrity
Anionic: Sodium lauryl sulfate Cationic: Cetyl pyridinium chloride Nonionic: Poloxamer, Brij, Span, Myrj, Tween
Surfactants
Sodium glycocholate, Sodium tauro deoxycholate, Sodium tauro cholate
Bile salts
Increase fluidity of phospholipid domains
Oleic acid, Caprylic acid, Lauric acid, Lyso phosphatidyl choline, Phosphatidyl choline
Fatty acids
Changing drug solubility and permeability
α, β, γ, Cyclodextrin, methylated β –cyclodextrins
Cyclodextrins
Interfere with Ca+
EDTA, Citric acid, Sodium salicylate, Methoxy salicylates
Chelators
Ionic interaction with negative charge on the mucosal surface
Chitosan, Trimethyl chitosan
Positively charged Polymers
Poly-L-arginine, L-lysine
Cationic Compounds

9. Buccoadhesive polymers
Generally, some of the necessary structural characteristics for bioadhesive polymers include strong hydrogen bonding groups, strong anionic or cationic charges, high molecular weight, chain flexibility, and surface energy properties which favor spreading on mucus layer.
Can be classified according to different criteria
Source:
Semi-natural/natural: Agarose, chitosan, gelatin, Various gums (guar, xanthan, carragenan, pectin, and sodium alginate), cellulose derivatives (CMC, thiolated CMC, sodium CMC, HEC, HPC, HPMC, MC).
Synthetic: Poly(acrylic acid)-based polymers, PVA, PVP, thiolated polymers.

10. Aqueous solubility:
Water-soluble: HPC, HPMC, sodium CMC, sodium alginate
Water-insoluble: Chitosan (soluble in dilute aqueous acids), EC
Charge:
Cationic: Aminodextran, chitosan, dimethylaminoethyl (DEAE)-dextran, trimethylated chitosan
Anionic: Chitosan-EDTA, CMC, pectin, PAA, sodium alginate, sodium CMC, xanthan gum.
Non-ionic: Hydroxyethyl starch, HPC, poly(ethylene oxide), PVA, PVP

11. Dosage forms
Buccal Tablets: Several bioadhesive buccal tablet formulations have been developed by direct compression method in recent years either for local or systemic drug delivery. They are designed to release the drug multi-directionally into the saliva. Alternatively, the dosage form can contain an impermeable backing layer to ensure that drug is delivered unidirectionally.
Disadvantages of buccal tablets may be patient acceptability (mouth feel, taste and irritation)

12. Bioadhesive Micro/nanoparticles
Bioadhesive micro/nanoparticles offer the same advantages as tablets but their physical properties enable them to make intimate contact with a lager mucosal surface area. These are typically delivered as an aqueous suspension or are incorporated into a paste or ointment or applied in the form of aerosols. Particulates have the advantage of being relatively small and more likely to be acceptable by the patients. The small size of microparticles compared to 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 reduced
Medicated chewing gums
Although medicated chewing gums pose difficulties in regulation of the administered dose, they still have some advantages as drug delivery devices, particularly in the treatment of diseases of the oral cavity and in nicotine replacement therapy.

13. Buccal patches/films
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 attachment. Flexible films/patches have been prepared either by solvent casting or hot melt extrusion technique to deliver drugs directly to a mucosal membrane.

14. Solvent casting technique
In this technique the required quantity of mucoadhesive polymer is treated with required volume of solvent system and vortexed to allow polymer to swell. After swelling, mixture is treated with, measured quantity of plasticizer (propylene glycol or glycerin or dibutyl phthalate) and vortexed. Finally the required quantity of drug is dissolved in small volume of solvent system and added to the polymer solution and mixed well. The mixture set aside for some time to remove any entrapped air is then transferred into a petri plate. Drying of the patch is carried out in an oven at 40 C.
Hot melt extrusion technique
The Hot-melt extrusion: technique is an attractive alternative to traditional processing methods and offers many advantages over the other pharmaceutical processing techniques . Molten polymers during the extrusion process can function as thermal binders and act as drug depots and/or drug release retardants upon cooling and solidification. Since solvents and water are not necessary, the numbers of processing and time-consuming drying steps are reduced.