Maria Gabriella Siragusa

The adequate absorption and transport of drugs in the body is part of optimal therapy. Drug administration perorally is easy, common and traditional, but occasionally alternative routes are required. The major obstacles of this drug delivery method are the extensive presystemic degradation processes in the gut and/or liver, resulting in inadequate or erratic absorption and low systemic bioavailability. The parenteral route is the only established way that overcomes these drawbacks, but it may not achieve the maintenance of adequate drug levels at the receptor for as long as it is needed, which results in it high costs, poor patient compliance — especially in long-term therapies — and various further inconveniences and risks. Moreover, it requires repeated administration and is potentially hazardous as rapid drug removal is unachievable. 

During the last two decades, transepithelial routes have been extensively explored by pharmaceutical researchers as alternative routes of delivery. Drug application to absorptive mucosae is often chosen to reach the site of action with little systemic drug concentrations to lessen side-effects.

Among the various transepithelial sites available, the oral mucosa is the most convenient and accessible. If low drug concentrations are required to gain access to the blood, the transbuccal route may be very satisfactory, provided the physicochemical properties of a given drug allow permeation through the mucosa. Buccal delivery specifically refers to the delivery of drugs within/through the mucosa lining the inner cheeks. Compared with other mucosal tissues, buccal mucosa is more tolerant to potential allergens and has a lesser tendency to irreversible damage. Additionally, it is a well-vascularized, relatively immobile tissue and has relatively lower enzymatic activity.  

Buccal mucosa allows drug delivery for both local and systemic therapies. Local delivery to tissues of the oral cavity has a number of applications, including treatment of local conditions such as periodontal disease, bacterial and fungal infections, aphthous stomatitis and vesiculo bullous diseases. When drugs are systemically administered through buccal mucosa, many drawbacks associated with the peroral route are circumvented as drugs directly enter the systemic circulation, avoiding the hepatic first pass metabolism and leading to high bioavailability. The buccal mucosa offers an easily accessible and generally well-accepted site for delivering systemically acting drugs mainly for the treatment of chronic diseases.

Table 1 displays a nonexhaustive list of drugs investigated in buccal delivery systems.

Table 1: List of APIs investigated for buccal delivery. 

The principal mechanism of buccal absorption is passive diffusion. However, this assumption may be misleading as the oral mucosa contains active, carrier-mediated transport systems for few small molecules, such as monosaccharides and amino acids.

  On occasion, absorption occurs by endocytosis where molecules are engulfed by the cells.

  Two main pathways seem to be implicated in passive diffusion across mucosae: intracellular (or transcellular) and intercellular (or paracellular). Within the intercellular spaces there are two ways: one, hydrophobic, goes through the lipid domains; the other, hydrophilic, relates to the aqueous channels associated with the polar head groups of lipids and proteins. The intrinsic physicochemical properties of the drug, such as solubility, partitioning, stability, crystallinity, thermodynamic activity, molecular size, pKa and half-life, can constitute limiting factors to drug absorption:  

Low solubility determines a small concentration gradient to the plasma and the rate of diffusion is accordingly low. 

Highly lipophilic compounds could permeate through the transcellular route by partitioning into the lipids of the intercellular matrix while hydrophilic compounds could diffuse through the paracellular pathway. Some drugs can permeate using both routes simultaneously, but the route with the least penetration resistance is usually preferable. 

Crystalline status and thermodynamic activity of a drug are correlated with the diffusant concentration, thus affecting permeation. 

Small molecules, <~100 Da, cross the mucosa rapidly; permeability decreases as molecular size increases; high molecular weight drugs, such as peptides, oligonucleotides and hormones, usually have low permeability leading to a low bioavailability. 

The pKa is indicative of the molecule degree of ionization and affects permeability: maximum absorption occurs when molecules are not ionized and absorption decreases as the degree of ionization increases. Most drugs are weak acids or bases, and exist in solution as equilibrium between the unionized and ionized forms. Only unionized nonpolar drugs penetrate the membrane and, at equilibrium, the concentrations of the unionized species are equal on both sides of the membrane. The unionized form is assumed to be sufficiently lipophilic to cross membranes. The fraction ionized is controlled by both the environmental pH and the drug pKa.

The physical state and composition of the formulation may affect dissolution rate. The physicochemical characteristics of the dosage form affect the rate and the amount of the released API, and primarily depend on drug affinity to the vehicle. The permeation rate across the buccal mucosa can be satisfactorily modified by changing the composition and drug concentration in a formulation.

Being absorption restrained by a diffusion process, the absorbing surface plays a key role. Most drugs administered as buccal solid formulations exhibit low bioavailability, mainly because of the relatively small area available for absorption. Semisolid formulations seem suitable for local treatments because they can be spread over a large portion of the mucosa.

The drug vehicle has been suggested to be quite complex as it could affect membrane hydration, stimulate or prevent saliva secretion and interact with the local mucins. Wettability of soft tissues in the oral cavity can be expected to change greatly during the day under the influence of dietary components and oral hygiene measures.

As the buccal mucosa is relatively immobile, the placement of retentive sustained-release transmucosal drug delivery systems is feasible and well-accepted by patients.

  Vascularity and blood stream are also important because some drugs may cause vasoconstriction and limit drug absorption. 

Some other less well-defined factors, such as the presence of a 3D mucus network, presence of bacteria, salivary flow rate, foods and involuntary swallowing, result in drug losses from the site of absorption. Injuries and disease states, where the mucosa is seriously damaged, would be expected to increase permeability (e.g., in conditions that result in erosion of the oral mucosa such as lichen planus, pemphigus, viral infections and allergic reactions). 

Assessing drug permeation through the buccal mucosa

Given that the most important determinant of buccal delivery is the degree of permeability of the mucosa, comprehensive knowledge of permeability barrier, transport mechanisms and pathways is crucial in developing transbuccal formulations. Accordingly, the aptitude of a drug to penetrate the barrier should be assessed by 

 methods. Low availability of human buccal tissue for experimental use has led to the application of animal tissue resembling human mucosa to evaluate drug mucosal permeability. The main concern of choosing a particular animal model is the resemblance of its oral mucosa to the human one, both in ultrastructure and enzymatic activity. No animal can fully represent human tissues, but what is sought is an animal oral mucosa with equivalent physical and biochemical properties. Porcine buccal mucosa has been considered as a representative model as it resembles human tissue more closely than any other animal model in terms of lipid content and composition; membrane morphology and permeability barrier functions; composition and structure; and being nonkeratinized similar to human buccal mucosa.

In the last decade, cultured normal (noncancerous) donated human cells grown on inserts at the air–liquid interface have been developed for rapidly and efficiently evaluating drug permeation across buccal mucosa.

  Also, stratified cultured TR146 cell layers (so-called reconstituted human oral epithelium) have been suggested as a valuable new 

 model for permeability studies, as they are analogous to normal human buccal epithelium. The cells, derived from a human neck metastasis originating from a buccal carcinoma, have been shown to grow on polycarbonate permeable inserts and form cell layers resembling the stratified human tissue. The model has similar morphology, ultrastructure and permeability barrier properties to intact buccal mucosa. Studies on bidirectional permeability have shown close correlation to the data obtained using human, monkey and porcine buccal mucosa.

Various types of diffusion devices, including continuous flow perfusion chambers, using chambers, vertical and horizontal Franz cells, Grass–Sweetana diffusion chambers, Transwell and a choice of further side-by-side flow through cells, are commercially available for permeation studies — most of which have been used to determine the permeability of oral mucosa.

Similar to other mucosal membranes, the buccal mucosa has some disadvantages including short residence time and small absorption area. Moreover, the dosage form resides in a taste-sensing organ, and organoleptic aspects of formulation could become central and limiting factors for drug application. Suitable palatal properties are often required to improve acceptability of dosage form or to mask less desirable properties of the active component. Some additives should be incorporated to improve drug release and absorption, but the major limitation to buccal drug delivery is the barrier property of the tissue, which has inadequate permeability for certain molecules, resulting in low drug bioavailability. 

Permeation of drugs throughout epithelial barriers could be promoted by 'penetration enhancers' capable of decreasing the barrier properties of the mucosa by different mechanisms. Enhancement is founded on different techniques that are usually subdivided in chemical or physical methods.

 Chemical enhancers are thought to improve absorption without irritation or damage of the mucosa by:  

Altering the rheology of the mucus layer. 

Transiently altering the lipid bilayer membrane. 

Increasing the thermodynamic activity of the permeant.

Chemical enhancers could be added to a formulation, alone or in combination; their efficacy depends on the physicochemical properties of both the drug and the vehicle.  

Various chelators, surfactants, bile salts and fatty acids have been used as permeation enhancers; chitosan and its derivates have been used as enhancers of small polar molecules and hydrophilic large molecules. Recently, lysalbinic acid, a product of the egg albumin hydrolysis, has been successfully used as an enhancer of peptide drugs. 

Enzymatic drug inactivation is neither rapid nor extensive as the enzymatic activity of buccal mucosa is relatively low. Nevertheless, enzymes of the oral cavity could degrade some peptide and protein drugs. Co-administration of enzyme inhibitors, such as aprotinin, bestatin and puromycin, and bile salts could be effective as they reduce the activity of proteolytic enzymes. Table 2 shows a nonexhaustive list of molecules investigated as buccal permeation enhancers. 

Table 2: List of molecules investigated as buccal permeation enhancers. 

 Enhancement can be obtained by a variety of techniques. 

Removal of the outermost layers of the epithelium to decrease the barrier thickness. 

Sonophoresis (phonophoretic drug delivery) that provisionally reduces the density of the lipids domain as a result of micromechanical, thermal and cavitation effects.

Electrically (when electric fields are applied to a mucosal membrane transport enhancement of ions can be provided) by:   

 which is an effective and rapid method of delivering water-soluble, ionized or ionizable medications, and involves electrically induced transport by application of low level current.

, the process by which charged particles tend to migrate toward a less charged area. 

, the process by which a large electric pulse temporarily disturbs the membrane phospholipid bilayer allowing molecules permeation throughout the tissue.

Many dosage forms have been developed including toothpastes, mouthwashes, lozenges, gels, ointments, wafers, microparticles, chewing gums, lollipops, films, patches, tablets and some specialized devices. Conventional dosage forms exhibit some drawbacks; for example, the low bioavailability as a result of the washing effect of saliva and mechanical stresses.  

Unconventional dosage forms allow control of the buccal environment, optimization of drug permeation and governance of the drug dissolution rate. Formulations able to prolong the drug residence time on the absorptive tissue offer great advantages in promoting transmucosal delivery for systemic therapies. Recent research on mucoadhesive polymers has led to the development of several buccal delivery systems able to maintain a steady release of drug in the systemic circulation. Thanks to the lack of the transient spikes in drug concentration typical of daily multiple-dose regimens, these delivery systems decrease the risks of toxic side-effects. For efficient and prolonged release of drugs, these delivery systems must be in close contact with the mucosal membrane, which results in high concentration in a local area and high drug flux through the mucosa.

Articles

The adequate absorption and transport of drugs in the body is part of optimal therapy. Drug administration perorally is easy, common and traditional, but occasionally alternative routes are required.