Numerous potential compounds in pharmaceutical development are categorized under BCS classification III and IV. These compounds exhibit poor bioavailability due to their low permeability across biological membranes. These includes hydrophilic small molecules, which do not sufficiently partition into biological membranes or peptides, proteins, and other macromolecules, which have poor membrane permeability due to their large molecular weight. Low drug permeability presents significant challenges in developing bioavailable and reproducible dosage forms for buccal administration.

Buccal Delivery

Buccal cavity is an attractive route for administration for both small molecules a well as macromolecules such as peptides and proteins.  Buccal mucosa is highly perfused with blood vessels which enables rapid absorption and improved bioavailability of many drugs for both local and systemic treatments.  It combines the beneficial aspects of oral dosage forms such as ease of administration, increased stability, and cost effectiveness with those of parenteral dosage forms such as increased bioavailability, eliminating hepatic first pass metabolism and rapid onset of action.  Depending on the application, pharmaceutical products intended for buccal administration can be developed in various dosage forms.  The choice of dosage form depends whether the drug is intended for rapid release or extended release and for local or systemic action.  Drugs intended for rapid release can be formulated as solutions, suspensions, gels, emulsions, creams, orally disintegrating tablets, films, troches and lozenges.  Mucoadhesive buccal dosage forms help prolong the duration of action and have found use in extended release applications.

Bioavailability Enhancement through Permeability Enhancers

To overcome the challenges due to low drug permeability, the use of chemical permeability enhancers has been one of the simplest and prominent formulation approaches. Permeability enhancers, are substances that facilitate the transport of drugs across biological membranes. They work by transiently altering the physicochemical properties of the membrane, thereby increasing drug permeability.  These excipients enable increased systemic exposure after oral, transmucosal, or transdermal administration as demonstrated by enhanced bioavailability and improved therapeutic outcomes. Permeability enhancers can be broadly classified into several categories as exemplified in the table below

Class / Type Examples
Bile salts Na taurocholate, Na glycholate, Na cholate, Na fusidate
Surfactants Sodium lauryl sulphate, Polysorbate 80, laureth-9, sorbitan laurate, glyceryl monolaurate
Fatty acids and their derivatives Oleic acid, capric acid, lauric acid, cod liver oil, monocaprin, palmitoylcarnitine, sodium caprate, SNAC, 5-CNAC
Polymers Chitosan, trimethyl chitosan; Chitosan-4- thiobutylamide
Chelating agents EDTA, EGTA, citric acid, methoxy salicylates, Na salicylate
Phytochemicals Aloe vera, black cumin, caraway, curcumin, diosmin and emodin.
Others Sulfoxides, dextran sulfate, cyclodextrins, azone

Bioavailability of buccal formulations can be further enhanced by combining the use of permeability enhancers with several formulation design approaches involving use of other functional excipients such mucoadhesive polymers, enzyme inhibitors, stabilizers, viscosity and pH modifiers. Mucoadhesive polymers enhance drug absorption by increasing the residence time in the buccal cavity.  Other excipients increase systemic drug exposure by providing appropriate environment to reduce drug metabolism and enhance drug stability.

Evaluation of Permeation Enhancers for Buccal Delivery

During early phase development, potential absorption enhancement excipients can be screened using validated and standardized in-vitro permeability methods using Caco2 cells monolayers.  In-situ animal intestinal perfusion studies can also be used to assess permeability of the drug through buccal mucosa.  Specific tests can be performed to evaluate properties related to bioavailability enhancement such as muco-adhesivity, swelling index and in-vitro permeability studies.  Modified in-vitro dissolution methods to more closely simulate the conditions in the buccal cavity such as use of artificial saliva and smaller quantities of media have also been employed to guide product development.

Vici Health Sciences – Capabilities and Services

Permeability enhancers play a crucial role in enhancing the bioavailability of low permeability drugs through the buccal route. However, their use must be carefully considered and thoroughly evaluated to ensure efficacy, safety and stability.  Vici Health Sciences has extensive experience and knowledge in development of buccal dosage forms as well as the use of permeability enhancers for bioavailability enhancement for both small and large molecule drugs.  This makes us an ideal CDMO partner for product development, analytical characterization and regulatory support.