Oromucosal bioadhesive prolonged release suspensions

The bioavailability of drugs administered onto the buccal mucosa by using conventional dosage forms is greatly affected by their rapid removal from the oral cavity following the swallowing. The objective of this work was to develop an oral formulation which can guarantee both fast onset of action and prolonged release. The basic idea was to prepare an oromucosal suspension combining the peculiarities of an oromucosal solution with those of prolonged release mucoadhesive microparticles which can guarantee the uniform distribution of the drug because of their high surface. Mucoadhesive microparticles containing clobetasol propionate (CP) were prepared in a one-step process by ionic gelation method using sodium alginate (ALG) as encapsulating agent and linear (Carbopol 934P, L-PAA) or crosslinked (Noveon AA-1, C-PAA) acrylic acid-based polymers as bioadhesive polymer. The effects of different types of acrylic polymer, ALG/acrylic acid-based polymer ratios (3:1 or 1:1) and spraying pressure (450 or 550 mBar) on the properties of microparticles were studied and elucidated by using a 23 factorial design. The influence of the ALG/acrylic acid-based polymer ratios and microparticles size on mucoadhesive properties measured by a BCA colorimetric assay were preliminary evaluated. The amount of CP penetration into porcine cheek mucosal segments was determined at different times after administration. For each response, a multiple regression and ANOVA were performed and the models were tested using the statistical factorial design. Well-formed and spherical microparticles were obtained combining ALG with both acrylic acid-based polymers. The particle size of placebo microparticles was influenced by the spraying pressure (average diameter: 170 μm at 450 mBar and 50 μm at 550 mBar) independently of the feed composition. Both C-PAA and L-PAA conferred mucoadhesive properties to ALG since the amount of mucin bound to microparticles was significantly higher (p < 0.05) than that of ALG microparticles. The CP loading affected neither the particle size distribution, nor the particle morphology. The encapsulation of CP in mucoadhesive microparticles caused a significant increase of the amount of drug penetrated in porcine cheek mucosal segments with respect to the pure drug solution at the same concentration after 6 hours from administration. The factorial design evidenced that mucoadhesive microparticles obtained by using the mixture ALG/L-PAA in the ratio 1:1 permitted to accumulate the highest amount of drug. Moreover, the microparticles sizing at about 50 μm resulted stable over time without evidencing aggregation issues. This formulation was further optimized by using PEG400 to solubilise CP and assure the uniformity of drug content. Hence, the proposed oromucosal bioadhesive prolonged release suspension could be advantageously exploited for drug delivery in the oral cavity allowing the reduction of the frequency of the administration dose.