In vitro and ex vivo evaluation of bilayered effervescent microenvironmental pH modifying buccal films with saquinavir

Abstract

Buccal delivery of saquinavir has the advantage to bypass the hepatic first-pass metabolism associated with oral administration. Local microenvironmental pH (pHM) modification at the buccal mucosa might increase absorption of saquinavir by balancing the solubility and partition of saquinavir into the buccal mucosa. The present study aimed to evaluate a novel saquinavir pHM modifying buccal film using effervescence, as well as to elucidate the relationship between pHM and permeation of saquinavir released from the buccal films. Hydroxypropyl methylcellulose-based films were prepared: 1) a bilayered effervescent film composed of an alkaline layer and a layer containing saquinavir and malic acid, 2) a monolayered film composed of saquinavir and malic acid (pHM modifying film), and 3) a monolayered film composed of saquinvir (control). The release of saquinavir from these films and permeation of saquinavir across porcine mucosae were evaluated. The monolayered pHM modifying film led to a decrease in pHM from pH 6.8 to 3.0 after 5.5 min, while the effervescent film had an initial decrease in pHM (from pH 6.8 to 4.0) caused by the co-release of malic acid and a subsequent pHM increase (from pH 4.0 to 5.9) caused by the release of carbonate from the alkaline layer within 15 min. Saquinavir released faster from the pHM modifying film than from the effervescent film. However, a higher permeation of saquinavir and mucosal accumulation was observed for the effervescent film. This could be attributed to the higher concentration of ionized specie and a faster tissue partitioning of unionized saquinavir, respectively. These results suggest that effervescent pHM modifying film is a potential formulation strategy for buccal delivery of saquinavir.