Development and evaluation of sublingual formulation of immunosuppressive drugs

Sirolimus is an immunosuppresive agent possesing multitherapeutic properties, which is characterized by some drawbacks such as poor aqueous solubility, extensive first-pass metabolism, low bioavaliability and non-specific distribution in off-target sites. In order to eliminate these limitations, various formulation strategies have been developed among which pharmaceutical nanotechnology have become a prominent approach. The objective of this study was to develop sirolimus loaded micelles and mixed micelles for sublingual administration. In this context, D-α-tocopheryl 1000 succinate (TPGS), soy phosphatidylcholine (SPC) and sodium cholate (NaC) were utilized for the formulation of sirolimus loaded micelles. The formulation studies exhibited that TPGS micelles exhibited small particle size, low polydispersity index, high encapsulation efficiency and high loading capacity. It was observed that SPC caused only an increasing effect on the particle size and PDI of micelles, but no negative effect on the other properties. However, NaC showed a significant negative impact on the characteristics of micelles. The molar solubilization capacity and molar micelle-water partition coefficient of micelles, micellization process and locus of sirolimus in micelles were evaluated from a thermodynamical point of view. In vitro dissolution studies as well as in vitro diffusion of micelle formulations through nitrocellulose membranes using Franz cells were performed. The permeation of micelles through bovine sublingual mucosa was examined and an increased permeation of micelles compared to sirolimus solution was observed. Moreover, an enhancing effect of SPC on the tissue penetration of micelles was determined. The stability tests performed under the storage conditions of 4°C revealed that micelles maintained their characteristics at 90 days when stored at 4°C. However, NaC exhibited a deteriorating effect on the stability of micelles. In this study, sirolimus loaded micelles and mixed micelles were developed for the first time for administration through sublingual route and in vitro/ex vivo evaluations were performed.