Preparation, Characterization and Prevention of Auto-oxidation of Amorphous Sirolimus by Encapsulation in Polymeric Films Using Hot Melt Extrusion

Abstract

Background: Sirolimus (SIR) is a macrocyclic lactone antibiotic and used therapeutically as a potent immunosuppressant for prophylaxis of kidney transplant rejection. The development of an oral dosage form is challenging because of very poor aqueous solubility (2.6µg/ml). The oral bioavailability of SIR is only 15-20 % and is affected by food and other drugs. The main reasons for low bioavailability are intestinal degradation by enzymes especially by cytochrome P4503A4, efflux by P-glycoprotein and hepatic first-pass metabolism. Objective: The main objective was to prepare a mouth dissolving film dosage form of amorphous SIR to improve dissolution. Methods: Crystalline SIR was transformed to its form amorphous by milling for 2 h at room temperature. Thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD) were used for characterisation. The stability of amorphous SIR was studied at 4°C and 40°C/75% RH. Amorphous SIR was formulated as oral films by melt extrusion with polyvinylpyrrolidone- vinyl acetate (PVP-VA), Soluplus® and hydroxypropyl cellulose (HPC) as carriers. The films were characterized for drug content, physical state, dissolution profile and stability at 4°C and 40°C/75% RH. Results: The PRXD and DSC confirmed the conversion of crystalline SIR to amorphous form by milling. The solubility of amorphous SIR was several folds higher than its crystalline form, but amorphous SIR was highly unstable at all tested temperatures (4° and 40°C). The extruded films exhibited higher dissolution and stability compared to milled SIR powder alone, but the process of extrusion had some detrimental effect on the chemical stability of amorphous SIR. Conclusion: The film formulations showed a significant improvement in the storage stability of the amorphous form of SIR and the solubility advantage of the amorphous form was evident in the dissolution testing. The oral films can potentially improve the bioavailability of SIR by absorption through the buccal mucosa.