Modulation of Oleanolic Acid Dissolution Profile via Solid State Manipulation and Nanoemulsion Preparation

摘要

Oleanolic acid (OA) is a lipophilic compound which clinically used as an oral drug for the treatment of hepatitis B in China. It has poor aqueous solubility, dissolution and bioavailability in vivo. Objective To modify the in vitro dissolution of oleanolic acid by preparation of its crystalline materials and self-emulsifying nanoemulsion. Method Crystalline forms of OA, including a methanol solvate, an ethanol solvate and an acetone non-solvate, were prepared by dissolving its raw material into different organic solvents and evaporating organic solvents at room temperature in a dark place for several weeks. The filtered crystals were carefully dried and stored under ambient conditions. Specific surface area of the three crystalline materials was determined by BET nitrogen adsorption. Nanoemulsion of OA was also prepared. HPLC was utilized to quantify the in vitro dissolution of OA raw material (OA-RW), solvates, non-solvate nan6emulsion and commercial available tablet. Result Dissolution studies showed that ~89.5% of OA could be released from the raw material in 1% SDS (pH 7.0) after 24 hours, which is higher than those of the crystalline forms (<70%). Both of the initial and intrinsic dissolution rates of OA-RW were obviously faster than those of the other forms which may due to its higher specific surface area. For the other crystalline forms, methanol and ethanol solvates showed higher intrinsic dissolution rates than the acetone non-solvate because of the favorable reduction in free energy through the mixing of methanol/ethanol with water. OA could be rapidly and completely released from the nanoemulsion within 10minutes. In contrast, none of the OA could be detected in dissolution medium (water) from the OA-RW and commercial available tablet, and the equilibrated concentration is below the detection limit of HPLC (1g/ml). Conclusion OA could be slowly released in I% SDS solution from its raw material and ethanol solvate for 24 hours, suggesting that SDS could be considered as a wetting agent to develop an oral sustained release form of OA. While OA could be rapidly and completely released from its nanoemulsion, suggesting that nanoemulsion may be developed as an oral immediate release dosage form of OA.