Preparation And Evaluation Of Ursolic Acid Self-microemulsion

Ursolic acid(UA) is a atriterpenoid compound possessing A wide range of biological effects, such as Anti-hepatitis, anti-virus, anti-tumor anti-ulcer, antidiabetogenic activities, and so on. It has low toxicity and adverse reactions, thus has broad development prospect. UA was not soluble in water and the dissolution speed is very slow, leading to a very low bioavailability when administrated orally, which limits its clinical application. Self-microemulsifying drug delivery system(SMEDDS) is uniform, transparent solution composed of oil phase, surfactant and cosurfactant, can spontaneously forme transparent or semitransparent microemulsion once contact with the aqueous mixture at ambient temperature (usually refers to a temperature of37degree) with gentle agitation. Microemulsions can increase the solubility of drugs and absorption area. The surfactant in the system can improve the dissolution of drug and increased intestinal epithelial permeability, helps to improve the bioavailability of the drug.SMEDDS is a very good carrier for the poorly soluble drugs as it has the advantages of simple preparation, stable property and could be packed in soft capsule which has accurate dosage and good compliance. So it is really a meaningful thing to study the oral ursolic acid SMEDDS which could provide new evidence for the preparation development of Ursolic acid. The main research work was as follows:1. Preformulation studies of ursolic acid SMEDDS.(1) Establish HPLC method for determination of ursolic acid;(2) Determination of the equilibrium solubility ursolic acid in different medium, provide the basis for prescription screening;(3) Determination the oil-water partition coefficient of ursolic acid in different pH buffers and medium.2.Foumula and preparation of ursolic acid SMEDDS.(1) The oil phase and emulsifier were selected as ethyl oleate and CremoPhor EL respectively according to the solubility test and the interaction between surfaetants and oils. Transcutol P was picked as the cosurfacant by evaluating the area of microemulsion in the pseudo-ternary phase diagram;(2) SMEDDS formulation was optimized by selecting the drug loading and particle size distribution as variables and the final formulation was found consisting 15%of ethyl oleate,40%of Cremophor EL,45%of Transcutol P, the drug content was lOmg/g.3. In vitro quality evaluation of ursolic acid SMEDDS.(1) Quality assessment of ursolic acid SMEDDS was evaluated by observation of the appearace, the morphology, particle size, zeta potential and the content.(2) For ursolic acid self-microemulsion and homemade capsules, in vitro release test was carried out. The results showed SMEDDS dissolution amounts to80%above in lOmin while the capsule only about20%in60min, demonstrated that SMEDDS can greatly improve the drug dissolution of ursolic acid.(3) primary stability tests indicated that the ursolic acid SMEDDS was stable.4. Absorption kinetics of ursolic acid SMEDDS in rat intestines.(1)In situ rat intestinal perfusion experiment was used to investigate the absorption kinetics of ursolic acid SMEDDS in different intestinals, determining the optimal absorption site. Since in the duodenum, jejunum, ileum and colon, the absorption rate constant Ka were0.108±0.010、0.170±0.016、0.092±0.022and0.070±0.013h-1respectively; and the percentage of absorption were18.48±1.85%、28.40±1.43%、14.78±2.27%and12.95±2.37%respectively, indicating that the jejunum was the best absorption site for ursolic acid SMEDDS;(2) the Ka of different concentrations of ursolic acid SMEEDS in jejunum were0.172±0.010、0.170±0.016、0.166±0.015h-1respectively, and lnX and time presented a linear relationship, showing that the principal mechanism fo ursolic acid SMEDDS in intestinal absorption conformed to passive diffusion;(3) compared to ursolic acid suspension, SMEDDS improved the intestinal absorption of ursolic acid remarkably, as the Ka of SMEDDS and suspension were0.170±0.016and0.045±0.007h-1, and the percentage of absorption were28.40±1.43%and8.20±1.19%,which had significant difference.