Research On Ursolic Acid And Its Derivative Nanocrystals

Ursolic acid(UA), a natural pentacyclic triterpenoid, has been reported to possess a variety of pharmacological activities, especially antitumor effect, with the potential pharmaceutical value. But the poor oral bioavailability of UA owing to the poor aqueous solubility and membrane permeability limits the drug efficiency. It is necessary to improve the solubility of UA, optimize its pharmacokinetics properties, and study the applicability of various routes of administration. Nanocrystals or nanosuspension technology, which presents significant improvement of solubility and dissolution rate of insoluble drugs, applicability to a variety of administration routes and unique pharmacokinetics properties, has a promising application. Based on above, the purpose of the thesis was to enhance UA bioavailability by two different strategies: exploring UA-NC to improve the oral bioavailability of UA and investigating injection route of UA derivatives NC to achieve sustained release after intramuscular injection.Firstly, the purpose of the present study was to develop UA nanocrystals employing different fabrication process and to evaluate their effects on UA oral bioavailability. UA-NC was prepared by solvent precipitation(SP) and high pressure homogenization(HPH) method, and the parameters were optimized. The central composite design-response surface method was used to and determine the influencing factors of high pressure microfluidization homogenization. Freeze drying conditions were also carried out to investigate the solidification and redispersion of UA-NC.The crystalline morphology of UA-NC observed by scanning electron microscopy(SEM) showed that the UA-NC(HPH) was short small rod, while the UA-NC(SP) is nearly spherical particles. The results of differential scanning calorimetry(DSC) and powder X-ray diffraction(PXRD) exhibited that part of UA transformed into amorphous during HPH and the crystalline state of UA-NC(SP) kept in amorphous form. The in vitro dissolution test showed that UA-NC significantly increased the dissolution rate of UA.Oral bioavailability of UA-NC was evaluated in SD rats after 50 mg/kg administration. The Cmax of HPH group and SP group exhibited 2.4 and 3.5-fold increase than that of UA coarse suspension, respectively. AUC0-∞ of HPH and SP group presented 2.5 and 3.8-fold enhancement which indicated UA-NC significantly increased the oral bioavailability of UA, reduced the elimination rate and prolonged the retention time.Secondly, the purpose of the present study was to investigate long-acting injectable drug delivery system loaded UA. Through the design and preparation of UA derivatives NC, the applicability and the different in vivo behaviour were explored after intramuscular administration of the nanosuspensions loaded UA and its derivatives synthesized according to the ester prodrug strategy.C-3 derivatives acetoxy ursolic acid(AUA) and octanoloxy ursolic acid(OUA) and C-28 derivatives ursolic acid ethyl ester(UAA) and ursolic acid octyl ester(UAO) were synthesized. UA derivative NCs with the mean particle size about 300 nm were prepared by HPH.The in vivo pharmacokinetics after intramuscular administration of UA and its four derivatives NCs in rats demonstrated that AUA and OUA group displayed same Tmax and markedly decreased Cmax. For UAA and UAO group, evidences of significantly prolonged Tmax, Cmax decrease, AUC0-∞ increase and reduced elimination rate(CL/F) indicated UAA-NC and UAO-NC profiled a more significant sustained release characteristics than UA-NC. Low UA exposures after i.m. administration of four derivative groups in rats were relevant to the side carbon chain of UA, which was worthy of more research.