伊潘立酮-羟丙基-β-环糊精包合物的制备及表征、肌肉刺激和药代动力学研究

Preparation,Characterization,Muscular Stimulation and Pharmacokinetics of the Inclusion Complex of Iloperidone-Hydroxypropyl-β-Cyclodextrin

目的通过对伊潘立酮与羟丙基-β-环糊精(HP-β-CD)包合作用进行对比研究,达到制备安全、有效的肌肉注射给药制剂的目的。方法分别研究伊潘立酮在HP-β-CD水溶液与HP-β-CD 0.2%磷酸溶液中的相溶解度曲线;采用溶液搅拌法,冷冻干燥技术制备包合物;采用红外、分光光度法、差示扫描量热分析法(DSC)、溶解度法对包合物进行验证;肌肉注射给予伊潘立酮-HP-β-CD包合物溶液,对兔股四头肌进行肌肉刺激性试验;对比格犬进行伊潘立酮-HP-β-CD包合物溶液肌肉注射给药和伊潘立酮片口服给药,对药代动力学指标进行研究。结果相溶解度曲线呈Ap型,表明客分子与主分子包合比例为1∶n(n≥2);红外、DSC、溶解度试验结果表明,伊潘立酮包合于HP-β-CD的空腔结构中;包合物溶液对肌肉注射部位无刺激性;药代动力学结果表明,伊潘立酮与HP-β-CD包合后,肌肉注射给药药物吸收较快,与口服片剂相比,其相对生物利用度为143%。结论伊潘立酮-HP-β-CD包合物可显著提高溶解度,能很好地应用于注射给药途径。

Objective To study the inclusion complex of Iloperdone- Hydroxypropyl- β- Cyclodextrin（HP- β- CD）,in order to prepare a stable and effective parenteral formulation. Methods Phase solubility study was carried out using distilled water and 0. 2% phospho- ric acid solution as dissolution medium, respecticely; the solution method and lyophilization techniques were used for inclusion complex preparation. The complexes were characterized by fourier transform infrared spectroscopy and differential scanning calorimetry studies and the solubility was determined by UV spectroscopy. The muscular stimulation test of Iloperdone- HP- β- CD inclusion complex solution was perform in rabbits,the pharmacokinetic of Iloperdone tablet and Iloperdone inclusion complex were evaluated after oral administration and muscular injection in dogs. Results The phase- solubility profiles were classified as Ap type,indicating the formation of 1 ： n（n〉2） stoichiometric inclusion complexes. The complexes were characterized by fourier transform infrared spectroscopy（IR） and differential scan- ning calorimetry（DSC） indicated that Iloperdone was able to form an inclusion complex with HP- β-CD. Iloperdone- HP- βCD inclusion complex solution had no significant stimulation on muscles. In vivo pharmacokinetic study showed that the absorption rates of Iloperdone across muscles tissues were enhanced compared with oral administration. The relative bioavailabity was 143%. Conclusion The Iloperdone-HP-β-CD complex can significantly improve the sotubility,it is an attractive formulation for use in the parenteral.