【作者】 张颖；

【导师】 蒋学华；

【作者基本信息】 四川大学 ， 药剂学， 2007， 硕士

【摘要】 本课题的目的是以生物药剂学和药物动力学理论为指导，以TET为模型药物，研究其吸收机理和能够持续缓慢12 h释放的缓释胶囊。研究药物在胃肠道的吸收速率和吸收动力学可以为口服制剂的研制提供理论指导。所以在研制处方之前，采用大鼠胃肠道原位灌注的方法先进行了TET吸收动力学的研究。研究结果表明：TET在大鼠胃部有少量吸收，在小肠全段和结肠都有较好吸收，在小肠的吸收呈一级动力学过程，吸收机制为被动扩散，因此考虑制成能缓慢释药12h的缓释胶囊。在处方工艺筛选及优化中，初步建立了TET缓释胶囊释放度的紫外测定方法，以释放度为指标，对TET缓释胶囊进行处方工艺筛选。考察了影响TET缓释胶囊释放的各种因素，在单因素考察的基础上采用均匀设计优化处方，按选定处方制备三批样品，测定释放度，结果表明：本课题研制的TET缓释胶囊的释放度具有较好的重现性和均一性，体外释药特性符合缓释制剂的要求。在质量控制理论的指导下，从整体的角度对TET缓释胶囊的质量进行全面的研究，在此基础上初步拟定了TET缓释胶囊的质量标准。分别建立了TET缓释胶囊的鉴别方法；确定了HPLC含量测定方法，建立了TET缓释胶囊的释放度测定方法，并把2、6、10 h的释放度限度初步定为标示量的25～45％、50～80％和75％以上；建立了TET缓释胶囊有关物质的检查方法。对TET缓释胶囊质量评价研究结果表明，质量评价方法科学合理，TET缓释胶囊质量可控。参照中国药典2005版二部附录“药物稳定性试验指导原则”，以初步拟定的TET缓释胶囊质量标准草案中主要项目为指标，对TET缓释胶囊进行了初步稳定性研究。影响因素实验表明，TET缓释胶囊在光照条件下稳定，在高温和高湿条件下不稳定。在高温条件下，缓释胶囊的外观、有关物质检查、释放度和含量测定均产生明显改变；在高湿条件下，TET缓释胶囊的部分检查项目的检查结果发生了改变。TET缓释胶囊成品应采用防潮包装，置阴凉干燥处保存。对TET缓释胶囊体外释放规律进行研究，模型拟合结果表明，Niebergull模型为最佳拟合模型，Ritger-Peppas方程释放参数n=0.46，0.45＜n＜0.89，说明缓释胶囊中TET的释放机制是扩散和骨架溶蚀协同作用的结果。与普通片体外溶出度相比，TET缓释胶囊在体外释放介质中具有明显的缓慢释放的特性。本研究建立了TET血浆样品的反相高效液相色谱测定方法，以吴茱萸次碱为内标。方法学系统研究表明该方法较好地满足了TET制剂在Beagle犬体内药动学实验的样品测定要求。以TET普通片为参比制剂进行了TET缓释胶囊的药动学和生物利用度初步研究。实验结果表明：单剂量给予Beagle犬供试品T和参比制剂R后，TET缓释胶囊的AUC_0→∞和AUC_0→t与普通制剂相比，无显著性差异；C_max较普通制剂小，t_max延长，TET缓释胶囊在体内具有较好的缓释效果。采用W-N法和逆卷积分法对TET缓释胶囊的体内外相关性进行评价，结果表明TET缓释胶囊的体内吸收与体外释放度有良好的直线回归关系。该研究结果为释放度评价TET缓释胶囊的体内吸收提供了理论基础。体内外实验均证明本制剂缓释效果确切，达到了课题预期设计的目的。本课题在生物药剂学和药物动力学理论的指导下，以TET的胃肠道吸收特性为基础进行制剂研制，减少了制剂开发的盲目性，这种研究思路正处于探索阶段。本课题的研究结果为今后TET其它剂型设计的处方工艺、质量评价、稳定性、体内动力学等方面提供参考。更多还原

【Abstract】 The objective was to study absorption mechanism of TET and to develop TETsustained-release capsule which could steadily release it in 12 hours in vivo, on thebasis of principles in biopharmaceutics and pharmacokinetics.Absorption kinetics of TET was studied by means of in situ rat intestinalperfusion before TET formulation was developed because studies on absorption rateand kinetics of drugs provide theoretical support to oral preparations development.My results demonstrate that TET absorption in the entire intestine and colon is betterthan that in stomach., and the absorption in rat intestine is a first-order processes withpassive diffusion mechanism. So a 12-hr sustained-release formulation is considered.A UV method to determine dissolution of TET sustained-release capsules wasestablished for formulation preparation selections and optimizations. Factors whicheffect the TET release were studied and a formulation was developed and optimizedon the basis of homogeneous factor researches. Dissolution profile of 3 batches ofthe developed formulation demonstrates good reproducibility and homogenicity. Itsrelease characteristics in vitro comply with designing requirement ofsustained-release formulation.Specification of TET sustained-release capsule was established based on itsquality study according to principles of quality control: Identification; Assay byHPLC method; Dissolution: 25～45%, 50～80% and not less than 75% of labeled assay at 2hr, 6hr and 10hr respectively; Test for related substances. My researchesdemonstrate that this established specification is scientifically reasonable for qualitycontrol of TET sustained-release capsule.Stability study with the established specification on TET sustained-releasecapsule, carried out in accordance with principles of stability test on drug substances,defined in APPENDIX of CP2005, showed that it is stable under light but susceptibleto high temperature and high humidity: magnificent changes in appearance, relatedsubstances, dissolution and assay were observed after stored in high temperature; andin some tests after stored in high humidity conditions. Therefore it is recommendedto be stored in dry, cool places with moisture-proof packages.The study of release mechanism demonstrates good conformance to Niebergullmodel.The n in Ritger-Peppas equation is 0.46 （0.45＜n＜0.89）, which indicates thesynergy of diffusion and matrix erosion. Its sustained-release character in medium invitro is convincingly demonstrated in comparison with dissolution profile of TETtabletsA RP-HPLC method using Rutacarpine as internal standard is established fordetermination of TET concentration in plasma of Beagles dog. Its methodologicalstudy demonstrates good suitability for test of TET formulation in pharmacokineticsstudies in Beagles dog. Study on pharmacokinetics and bioequivalence of TETsustained-released capsules in comparison with TET tablets showed no significantdifferences was found in AUC_0→∞ and AUC_0→∞between capsules and tablets of singledosage; c_max is less and t_max is more for capsules than that of tablets, whichdemonstrates the former has good sustained release in animals.Evaluation on in vivo-in vitro correlation of the TET sustained-release capsuleaccording to W-N method and deconvolution method proved good linearityregression between absorption of TET in vivo and dissolution in vitro.. It providestheoretical basis for evaluation on in vivo absorption of TET sustained-releasecapsule with regard to dissolution. Results in vitro and in vivo demonstrate goodsustained-release as we anticipated.My formulation design, based on the absorption kinetics of TET in stomach and intestine according to principles of biopharmaceutics and pharmacokinetics,reduced blindness of formulation development although this kind of strategy is justthe beginning. My research provides references for other formulation designs of TETin process, quality evaluation, stability, pharmacokinetics in vivo.更多还原