| 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 AUC0→∞ and AUC0→∞between capsules and tablets of singledosage; cmax is less and tmax 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.
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