Studies On Synthesizing Dexamethasone Palmitate And Formulating Dexamethasone Palmitate Fat Emulsion With Its Pharmacodynamics Study

This study is oriented on new drug development to research the chemical synthesis route of Dexamethasone Palmitate as well as preparation process and pharmacodynamics study of Dexamethasone Palmitate Emulsion. The study also achieved the first generic Dexamethasone Palmitate Emulsion equivalent to the import drug, changing the situation of dependence on import drug.Dexamethasone Palmitate was synthesized by two-stage reaction of Dexamethasone and palmitinic acid with the yield ranging from 65% to 75%. The assay of Dexamethasone Palmitate was determined by HPLC, and the structure analysis of purified Dexamethasone Palmitate was conducted by IR,1H-NMR,13C-NMR,MS. The free fatty acids was test by TLC after hydrolysis of Dexamethasone Palmitate. All the test results showed the synthesis route of Dexamethasone Palmitate is optimized, the structure of product is correct and the assay also meet the specification. A long-term and accelerated stability studies were conducted to successive 3 batches of Dexamethasone Palmitate specimen, with the condition at high temperature (40℃), high humidity (RH75%)and lightening (4500±500Lx). Due to its lower melt point (about 60℃), the specimen were subject to high temperature test under 40±2℃, the test result showed Dexamethasone Palmitate is hygroscopic and unstable at high temperature and light condition.With reference to the imported Limethason(?), the formulation was developed successfully with homemade Dexamethasone Palmitate, the test result showed the particle size meets requirement and the product is stable.Contrasted with Limethason(?), the study on bioavailability of Dexamethasone Palmitate emulsion was conducted. After Subject was injected into drug A, the half life in blood plasma was 1.20±0.17h, Cmax and Tmax respectively were 0.12±0.04 h and 528.59±80.50ng/mL. AUC(0-8h) was 845.09±141.99 ng·h/ml. After single injection of Drug A the half life of Dexamethasone was 4.97±1.34h, Cmax and Tmax respectively were 1.65±0.40 and 36.87±7.74ng/mL, AUC(0-24h)was 247.40±59.78 ng·h/ml. After single injection of Drug R, the half life in blood plasma was 1.29±0.25h, Cmax and Tmax respectively were 0.14±0.06h and 577.13±96.11 ng/mL,AUC (0-8h) was 868.86±160.99ng·h/ml. After single injection of Contrast drug R, the half life of Dexamethasone was 5.22±1.28h, Cmax and Tmax respectively were 1.55±0.43h and 35.70±6.27ng/mL, AUC(0-24h) was 228.62±59.59ng·h/ml. The 90% of fiducial interval of AUC in the test drug A parameter was within 80%-125% of the contrast drug R, the 90% fiducial interval of Cmax in the test drug A parameter was within 70%-143% of the contrast drug R. Tmax statistics was based on non-parameter Wilcoxon, the result showed insignificant difference (P>0.05) that means the test drug and the contrast drug are bioequivalent.