Preparation And Study Of Drug CA Solid Dispersion Sustained-release Capsule

Objective: Drug CA is a neural macrolide antibiotic isolated from a kind of streptomycete fermentation in soil, and drug CA is a new powerful immunosuppresion. Lots of animal experiments and clinical trials indicate that drug CA has better immunosuppressive action than cyclosporin (10~100 fold), and has less rate of adverse effect and less adverse action. Throuhgh the research of preformulation, drug CA is scarcely solved and oral administration bioavailability of drug CA is low, which limits its clinical application. Its delayed release solid dispersion prepared. Then the solid dispersion sustained-release Capsule prepared. The sustained-release solid dispersion could enhance dissolution rate and bioavailability, reduce the release rate of drug, decrease the frequency of drug administration and rate of adverse effect for extensive clinical application.Methods:1 Drug CA solid dispersion sustained-release capsule preparation: According to literature and pretest, the factors of solid dispersion capsule's formulation and preparation technique were determined. According to the characters of drug CA and adjuvants, solvent method was selected for preparing drug CA solid dispersion sustained-release capsule. Solubility and stability as indexes, single factor test investigated 3 formulation factors and 4 technique conditions, and stirring speed, drying temperature,degree of solvent volatilizating and mesh level were determined. Basis of the single factor test, the ratio of drug CA and adjuvant as investigation factors, release rate on 0 day, release rate after 3 months and operation process were used as indexes, 3 factors and 3 levels orthogonal experiment was designed for optimizing formulation.Data analysis was conducted, and the optimal formulation of drug CA solid dispersion capsule was determined. 3 batches of drug CA solid dispersion sustained-release capsules were prepared with optimal formulation and technique conditions, and release rate were determined to study stability.2 Study of quality evaluation and stability: It is provde to solid dispersion in differential scanning calorimetry and X-ray diffraction analysis. According to literature and pretest, high performance liquid phase assay was set up to determine content and related substances. Release rate detection experiment was designed according to 1rd method of appendix XD (dissolution rate detection method), volume two,《China Pharmacopoeia》(2005 edition). Determination of Content and Content Uniformity referring to method of appendix XE (Content and Content Uniformity detection method), volume two,《China Pharmacopoeia》(2005 edition).3 Drug CA solid dispersion sustained-release capsule stability test:Temperature, humidity and light stress test were conducted to see the influence of high temperature, high humidity and strong illumination on drug CA solid dispersion optimal formula capsule stability, so as to determine package. Accelerative test in 6months were conducted to see stability of drug CA solid dispersion capsule.4 Drug CA solid dispersion sustained-release capsule pharmacokinetic experiment:Dogs were selected as laboratory animals and divided into two groups in random. One group was given reference drug and the other was given test drug. Crossover experiment was taken after two weeks. A foreign imported drug CA solid dispersion sustained-release capsule was find as referance sample. Bioequiavailability analyse were conducted between self-made capsule and reference sample. Drug content in whole blood was determined by LC-MS/MS, a software 3p87 was used to calculate pharmacokinetic parameter and relative bioavailability, ANOVA and t-test were used to evaluate bioequiavailability of self-made capsule and reference sample. Results:1 Drug CA solid dispersion sustained-release preparation: Formulation: CA drug 1.0g EC(10cp) 0.4g HPMC2910 0.3g Lactose 4.0g Drug CA sustained-release solid dispersion preparation process: solvent method was selected for preparing drug CA sustained-release solid dispersion , EC and HPMC was used as carrier, and ethanol was used as solvent.,stirring speed was 300 rpm, drying temperature was 40℃and mesh level was 80~100. According to formulation, drug CA powder and EC were solved in ethanol with continuely stirring, then HPMC and lactose were added. Solvent was volatilized by stirring until the mixture changed to semisolid. Drying process was conducted under 40℃and vacuity until the semisolid changed to solid and then the solid was comminuted and sieved.2 Drug CA solid dispersion sustained-release capsule preparation:Capsule was preparated with action ingredients of 1mg /table. The table is 120mg weight. Solid dispersion was mixed with Magnesium Stearate(0.06%W/W),micropowder silica gel (0.10%W/W), After mixed with DC lactose and magnesium stearate, the solid dispersion was put into capsule.3 Drug CA solid dispersion capsule determination method:3 batches of drug CA solid dispersion sustained-relese capsules, which were prepared according to optimal formulation and conditions, were determined by HPLC, drug contents were 102.8%,102.6%,99.7%, relative to labeled dosage, which were all in the limited range of 90%~110%.4 Drug CA solid dispersion sustained-relesease capsule determination release rate method:Release profile of test drug was compared with release profile of reference drug in methd of resemble factor. Value of f2 was 91.80, relative to labeled dosage, which were all in the limited range of 50~100. The result indicated that release profile of test drug CA solid dispersion capsule(batch No.090901)and referance sample were coincident.5 Drug CA solid dispersion capsule stability test:In high temperature or high humidity conditions, appearance of drug CA solid dispersion sustained-release capsule had on changes, but dissolution rate and drug content decreased significantly. These results indicated that drug CA solid dispersion capsule was sensitive to high temperature and high humidity. So moistureproof package material was advised. In given strong illumination condition, drug CA solid dispersion capsule show no significant difference in appearance, drug content and dissolution rate, that indicated drug CA solid dispersion sustained-release capsule is stable to strong illumination. The results of accelerative test in every index had no significant change in 1 month, 2 month, 3 month, 6month. Results of test indicate that drug CA solid dispersion capsule was stable under the test conditions.6 Drug CA solid dispersion sustained-release capsule pharmacokinetic experiment:3p87 was used to analysis drug content data of self-made drug CA solid dispersion capsule and imported control particle in blood of dogs. Compared to AUC(0-t) and AUC(0～∞) of self-made drug CA capsule and impored capsule, Relative bioavailability of self-made drug CA capsule is 108.67%±12.87% and 113.8 %±10.8%. According to AIC method, the concentration-time curve fitted two compartment model. By ANOVA and T-test, The 90% confidence intervals of AUC(0-t) and AUC(0-∞) of self-made drug CA solid dispersion sustained release capsule were 94.6%~112.2 % and 91.4%~121.4%, which were in the interval of imported capsule 80%~125%. The 90% confidence intervals of Cmax was 99.8%~130.8%, which was in the interval of imported capsule 70%~143%. Tmax had no significant difference with imported control particle by non-parameter test. So drug CA solid dispersion capsule and imported control particle had bioequiavailability. Conclusion: All the results indicated that drug CA solid dispersion sustained-release capsule improved solubility of drug CA and bioavailability and decrease dissolution rate and bioavailability. Compared with imported referance sample, self-made drug CA solid dispersion capsule had bioequiavailability. The preparation method of drug CA solid dispersion capsule was suitable for industry production. Drug CA solid dispersion sustained-resease capsule had good stability and wide application future.