Study on the Preparation of New Rapamycin Solid Formulations and Their Pharmacokinetics in Rats
|School||Huazhong University of Science and Technology|
|Keywords||Rapamycin Since microemulsion Semi-solid skeleton Solid dispersion Stability Bioavailability|
Rapamycin (Rapamycin, Rapa) was originally isolated from Streptomyces hygroscopicus as antifungal applications, a subsequent study it was found that the potential value of rapamycin in the organ transplantation, as the third generation of potent immune suppression agent widely used in clinical. Vitro test table rapamycin immunosuppressive activity is 100 times of the cyclosporin A, and the application has been confirmed in various animal model of kidney transplantation rapamycin can significantly improve renal transplantation the animals' survival. Rapamycin molecular weight lipophilic, water solubility is only 2.6mg · L-1, low oral bioavailability (eg, oral solution bioavailability of only 14%). Listing of dosage forms of oral liquid and nano-crystal plates, oral solution to low temperature storage, and patients taking quantitatively very inconvenient; milling prepared nanocrystals piece no significant improvement in bioavailability compared to the oral solution, and the preparation process is complex, The long production cycle. This study were prepared from the micro-emulsion technology and solid dispersion of rapamycin from the semi-solid matrix capsule of the micro-emulsion and a rapamycin solid dispersion, to improve the dissolution properties of rapamycin, and increase its dissolution rate and stomach intestinal absorption, thereby improving oral bioavailability. Combination of solid technology and semi-solid skeleton capsule technology self-micro-emulsifying drug the melt prepared rapamycin semi-solid skeleton from microemulsifying capsule and inspected the filling temperature, cooling rate, the type of vehicle content, the type of co-surfactant, content and other factors impact capsule capsule shell, drug content, dissolution behavior and Microemulsion particle size, etc., to determine the preferred range of the semi-solid matrix capsule formulation process. Through single factor and orthogonal experimental design to optimize the prescription process rapamycin from the preparation process of the micro-emulsion semi-solid skeleton capsule. Rapamycin in the final formulation of the self-microemulsifying semi the solid skeleton capsules (1mg / tablets): Rapa (1 mg), Transcutol P (TP, 10%, W / W), Cremophor RH40 (35%, W / W), MCT (15%, W / W), Poloxamer 188 (F68, 40%, W / W), a filling temperature of 45 ° C, a cooling temperature of -20 ° C. The capsule hydration optimized to form microemulsion particle size is small and evenly distributed, content uniformity, in vitro release, which adhere to the requirements of pharmaceutics prescription process reproducibility. The FTIR scan spectra, X-ray diffraction analysis and differential scanning calorimetric analysis of Step rapamycin in amorphous form dispersed in a semi-solid matrix, is conducive to the rapid dissolution of the drug. Impact factor test results table rapamycin from micro-emulsion semi-solid skeleton capsule of light, temperature, humidity and other factors than those sensitive preparations must be sealed and dry place. After three months plus preliminary speed trials, since the micro-emulsion semi-solid skeleton capsule quality is stable, drug content, microemulsion particle size, in vitro dissolution had no significant changes of self-micro-emulsifying concentrate drug content and in vitro dissolution significantly reduced. Prepared by solvent molten Rapa-F68 (1:60) The solid dispersions significantly accelerate the elution of rapamycin, 45min dissolution of more than 85%, a good performance of the in vitro release. Fourier transform infrared scan spectra, X-ray diffraction analysis and differential scanning calorimetric analysis card rapamycin dispersed in amorphous form in the solid dispersion, solubilization principle may change with the crystallographic orientation, grain size, grain The grid lattice plane spacing changes are closely related to. Article also homemade rapamycin as a reference from the micro-emulsion concentrate formulation were rapamycin from the semi-solid skeleton microemulsifying capsule rapamycin solid dispersion preliminary pharmacokinetics of the two formulations in rats dynamics and relative bioavailability study. High performance liquid chromatography - mass spectrometry determination of rat whole blood concentration of rapamycin, the methodology investigation confirmed that this method can meet the requirements of the pharmacokinetic studies in rats rapamycin. The test results showed that, after a single oral dose of the above formulation, rapamycin self-microemulsifying concentrate rapamycin from the semi-solid matrix capsule of the micro-emulsion and a rapamycin solid dispersion AUC0-∞ (197.07 ± 39.78 ) μg · L-1? h, (213.80 ± 42.27) μg · L-1? h, (169.73 ± 50.25) μg · L-1? h; peak time Tmax were (0.95 ± 0.52), (2.14 ± 0.21) h, (1.5 ± 0.46) h; Cmax were (16.89 ± 5.08) μg · L-1, (13.77 ± 4.36) μg · L-1, (10.37 ± 3.96) μg · L-1; Rapa self-micro-emulsifying semi-solid skeleton capsules and the Rapa solid dispersion relative bioavailability of 108.48% and 86.12%, respectively. The rapamycin from this experiment, obtained semi-solid matrix capsule of the micro-emulsion and rapamycin solid dispersions in vitro dissolution rate significantly improved Rapa thereby improving drug absorption; significantly improved compared with the self-microemulsifying concentrate the drug in the formulation in stability; pharmacokinetic test results show that rapamycin from the semi-solid matrix capsule of the micro-emulsion having the concentrated liquid phase with the self-microemulsifying like rats bioavailability (108.48%), which was significantly higher than the solid dispersion ( 86.12%). The study laid a foundation for the further development of novel rapamycin solid dosage forms.