Study On The Preparation Of New Rapamycin Solid Formulations And Their Pharmacokinetics In Rats

Rapamycin,a carbocyclic lactone-lactam macrolide antibiotic derived from the Streptomyces hygroscopin , has been shown to have a novel mechanism of immunosuppressive action. A variety of In vitro studies have shown Rapa to be 100 times more potent than Cyclosporine A. Data of preclinical studies in a variety of animal transplant models have also suggested that Rapa could significantly add to graft survival time. Due to Rapa's great molecular weight and strong lipophilicity, it has practically low solubility in water (2.6 mg·L-1) which has made it particularly difficult to make clinically acceptable injectable dosage forms. The dosage form of Rapa appeared in foreign countries were oral self-emulsifying suspension and nanocrystal tablet. The oral self-emulsifying suspension must be stored under low temperature (4-8℃), and it was difficult to quantification. Compared with oral self-emulsifying suspension, the bioavailability of nanocrystal tablet remained together with a long production cycle.In this study, solid self-microemulsify technology and solid dispersion technology were used to improve the dissolution and absorption rate of Rapa in the gastrointestinal tract, and thus to increase its oral bioavailability.The self-microemulsify technology was combined with the Semi-solid matrix technology, and the self-microemulsifying semi-solid capsules were prepared by melting method. At the beginning, single factor examine was applied to optimize formulation and technique parameters. The stability of capsules, dissolution in vitro, sizes of micro-emulsion were selected as the main objectives of the study. The influence of different carriers, co-surfactants, contents of carriers, contents of co-surfactants, temperature of Semi-solid matrix, cooling temperature was analyzed. The results showed that the quality of capsules was significantly influenced by the factors of co-surfactants, contents of carriers, contents of co-surfactants. Based on the four factors and three levels orthogonal experimental design, the optimized formulation and technique parameters were ascertained: Rapa (1mg), Transcutol P (TP, 10%, W/W), Cremophor RH40 (35%, W/W), MCT (15%, W/W), Poloxamer 188 (F68, 40%, W/W); Filling temperature: 45℃; Cooling temperature: -20℃. Fourier Transform Infrared, X-ray diffraction and Differential Scanning Calorimeter suggested that Rapa semi-solid matrix capsule existed of the amorphous. The results of stability determination tests proved that the illumination, the humidity and high temperature showed impact to the quality of semi-solid matrix capsule. Which also suggest that the capsule should be packed sealed in dark containers. After three months'accelerated tests the preparation was stable, and drug content in capsule had little change during the accelerated experiment, while the content of Rapa reduced significantly in liquid Rapa self-microemulsifying drug delivery system (SMEDDS).The Rapa solid dispersion (Rapa: F68 1:60) prepared by solvent-melting method can significantly increased the dissolution of Rapa. The dissolution percentage of Rapa SD can be up to 85% (45min). Fourier Transform Infrared, X-ray diffraction and Differential Scanning Calorimeter suggested that Rapa SD existed of the amorphous, which had closely connection with the change of crystal parameters.The pharmacokinetics and bioavailability of self-microemulsifying semi-solid capsules and solid dispersion in rats were studied comparing with liquid Rapa SMEDDS. The HPLC-MS/MS method was established to determine Rapa concentration in rat blood, and the method was proved to be suitable for the pharmacokinetics study of Rapa. The AUC0-∞of liquid Rapa SMEDDS, Rapa self-microemulsifying semi-solid capsules and Rapa solid dispersion were (197.07±39.78)μg·L-1?h, (213.80±42.27)μg·L-1?h, (169.73±50.25)μg·L-1?h, respectively. The peak concentration Cmax were (16.89±5.08)μg·L-1, (13.77±4.36)μg·L-1, (10.37±3.96)μg·L-1, respectively; Tmax were (0.95±0.52)h, (2.14±0.21)h, (1.5±0.46)h, respectively. The relative bioavailability of Rapa self-microemulsifying semi-solid capsules and Rapa solid dispersion were 108.48% and 86.12%.This study proved that Rapa self-microemulsifying semi-solid matrix capsule and Rapa solid dispersion have good therapy effect as well as favorable preparation and preservation stability. Besides, the technology can improve patients′compliance and reduce the costs of manufacturing. They have special prospect in becoming new preparations for clinical in the future.