雷帕霉素固体新制剂的制备及其在大鼠体内的药动学研究
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摘要
雷帕霉素(Rapamycin,Rapa)最初从吸水链霉菌中分离出来作为抗真菌药物应用,后续研究中人们发现了雷帕霉素在器官移植方面的潜在价值,目前作为第三代强效免疫抑制剂广泛应用于临床。体外试验表明雷帕霉素的免疫抑制活性是环孢素A的100倍,并且在各种动物肾移植模型中的应用证实雷帕霉素能显著提高肾移植动物的存活率。雷帕霉素分子量大,亲脂性强,水中溶解度仅有2.6mg·L-1,口服生物利用度较低(如口服液的生物利用度仅为14%)。目前上市的剂型有口服液和纳米结晶片,口服液须低温储藏,且患者服用定量非常不便;与口服液相比采用球磨法制备的纳米结晶片生物利用度无明显改善,且制备工艺复杂,生产周期长。
本研究分别采用自微乳化技术和固体分散技术制备了雷帕霉素自微乳化半固体骨架胶囊和雷帕霉素固体分散体,以改善雷帕霉素的溶解性能,增加其溶出速率和胃肠吸收,进而提高口服生物利用度。
本文将自微乳化制剂固体化技术与半固体骨架胶囊技术相结合采用熔融法制备了雷帕霉素自微乳化半固体骨架胶囊,并考察了灌装温度、冷却速率、赋形剂的种类、含量、助表面活性剂的种类、含量等因素对胶囊囊壳、药物含量、溶出行为及微乳粒径等的影响,确定半固体骨架胶囊处方工艺的优选范围。通过单因素考察和正交试验设计优化处方工艺,确定了雷帕霉素自微乳化半固体骨架胶囊的制备工艺。雷帕霉素自微乳化半固体骨架胶囊(1mg/粒)的最终处方为:Rapa (1mg),Transcutol P (TP, 10%, W/W),Cremophor RH40 (35%, W/W),MCT (15%, W/W),Poloxamer 188 (F68, 40%, W/W),灌装温度为45℃,冷却温度为-20℃。优化后的胶囊水化形成微乳的粒径小且分布均匀,含量均匀度、体外释放度等均符合制剂学要求,处方工艺重现性高。傅里叶红外扫描图谱、X-射线衍射分析和示差扫描热量分析提示雷帕霉素以无定形态分散于半固体基质中,有利于药物的快速溶出。影响因素试验结果表明雷帕霉素自微乳化半固体骨架胶囊对强光、高温、高湿等因素均较敏感,制剂需密闭干燥处储存。经三个月加初步速试验后,自微乳化半固体骨架胶囊质量稳定,药物含量,微乳粒径,体外溶出度均无显著性变化,而自微乳化浓缩液中药物含量及体外溶出度显著降低。
采用溶剂熔融法制备的Rapa-F68(1:60)固体分散体能显著加快雷帕霉素的溶出,45min溶出度达85%以上,体外释药性能良好。傅里叶红外扫描图谱、X-射线衍射分析和示差扫描热量分析证明雷帕霉素以无定形态分散于固体分散体中,其增溶原理可能跟晶格取向的改变、晶粒大小、晶格点阵面间距等的变化密切相关。
本文还以自制的雷帕霉素自微乳化浓缩液为参比制剂,进行了雷帕霉素自微乳化半固体骨架胶囊,雷帕霉素固体分散体两种制剂在大鼠体内初步药代动力学和相对生物利用度的研究。建立了高效液相色谱-质谱联用测定大鼠全血雷帕霉素浓度的方法,方法学的考察证实此法能够满足雷帕霉素大鼠体内药代动力学研究的要求。试验结果表明,单剂量口服上述制剂后,雷帕霉素自微乳化浓缩液,雷帕霉素自微乳化半固体骨架胶囊和雷帕霉素固体分散体的AUC0-∞分别为(197.07±39.78)μg·L-1?h、(213.80±42.27)μg·L-1?h、(169.73±50.25)μg·L-1?h;达峰时间Tmax分别为(0.95±0.52)h、(2.14±0.21)h、(1.5±0.46)h;峰浓度Cmax分别为(16.89±5.08)μg·L-1、(13.77±4.36)μg·L-1、(10.37±3.96)μg·L-1;Rapa自微乳化半固体骨架胶囊和Rapa固体分散体的相对生物利用度分别为108.48%和86.12%。
本试验制得的雷帕霉素自微乳化半固体骨架胶囊和雷帕霉素固体分散体能明显改善Rapa的体外溶出速率从而改善药物吸收;与自微乳化浓缩液相比显著提高了药物在制剂中的稳定性;药动学试验结果表明,雷帕霉素自微乳化半固体骨架胶囊具有与自微乳化浓缩液相似的大鼠体内生物利用度(108.48%),显著高于固体分散体(86.12%)。本项研究为进一步开发新型雷帕霉素固体制剂奠定了基础。
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.
本研究分别采用自微乳化技术和固体分散技术制备了雷帕霉素自微乳化半固体骨架胶囊和雷帕霉素固体分散体,以改善雷帕霉素的溶解性能,增加其溶出速率和胃肠吸收,进而提高口服生物利用度。
本文将自微乳化制剂固体化技术与半固体骨架胶囊技术相结合采用熔融法制备了雷帕霉素自微乳化半固体骨架胶囊,并考察了灌装温度、冷却速率、赋形剂的种类、含量、助表面活性剂的种类、含量等因素对胶囊囊壳、药物含量、溶出行为及微乳粒径等的影响,确定半固体骨架胶囊处方工艺的优选范围。通过单因素考察和正交试验设计优化处方工艺,确定了雷帕霉素自微乳化半固体骨架胶囊的制备工艺。雷帕霉素自微乳化半固体骨架胶囊(1mg/粒)的最终处方为:Rapa (1mg),Transcutol P (TP, 10%, W/W),Cremophor RH40 (35%, W/W),MCT (15%, W/W),Poloxamer 188 (F68, 40%, W/W),灌装温度为45℃,冷却温度为-20℃。优化后的胶囊水化形成微乳的粒径小且分布均匀,含量均匀度、体外释放度等均符合制剂学要求,处方工艺重现性高。傅里叶红外扫描图谱、X-射线衍射分析和示差扫描热量分析提示雷帕霉素以无定形态分散于半固体基质中,有利于药物的快速溶出。影响因素试验结果表明雷帕霉素自微乳化半固体骨架胶囊对强光、高温、高湿等因素均较敏感,制剂需密闭干燥处储存。经三个月加初步速试验后,自微乳化半固体骨架胶囊质量稳定,药物含量,微乳粒径,体外溶出度均无显著性变化,而自微乳化浓缩液中药物含量及体外溶出度显著降低。
采用溶剂熔融法制备的Rapa-F68(1:60)固体分散体能显著加快雷帕霉素的溶出,45min溶出度达85%以上,体外释药性能良好。傅里叶红外扫描图谱、X-射线衍射分析和示差扫描热量分析证明雷帕霉素以无定形态分散于固体分散体中,其增溶原理可能跟晶格取向的改变、晶粒大小、晶格点阵面间距等的变化密切相关。
本文还以自制的雷帕霉素自微乳化浓缩液为参比制剂,进行了雷帕霉素自微乳化半固体骨架胶囊,雷帕霉素固体分散体两种制剂在大鼠体内初步药代动力学和相对生物利用度的研究。建立了高效液相色谱-质谱联用测定大鼠全血雷帕霉素浓度的方法,方法学的考察证实此法能够满足雷帕霉素大鼠体内药代动力学研究的要求。试验结果表明,单剂量口服上述制剂后,雷帕霉素自微乳化浓缩液,雷帕霉素自微乳化半固体骨架胶囊和雷帕霉素固体分散体的AUC0-∞分别为(197.07±39.78)μg·L-1?h、(213.80±42.27)μg·L-1?h、(169.73±50.25)μg·L-1?h;达峰时间Tmax分别为(0.95±0.52)h、(2.14±0.21)h、(1.5±0.46)h;峰浓度Cmax分别为(16.89±5.08)μg·L-1、(13.77±4.36)μg·L-1、(10.37±3.96)μg·L-1;Rapa自微乳化半固体骨架胶囊和Rapa固体分散体的相对生物利用度分别为108.48%和86.12%。
本试验制得的雷帕霉素自微乳化半固体骨架胶囊和雷帕霉素固体分散体能明显改善Rapa的体外溶出速率从而改善药物吸收;与自微乳化浓缩液相比显著提高了药物在制剂中的稳定性;药动学试验结果表明,雷帕霉素自微乳化半固体骨架胶囊具有与自微乳化浓缩液相似的大鼠体内生物利用度(108.48%),显著高于固体分散体(86.12%)。本项研究为进一步开发新型雷帕霉素固体制剂奠定了基础。
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.
引文
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