环孢素A-pH敏感性纳米粒的研究
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摘要
本文主要研究了口服环孢素A-pH敏感性纳米粒的处方组成、制备工艺、体外药剂学性质、体内药动学与过敏性反应;以及对纳米粒冷冻干燥后的药剂学性质、体内药动学与过敏反应研究。
基于提高环孢素A口服相对生物利用度以及降低上市制剂过敏性反应的目的,本文做了以下的研究。以肠溶包衣材料优特奇S100(Eudragit S100)为载体材料,运用乳化-溶剂扩散技术制备了环孢素A-pH敏感性纳米粒。以纳米粒的平均粒径、跨距以及对环孢素A的包封率为指标,采用正交设计综合评价法优化处方组成及工艺;透射电镜及动态激光散射法观察了纳米粒子的表面形态并测定了平均粒径与粒度分布;粉末X-射线衍射法对环孢素A纳米粒进行鉴别;低温超速离心法分离了该纳米粒,高效液相色谱法测定了环孢素A的包封率;恒温振荡法对纳米粒的在不同pH介质中的体外释药进行了研究;考察了该胶体分散系的影响因素实验以及长期放置的稳定性。结果表明:优化后的处方所制备的纳米粒,粒子呈均匀规则的圆球形,平均粒径为44.8±3.2nm、跨距为0.59±0.11、包封率为(99.7±0.1)%;体外释放实验中,当pH>6时,药物能迅速的释放出来呈现了明显的pH依赖性;影响因素实验发现,高温和强光照射均会引起纳米粒的聚集,提示要低温避光保存;将该纳米粒胶体分散系分别于常温和4℃,放置3个月后粒径逐渐增大至75.3 nm和66.2nm,并且常温放置部分有少量分层絮凝现象。
为提高环孢素A-pH敏感性纳米粒的长期稳定性,我们将纳米粒胶体分散系通过真空冷冻干燥法制成了纳米粒冻干粉末,筛选了冻干保护剂,测定了冻干纳米粒的粒径、包封率和表面形态,并考察了其体外释药特性。结果表明,优选3%乳糖做保护剂的冻干纳米粒平均粒径为52.7±4.6nm、包封率为(99.8±0.1)%;电镜下为分布均匀的圆球形;体外释药实验中,当pH>6时,药物释放迅速,具有与胶体纳米粒一致的pH敏感性。
以市售新山地明(Neoral)为参比制剂,将两种纳米粒分别对大鼠灌胃,研究其口服药代动力学。结果表明:与新山地明对照,两种纳米粒具有更高的峰浓度和AUC,胶体纳米粒的相对生物利用度为162.1%(P﹤0.01),冻干纳米粒为130.1%(P﹤0.01),均能够显著提高环孢素A口服相对生物利用度。胶体纳米粒的AUC略高于冻干纳米粒的AUC,但二者之间的差别没有统计学意义(P>0.05)。
此外,以新山地明为对照,分别对两种纳米粒制剂进行了豚鼠过敏性实验比较,实验证明,由于处方中使用泊洛沙姆188替代新山地明中的Cremophor EL做乳化剂,两种纳米粒的过敏性反应明显低于新山地明。
The main purpose of this paper was to develop a new pH-sensitive Cyclosporine A -loaded nanoparticles and its freeze-drying formulation, investigate on the physico-chemical characteristics, pharmacokinetics as well as hypersensitivity reaction of them.
In order to improve the bioavailability of lipophilic Cyclosporine A(CyA) and lessen the hypersensitivity reaction of its commercial preparation, a new pH-sensitive CyA nanoparticles consisting of enteric dissolved material Eudragit? S100 (CyA-NP) was prepared with quasi-emulsion solvent diffusion technique. The particle size, polydispersity index and encapsulation efficiency were introduced as indexes to optimize the compositions and conditions for the process in orthogonal design experiments; the morphological characteristic, size distribution, encapsulation efficiency and in vitro released characteristic from vehicles of CyA were studied individually. The results showed that the CyA-NP looked round and regular under transmission electron microscopy; the particle size was 44.8±3.2nm, and distributed between 20 and 82nm; a polydispersity index of 0.59±0.11 and a maximum encapsulation efficiency up to (99.7±0.1)%; the signification pH-dependant release profiles were revealed when the medium pH was above 6.0. It was found in the influencing facter tests that high temperature and high light can cause the aggregation of CyA-NP, which indicated it should be tightly preserved from light and stored at low temperature; the CyA-NP colloids was stored at 25℃and 4℃for 3 months respectively, and the particle size increased to 75.3 nm and 66.2nm accompanied with some flocculate.
Vacuum freeze-drying technique was bring to make the nanoparticle colloids into freeze dried CyA-NP power to improve its permanent stability. The particle size and encapsulation efficiency of Fd-CyA-NP remained relative stable by using 3% lactose (W/N) as cryoprotective agent (Lac-CyA-NP) before freeze-drying and after dissolving. the mean size of Lac-CyA-NP was 52.7±4.6nm and the encapsulation efficiency up to (99.8±0.1)%. The morphological characteristic of Lac-CyA-NP was regular spherical, and having the same in vitro release behavior as CyA-NP which was pH sensitive and could rapidly released when pH>6.0.
CyA-NP and Lac-CyA-NP were oral administrated to rats respectively, using Neoral as reference to study on their pharmacokinetics. As a result, the two nanopartilces showed higher Cmax and AUC, significantly improved the relative bioavailability of CyA to 162.1% and 130.1%(P﹤0.01)respectively. The AUC of CyA-NP was higher than that from Lac-CyA-NP, but there was no statistical significance between them. Thus, Lac-CyA-NP gave the bioavailability similar to that of CyA-NP in rats.(P>0.05).
Moreover, the hypersusceptibility of the two nanoparticles was tested with guinea pig by using Neoral as reference. The results proved that because of the replacement of Poloxamer 188 for Cremophor EL, the two nanoparticle’s incidence of hypersensitivity reaction and toxic symptom was weaker than Neoral.
基于提高环孢素A口服相对生物利用度以及降低上市制剂过敏性反应的目的,本文做了以下的研究。以肠溶包衣材料优特奇S100(Eudragit S100)为载体材料,运用乳化-溶剂扩散技术制备了环孢素A-pH敏感性纳米粒。以纳米粒的平均粒径、跨距以及对环孢素A的包封率为指标,采用正交设计综合评价法优化处方组成及工艺;透射电镜及动态激光散射法观察了纳米粒子的表面形态并测定了平均粒径与粒度分布;粉末X-射线衍射法对环孢素A纳米粒进行鉴别;低温超速离心法分离了该纳米粒,高效液相色谱法测定了环孢素A的包封率;恒温振荡法对纳米粒的在不同pH介质中的体外释药进行了研究;考察了该胶体分散系的影响因素实验以及长期放置的稳定性。结果表明:优化后的处方所制备的纳米粒,粒子呈均匀规则的圆球形,平均粒径为44.8±3.2nm、跨距为0.59±0.11、包封率为(99.7±0.1)%;体外释放实验中,当pH>6时,药物能迅速的释放出来呈现了明显的pH依赖性;影响因素实验发现,高温和强光照射均会引起纳米粒的聚集,提示要低温避光保存;将该纳米粒胶体分散系分别于常温和4℃,放置3个月后粒径逐渐增大至75.3 nm和66.2nm,并且常温放置部分有少量分层絮凝现象。
为提高环孢素A-pH敏感性纳米粒的长期稳定性,我们将纳米粒胶体分散系通过真空冷冻干燥法制成了纳米粒冻干粉末,筛选了冻干保护剂,测定了冻干纳米粒的粒径、包封率和表面形态,并考察了其体外释药特性。结果表明,优选3%乳糖做保护剂的冻干纳米粒平均粒径为52.7±4.6nm、包封率为(99.8±0.1)%;电镜下为分布均匀的圆球形;体外释药实验中,当pH>6时,药物释放迅速,具有与胶体纳米粒一致的pH敏感性。
以市售新山地明(Neoral)为参比制剂,将两种纳米粒分别对大鼠灌胃,研究其口服药代动力学。结果表明:与新山地明对照,两种纳米粒具有更高的峰浓度和AUC,胶体纳米粒的相对生物利用度为162.1%(P﹤0.01),冻干纳米粒为130.1%(P﹤0.01),均能够显著提高环孢素A口服相对生物利用度。胶体纳米粒的AUC略高于冻干纳米粒的AUC,但二者之间的差别没有统计学意义(P>0.05)。
此外,以新山地明为对照,分别对两种纳米粒制剂进行了豚鼠过敏性实验比较,实验证明,由于处方中使用泊洛沙姆188替代新山地明中的Cremophor EL做乳化剂,两种纳米粒的过敏性反应明显低于新山地明。
The main purpose of this paper was to develop a new pH-sensitive Cyclosporine A -loaded nanoparticles and its freeze-drying formulation, investigate on the physico-chemical characteristics, pharmacokinetics as well as hypersensitivity reaction of them.
In order to improve the bioavailability of lipophilic Cyclosporine A(CyA) and lessen the hypersensitivity reaction of its commercial preparation, a new pH-sensitive CyA nanoparticles consisting of enteric dissolved material Eudragit? S100 (CyA-NP) was prepared with quasi-emulsion solvent diffusion technique. The particle size, polydispersity index and encapsulation efficiency were introduced as indexes to optimize the compositions and conditions for the process in orthogonal design experiments; the morphological characteristic, size distribution, encapsulation efficiency and in vitro released characteristic from vehicles of CyA were studied individually. The results showed that the CyA-NP looked round and regular under transmission electron microscopy; the particle size was 44.8±3.2nm, and distributed between 20 and 82nm; a polydispersity index of 0.59±0.11 and a maximum encapsulation efficiency up to (99.7±0.1)%; the signification pH-dependant release profiles were revealed when the medium pH was above 6.0. It was found in the influencing facter tests that high temperature and high light can cause the aggregation of CyA-NP, which indicated it should be tightly preserved from light and stored at low temperature; the CyA-NP colloids was stored at 25℃and 4℃for 3 months respectively, and the particle size increased to 75.3 nm and 66.2nm accompanied with some flocculate.
Vacuum freeze-drying technique was bring to make the nanoparticle colloids into freeze dried CyA-NP power to improve its permanent stability. The particle size and encapsulation efficiency of Fd-CyA-NP remained relative stable by using 3% lactose (W/N) as cryoprotective agent (Lac-CyA-NP) before freeze-drying and after dissolving. the mean size of Lac-CyA-NP was 52.7±4.6nm and the encapsulation efficiency up to (99.8±0.1)%. The morphological characteristic of Lac-CyA-NP was regular spherical, and having the same in vitro release behavior as CyA-NP which was pH sensitive and could rapidly released when pH>6.0.
CyA-NP and Lac-CyA-NP were oral administrated to rats respectively, using Neoral as reference to study on their pharmacokinetics. As a result, the two nanopartilces showed higher Cmax and AUC, significantly improved the relative bioavailability of CyA to 162.1% and 130.1%(P﹤0.01)respectively. The AUC of CyA-NP was higher than that from Lac-CyA-NP, but there was no statistical significance between them. Thus, Lac-CyA-NP gave the bioavailability similar to that of CyA-NP in rats.(P>0.05).
Moreover, the hypersusceptibility of the two nanoparticles was tested with guinea pig by using Neoral as reference. The results proved that because of the replacement of Poloxamer 188 for Cremophor EL, the two nanoparticle’s incidence of hypersensitivity reaction and toxic symptom was weaker than Neoral.
引文
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[2] Carpenter CB. Immunosuppression in organ transplantation. N Engl J Med, 1990, 322(17): 1224.
[3] 李萍, 胡晋红. 环孢素A的临床应用进展及其血药浓度监测.药学实践杂志[J]. 1999, 17( 5) : 259-262.
[4] Bach JF, Cyclosporine in autoimmune disease. Transpl Proc, 1989, 21: 97.
[5] Mithani SD, Bakatselou V, Tenhoor CN, et al. Estimation of the increase in solubility of drugs as a function of bile salt concentration, Pharm. Res. 1996, 13: 163-167.
[6] Tjai JF, Webber IR, Back DJ. Cyclosporin metabolism by the gastrointestinal mucosa. Br.J. Clin. Pharmacol. 1991, 31: 344-346.
[7] Fahr A, Holz M, Fricker G. Liposomal formulation of coclosporinA: influence of lipid type and dose on pharmcokinetics[J] Pharm Res, 1995, 12(8): 1189.
[8] Al- Meshal MA, Khidr SH, Bayomi MA, et al. Oral administration of liposomes containing cyclosporin:pharmaeokinetie studys.[J] Int J Pharm, 1998, 168(6): 163.
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