甲磺酸多沙唑嗪缓释微球的研制
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摘要
目的:随着生活水平的提高,人们对健康越来越重视,高血压的发病率在近年一直呈上升趋势,成为威胁人类健康的主要疾病之一。甲磺酸多沙唑嗪是α1受体阻滞剂类降压药,通过阻滞α1-受体扩张血管,减小血管阻力,降低血压。本药适用于原发性轻、中度高血压及伴有良性前列腺肥大的高血压患者,同时对男性前列腺增生症也有很好的治疗作用。目前,关于甲磺酸多沙唑嗪的剂型都是口服制剂,需要每天服药,因为高血压患者必须要长期有规律的用药,中断用药可能导致很快发病,甚至有生命危险。因此,开发长效缓释剂型是很有意义的。本文将甲磺酸多沙唑嗪制备成微球给药系统,实现临床用药安全、便捷、有效地目的。
方法:本实验采用可生物降解的聚乳酸作为载体材料,采用改良的乳化-溶剂挥发法即有机相分散-溶媒扩散法制备甲磺酸多沙唑嗪微球。首先,对微球制备过程中的处方因素和工艺因素进行单因素考察,选出对制备工艺影响较大的几个因素以载药量、包封率、平均粒径为指标做正交试验设计,确定最佳处方工艺;其次,建立微球中药物含量的测定方法,并进行验证。本实验采用高效液相色谱法测定药物含量,先用二氯甲烷溶解包裹药物的聚乳酸,再用甲醇溶解甲磺酸多沙唑嗪,过滤进样测定含量。
在文献和预实验的基础上建立体外释放度的测定方法。采用透析法做体外释放度实验,用紫外分光光度法测定释放介质中药物的含量,并进行方法学的验证;在此条件下考察不同释放介质,不同pH值,含不同量的有机溶剂,不同载药量的微球对于释放度的影响,以突释、累积释放量为指标,最终确定出微球的体外释放方法;另外,本实验对微球的体外加速释放进行了初步研究,并与常规释放做了相关性的评价;通过初步稳定性实验,对微球的存放条件及其稳定性做了相关的研究。
本实验通过大鼠皮下注射做了药物体内的药代动力学研究,用高效液相色谱法对大鼠体内的药物含量进行测定。采用非隔室模型的矩量法,依据药-时曲线下面积,计算AUC0→t、AUMC、MRT等药动学参数,考察药物在体内的平均滞留时间。
结果:通过单因素考察,选出有机相PLA浓度、DOX与PLA投药比、分散转数、分散介质溶度、有机相/分散相体积比几个因素,以载药量、包封率、粒径为指标做正交试验设计,确定出最优化处方。
高效液相色谱法测定含量的方法学考察结果可知,甲磺酸多沙唑嗪在2.042~10.21μg/ml浓度范围内,其浓度与峰面积线性关系良好,日内精密度和日间精密度的RSD值均小于1.0%,高、中、低三个浓度的回收率分别为100.12%、100.11%、99.91%,符合要求。用最优化处方制备的微球的圆整光滑,载药量达到19.2%,包封率达到69.8%,平均粒径为17μm。
微球体外释放度测定采用紫外分光光度法,在1.674~8.37μg/ml浓度范围内药物浓度和吸光度线性关系良好,精密度RSD均小于2%,高、中、低三个浓度的回收率分别为101.36%、101.61%、101.42%,说明此方法可靠、准确、稳定。通过对释放条件的考察,最终确定含30%乙醇的pH7.4的磷酸盐缓冲液作为微球的体外释放介质,释放介质中加入0.2%的吐温20和0.2%吐温80分别作为润湿剂和分散剂,释放温度为37℃,振荡频率为100r/min,1天的突释量约为6%,释放30天后的累计释放率达到77%,有很好的缓释效果。微球的体外加速释放释放温度为63℃,时间为30小时,30小时的累计释放量约为74%,在5到12小时的释放量较大,与常规释放做相关性拟合,相关系数R=0.9727。
微球的稳定性实验表明,微球在60℃条件下发生聚集、结块现象,40℃条件下含量和释放均无明显变化,因此,微球不可在高温下储存,室温可长期保存;高湿条件下,微球重量没有明显变化,含量和释放也无显著变化;文献报道,甲磺酸多沙唑嗪需避光保存,尽管光照实验含量和释放均无显著变化,为保证质量,存储时应尽量避光。
微球体外加速释放不同释放时间的扫描电镜图片显示,微球的体外释放是扩散和降解相结合的过程,在释放的前段以孔道扩散为主,后端兼有聚合物的降解,但是到药物释放完全时聚合物仍可见微球的形状,降解现象不是非常的显著。
微球的体内药物含量测定采用高效液相色谱法,血浆中药物浓度在4~320ng/ml范围内,浓度(C)与峰面积(A)线性关系良好,R=0.9992,灵敏度和专属性良好,精密度符合要求,高、中、低三个浓度的方法回收率分别为95.81%、94.16%、97.99%,萃取回收率分别为88.14%、84.58%、96.19%。矩量法计算出体内药动学数据AUC0→∞、AUMC、MRT分别为2852.19 (ng·ml)d、44369.99、15.56天。药物在大鼠体内释药平缓、突释量小、缓释作用强。
结论:本实验制备的甲磺酸多沙唑嗪微球工艺稳定,制备的微球光滑、圆整、分散性好,可在常温下长期保存,体外释放缓释作用明显,符合Higuchi模型,体内实验表明药物在大鼠体内释放平缓,持续时间长,提高了药物的生物利用度,有望进一步开发。
Objective: Mesylate doxazosin (DOX) is selective postsynapticα1-adrenergic receptors blockers, by blocking theα1-receptors to expand blood vessels, reduce vascular resistance, in order to decrease the blood pressure. DOX is suitable to primary mild and moderate hypertension and accompanied by hypertension patients with innocence prostatic hypertrophy. It also can well treat masculine hyperplasia of prostate. Now, most dosage forms are oral application preparations about DOX. These preparations need to take medicine everyday because the hypertension patients may lead to insetting disease even to threaten the life if stop taking medicine. So developing a prolonged action and delayed release preparation have large practical and academic meaning. This paper will combine DOX and microsphere administration in order to come true the purpose:safe, convenient utility.
Methods : This experiment use the biodegradable polymers poly-L-lactide (PLA) as carry materials to prepare the microspheres by modified solvent evaporation method named organic-phase dispersing and solvent diffusion technique. First, the fundamental preparation condition such as formula factors and process factors were evaluated in the preliminary experiments and choose several significant factors to do the orthogonal design. Dependent variables or responses investigated in this study are loading efficiency, drug loading and mean diameter. Then we studied the methods which used to determine the drug loading and loading efficiency. We used methylene chloride to dissolve microspheres and then dissolve DOX by methanol. After filtered, the concentration of DOX was determined by HPLC system.
We studied the content of accumulative release of microspheres on the basis of pretesting and scientific literatures and determined the concentration of DOX by the method of ultraviolet spectrophotometer. In this study, we investigated the influence for the content of accumulative release of microspheres in different medium, different pH conditions, different proportion organic solvent and different drug loading and then definite the release method taking burst effect and accumulative amount as evaluation indexes. We also initially studied the accelerate release and compared it with routine release about associatively. By stability experiments we studied the store conditions and stability.
In this study, pharmacokinetics research was completed by rats hypodermic injection and the concentration of DOX in rats blood plasma was determined by HPLC system. We used model of in compartment to analyze the data. The pharmacokinetics parameters such as AUC0→t、AUMC、MRT was calculated by moment method according drug concentration time area under the curve.
Results: The optimal formulation and process were defined through preliminary experiments and the orthogonal design. It was found that PLA concentration, theoretical drug loading, disperse speed,disperse medium concentration, the volume ratio between organic phase and disperse phase had much more influence on indexes of microspheres. The consequence of technology indicated DOX concentration and peak area had well linear correlation between 2.042μg/ml and 10.21μg/ml. The RSD of both within-day precision and between-day precision are less than 1.0%.The three results of recoveries are 100.12%、100.11% and 99.91%. The optimized microspheres were spherical and smooth. The average drug loading, encapsulation efficiency and mean diameter were 19.2%, 69.8%, 17μm.
The content of DOX in release medium was determined by ultraviolet spectrophotometer. The linearity range was 1.674~8.37μg/ml.The RSD of precision was less than 2% and the results of recoveries were 101.36%、101.61%、101.42%. According the investigation about release conditions, we decided using the pH 7.4 PBS containing 30% EtOH as medium which including 0.2% Tween20 and 0.2%Tween80 as wetting agent and dispersant agent. The release temperature was 37℃and oscillation frequency was 100r/min. The burst release amount in 1 days was 6% and the release amount in 30 days was about 77%. The accelerate release temperature was 63℃and release time were 30 hours. In 30 hours, the accumulative release amount was about 74% and the release amount was great between 5~12 hours. The coefficient of correlation(R) between accelerate release and routine release was R=0.9727.
The stability experiments indicted the microspheres would to be together and had no change in temperature of 40℃, so the microspheres couldn’t be storaged in high temperature. In high humidity, the appearance,content and release have no marked change. According to the literature report, DOX need stored away from light, we also stored the microspheres away from light although the result of strong illumination experiment indicated the light had no influence on the quality.
According to the SEM picture in different time of the accelerate release, the release is a combinative process of diffusion and degradation, but main dependent on the diffuse process.
The content of DOX in rats blood plasma was determined by HPLC. The linearity range was 4~320ng/ml, R=0.9992. The sensitivity specificity and precision were consistent with request. The results of method recoveries were 95.81%、94.16%、97.99% and the results of method recoveries were 88.14%、84.58%、96.19%. Pharmacokinetics data were AUC0→∞=2852.19 (ng·ml)d、AUMC=44369.99、MRT=15.56d. DOX’s release in rats blood plasma is stability, little burst release, well delayed release.
Conclusions: Overall, the DOX microspheres in this study were smooth and spherical, and have good dispersibility and narrow size distribution and can be long term storaged in ordinary temperature. The release in vitro indicted the microspheres had well delayed release and consistent with Higuchi model. Experiments in rats indicated the DOX microspheres could prolong the residence time of drugin rats body and increased the bioavailability of DOX, so proved acandidate of new drug.
方法:本实验采用可生物降解的聚乳酸作为载体材料,采用改良的乳化-溶剂挥发法即有机相分散-溶媒扩散法制备甲磺酸多沙唑嗪微球。首先,对微球制备过程中的处方因素和工艺因素进行单因素考察,选出对制备工艺影响较大的几个因素以载药量、包封率、平均粒径为指标做正交试验设计,确定最佳处方工艺;其次,建立微球中药物含量的测定方法,并进行验证。本实验采用高效液相色谱法测定药物含量,先用二氯甲烷溶解包裹药物的聚乳酸,再用甲醇溶解甲磺酸多沙唑嗪,过滤进样测定含量。
在文献和预实验的基础上建立体外释放度的测定方法。采用透析法做体外释放度实验,用紫外分光光度法测定释放介质中药物的含量,并进行方法学的验证;在此条件下考察不同释放介质,不同pH值,含不同量的有机溶剂,不同载药量的微球对于释放度的影响,以突释、累积释放量为指标,最终确定出微球的体外释放方法;另外,本实验对微球的体外加速释放进行了初步研究,并与常规释放做了相关性的评价;通过初步稳定性实验,对微球的存放条件及其稳定性做了相关的研究。
本实验通过大鼠皮下注射做了药物体内的药代动力学研究,用高效液相色谱法对大鼠体内的药物含量进行测定。采用非隔室模型的矩量法,依据药-时曲线下面积,计算AUC0→t、AUMC、MRT等药动学参数,考察药物在体内的平均滞留时间。
结果:通过单因素考察,选出有机相PLA浓度、DOX与PLA投药比、分散转数、分散介质溶度、有机相/分散相体积比几个因素,以载药量、包封率、粒径为指标做正交试验设计,确定出最优化处方。
高效液相色谱法测定含量的方法学考察结果可知,甲磺酸多沙唑嗪在2.042~10.21μg/ml浓度范围内,其浓度与峰面积线性关系良好,日内精密度和日间精密度的RSD值均小于1.0%,高、中、低三个浓度的回收率分别为100.12%、100.11%、99.91%,符合要求。用最优化处方制备的微球的圆整光滑,载药量达到19.2%,包封率达到69.8%,平均粒径为17μm。
微球体外释放度测定采用紫外分光光度法,在1.674~8.37μg/ml浓度范围内药物浓度和吸光度线性关系良好,精密度RSD均小于2%,高、中、低三个浓度的回收率分别为101.36%、101.61%、101.42%,说明此方法可靠、准确、稳定。通过对释放条件的考察,最终确定含30%乙醇的pH7.4的磷酸盐缓冲液作为微球的体外释放介质,释放介质中加入0.2%的吐温20和0.2%吐温80分别作为润湿剂和分散剂,释放温度为37℃,振荡频率为100r/min,1天的突释量约为6%,释放30天后的累计释放率达到77%,有很好的缓释效果。微球的体外加速释放释放温度为63℃,时间为30小时,30小时的累计释放量约为74%,在5到12小时的释放量较大,与常规释放做相关性拟合,相关系数R=0.9727。
微球的稳定性实验表明,微球在60℃条件下发生聚集、结块现象,40℃条件下含量和释放均无明显变化,因此,微球不可在高温下储存,室温可长期保存;高湿条件下,微球重量没有明显变化,含量和释放也无显著变化;文献报道,甲磺酸多沙唑嗪需避光保存,尽管光照实验含量和释放均无显著变化,为保证质量,存储时应尽量避光。
微球体外加速释放不同释放时间的扫描电镜图片显示,微球的体外释放是扩散和降解相结合的过程,在释放的前段以孔道扩散为主,后端兼有聚合物的降解,但是到药物释放完全时聚合物仍可见微球的形状,降解现象不是非常的显著。
微球的体内药物含量测定采用高效液相色谱法,血浆中药物浓度在4~320ng/ml范围内,浓度(C)与峰面积(A)线性关系良好,R=0.9992,灵敏度和专属性良好,精密度符合要求,高、中、低三个浓度的方法回收率分别为95.81%、94.16%、97.99%,萃取回收率分别为88.14%、84.58%、96.19%。矩量法计算出体内药动学数据AUC0→∞、AUMC、MRT分别为2852.19 (ng·ml)d、44369.99、15.56天。药物在大鼠体内释药平缓、突释量小、缓释作用强。
结论:本实验制备的甲磺酸多沙唑嗪微球工艺稳定,制备的微球光滑、圆整、分散性好,可在常温下长期保存,体外释放缓释作用明显,符合Higuchi模型,体内实验表明药物在大鼠体内释放平缓,持续时间长,提高了药物的生物利用度,有望进一步开发。
Objective: Mesylate doxazosin (DOX) is selective postsynapticα1-adrenergic receptors blockers, by blocking theα1-receptors to expand blood vessels, reduce vascular resistance, in order to decrease the blood pressure. DOX is suitable to primary mild and moderate hypertension and accompanied by hypertension patients with innocence prostatic hypertrophy. It also can well treat masculine hyperplasia of prostate. Now, most dosage forms are oral application preparations about DOX. These preparations need to take medicine everyday because the hypertension patients may lead to insetting disease even to threaten the life if stop taking medicine. So developing a prolonged action and delayed release preparation have large practical and academic meaning. This paper will combine DOX and microsphere administration in order to come true the purpose:safe, convenient utility.
Methods : This experiment use the biodegradable polymers poly-L-lactide (PLA) as carry materials to prepare the microspheres by modified solvent evaporation method named organic-phase dispersing and solvent diffusion technique. First, the fundamental preparation condition such as formula factors and process factors were evaluated in the preliminary experiments and choose several significant factors to do the orthogonal design. Dependent variables or responses investigated in this study are loading efficiency, drug loading and mean diameter. Then we studied the methods which used to determine the drug loading and loading efficiency. We used methylene chloride to dissolve microspheres and then dissolve DOX by methanol. After filtered, the concentration of DOX was determined by HPLC system.
We studied the content of accumulative release of microspheres on the basis of pretesting and scientific literatures and determined the concentration of DOX by the method of ultraviolet spectrophotometer. In this study, we investigated the influence for the content of accumulative release of microspheres in different medium, different pH conditions, different proportion organic solvent and different drug loading and then definite the release method taking burst effect and accumulative amount as evaluation indexes. We also initially studied the accelerate release and compared it with routine release about associatively. By stability experiments we studied the store conditions and stability.
In this study, pharmacokinetics research was completed by rats hypodermic injection and the concentration of DOX in rats blood plasma was determined by HPLC system. We used model of in compartment to analyze the data. The pharmacokinetics parameters such as AUC0→t、AUMC、MRT was calculated by moment method according drug concentration time area under the curve.
Results: The optimal formulation and process were defined through preliminary experiments and the orthogonal design. It was found that PLA concentration, theoretical drug loading, disperse speed,disperse medium concentration, the volume ratio between organic phase and disperse phase had much more influence on indexes of microspheres. The consequence of technology indicated DOX concentration and peak area had well linear correlation between 2.042μg/ml and 10.21μg/ml. The RSD of both within-day precision and between-day precision are less than 1.0%.The three results of recoveries are 100.12%、100.11% and 99.91%. The optimized microspheres were spherical and smooth. The average drug loading, encapsulation efficiency and mean diameter were 19.2%, 69.8%, 17μm.
The content of DOX in release medium was determined by ultraviolet spectrophotometer. The linearity range was 1.674~8.37μg/ml.The RSD of precision was less than 2% and the results of recoveries were 101.36%、101.61%、101.42%. According the investigation about release conditions, we decided using the pH 7.4 PBS containing 30% EtOH as medium which including 0.2% Tween20 and 0.2%Tween80 as wetting agent and dispersant agent. The release temperature was 37℃and oscillation frequency was 100r/min. The burst release amount in 1 days was 6% and the release amount in 30 days was about 77%. The accelerate release temperature was 63℃and release time were 30 hours. In 30 hours, the accumulative release amount was about 74% and the release amount was great between 5~12 hours. The coefficient of correlation(R) between accelerate release and routine release was R=0.9727.
The stability experiments indicted the microspheres would to be together and had no change in temperature of 40℃, so the microspheres couldn’t be storaged in high temperature. In high humidity, the appearance,content and release have no marked change. According to the literature report, DOX need stored away from light, we also stored the microspheres away from light although the result of strong illumination experiment indicated the light had no influence on the quality.
According to the SEM picture in different time of the accelerate release, the release is a combinative process of diffusion and degradation, but main dependent on the diffuse process.
The content of DOX in rats blood plasma was determined by HPLC. The linearity range was 4~320ng/ml, R=0.9992. The sensitivity specificity and precision were consistent with request. The results of method recoveries were 95.81%、94.16%、97.99% and the results of method recoveries were 88.14%、84.58%、96.19%. Pharmacokinetics data were AUC0→∞=2852.19 (ng·ml)d、AUMC=44369.99、MRT=15.56d. DOX’s release in rats blood plasma is stability, little burst release, well delayed release.
Conclusions: Overall, the DOX microspheres in this study were smooth and spherical, and have good dispersibility and narrow size distribution and can be long term storaged in ordinary temperature. The release in vitro indicted the microspheres had well delayed release and consistent with Higuchi model. Experiments in rats indicated the DOX microspheres could prolong the residence time of drugin rats body and increased the bioavailability of DOX, so proved acandidate of new drug.
引文
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1 Yi Sun, JianCheng Wang , Qiang Zhang.Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: In vitro and in vivo studies. Journal of Controlled Release 129 (2008) 192-199
2韩永涛,黄桂华,席延卫.阿奇霉素聚乳酸微球的制备及其体外释药特性的研究. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES). 671-7554(2006)08-0853-04
3 Guo Ai ,Xing-Guo Mei. An accelerated method to evaluate thymopentin release from microspheres in vitro. G.Ai et a1./Journal of Chinese Pharmaceutical Sciences 17(2008)4l-45
4 WU zhen-zhen ,YANG Zhuo-li, Li Xin-ru.Accelerated release of simvastatin polylactic acid microspheres in vitro.Chinese Journal of New Drugs 2006,Vol.15 No.7
5杨亚兰.依托泊苷鼻用壳聚糖微球的研制[.硕士论文].河北医科大学,2005
6王建欣.玻璃体内注射用苦参碱聚乳酸缓释亚微球的研制. [硕士论文]2008 -河北医科大学:药剂学
1张建维.XG-07长效缓释微球的研制.[硕士论文].河北医科大学,2009
2赵颖.甲磺酸多沙唑嗪控释制剂的研究.[硕士论文].沈阳药科大学, 2004
3梁文权主编.生物药剂学与药物动力学[M].第二版,北京:人民卫生出版社,2003:328～344
1 Anderson JM,Shive MS. Biodegradation and biocompatibility of PLA and PLGA microsphere. Adv Drug Del REV,1997,28: 5
2 Liaz RV,Labres M Evora C. One-month sustained release microspheres of 1251-bovine calcitonin:In vivo syudies,【J】. Controlled Release, 1999,59(1):55-62
3 Chung T W:Huang Y Y Liu Y Z.Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres【J】.International Journal of Pharmaeeutics,2001,212(2):161-169
4 Roland B,Omlaksana R. Drug release from laminated p olymeric films prepared from aqueous latexe【J】.Journal of Pharmaceutical Sciences,1 990,79(1):32-36
5 McGinityJ W, O’Donnell P B. Preparation of microspheres by the solvent evaporation technique [J ]. Adv Drug DelivRev, 1997 ,28 1 :25-42
6扬帆,韩芸,赵耀明,旺朝阳,等.环丙沙星聚乳酸微球制备工艺的研究[s1.中国药科大学学报,2004,35(3):207-210
7王建欣.玻璃体内注射用苦参碱聚乳酸缓释亚微的研制[硕士论文].2008 -河北医科大学:药剂学
8 Jain R A. The manufacturing techniques of various drug loaded biodegradable poly( lactide-co-glycolide) (PLGA ) de vices [J]. Biomaterials ,2000,21(23):2475-2490
9 Akihiro Matsumoto , Takeo Kitazawa, Junichi Murata. A novel preparation method for PLGA microspheres using non-halogenated solvents. Journal of Controlled Release 129 (2008) 223–227
10 Chung T W,Huang Y Y,LiuY2.Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres[J].International Journal of Pharmaceutics,2001 ,212(2):161-169
11 ZhuKJ,ZhangJX,WangC,etal.Preparation and in vitro release behavioro 5-fluorouracil-loaded microspheres based on Poly(L-lactate) and itscarbonate eoPolymers[J].J Microeneencapsul,2003,6:731~739
12 R. Bodemier, H. Chen, P. Tyle, P. Jarosz,Pseudoephedrin HCl microspheres formulated into and oral suspension dosage form, J. Control. Release 15 (1991) 65–71
13 Kun Han, Kyu-Don Lee, Zhong-Gao Gao. Preparation and evaluation of poly(L-lactic acid) microspheres containing rhEGF for chronic gastric ulcer healing. Journal of Controlled Release 75 (2001) 259–269
14 UchidaT,YoshidaK,NinomiyaA,etal.Optimization of preparative conditions for polylactide microspheres containing ovalbumin. Chem Pharm Bull,1995,43(9): 1569-1573
15 Neelesh K. Varde, Daniel W. Pack. Influence of particle size and antacid on release and stability of plasmid DNA from uniform PLGA microspheres. Journal of Controlled Release 124 (2007) 172–180
16 Palmieri G F, Bonacucina G, Di Martino P, et al. Spraydrying as a methodfor microparticulate controlled release systems preparation: advantages and limits. I. Water-soluble drugs[J]. Drug Dev Ind Pharm, 2001 ,27 (3) :195-204
17 Pavan Kumar Naraharisetti, Magdeleine Duan Ning Lew, Yin-Chih Fu,Duu-Jong Lee. Gentamicin-loaded discs and microspheres and their modifications:characterization and in vitro release. Journal of Controlled Release 102 (2005) 345–359
18廖戎.聚乳酸微球制备的初步研究闭.西南民族大学学报·自然科学版2006,32(l):84-87
19 WiehertB,RohdewaldP.A new method for the Preparation of drug containing Polylactic acid microparticles without using organic solvents[J]. J Controlled Release,1990,14:269·283
20 Shirui Mao, Yi Shi, Luk Li, Jing Xu. Effects of process and formulation parameters on characteristics and internal morphology of poly(D,L-lactide-co-glycolide) microspheres formed by the solvent evaporation method. European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 214–223
21 Yi Sun , JianCheng Wang , Xuan Zhang. Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: In vitro and in vivo studies. Journal of Controlled Release 129 (2008) 192–199
22 Mohamed Abbas Ibrahim, Ahmed Ismail, Mohamed Ihab Fetouh. Stability of insulin during the erosion of poly(lactic acid) and poly(lactic-co-glycolic acid) microspheres. Journal of Controlled Release 106 (2005) 241–252
23吴伟,崔光华.聚乳酸或乳酸/羟乙酸共聚物的制备方法研究进展[J].国外医药一合成药生化药制剂分册,2000,21(6):367.369
24 Cory Berkland , Martin King , Amanda Cox . Precise control of PLG microsphere size provides enhanced control of drug release rate。Journal of Controlled Release 82 (2002) 137–147
25 Banu S. Zolnik , Diane J. Burgess. Evaluation of in vivo–in vitro release of dexamethasone from PLGA microspheres. Journal of Controlled Release 127 (2008) 137–145
26程国华,罗佳波.汉防己甲素肺靶向聚乳酸微球兔体内药动学的研究.China Pharmacy 2005 Vol.16.10
27 Okada H , Doken Y, Ogawa Y, et al. Preparation of three-month depot injectable microspheres of leuprorelin acetate using biodegradable polymers [J ]. Pharm Res , 1994 , 11(8):1143
28 anusz WK. Patrick PD1A novel in vitro release technique for peptide containing biodegradable microspheres [EB/OL]. http://www.pharmscitech1.com/volumnlissue/111/manuscript.htm, 2000 - 01– 01
29冼远芳,程凤梅,陈鸿玉.阿司匹林聚乳酸微球的体外加速释放试验.中国医院药学杂志2008 28(16) :1364-1367
2钟延强,周永刚,张国庆等.局部麻醉用缓释盐酸布比卡因PLGA微球的制备及特性研究.第二军医大学学报2004, 25(8): 865~868
3李金阳. HPLC法测定甲磺酸多沙唑嗪片剂的含量. Anhui Medical and Pharmaceutical Journal 2001Sep;5(3)
4 Neelesh K. Varde, Daniel W. Pack. Influence of particle size and antacid on release and stability of plasmid DNA from uniform PLGA microspheres. Journal of Controlled Release 124 (2007) 172–180
5鞠玉琳,崔莲花,金美花.贝尼尔聚乳酸微球的制备及体外药物释放.Heilongjiang Journal of Anirnal Science and Veterinary Medicine, S859, 53,1004-7034(2002)06-0045-02
6 Mohamed Abbas Ibrahim, Ahmed Ismail, Achim Go pferich. Stability of insulin during the erosion of poly(lactic acid) and poly (lactic-co-glycolic acid) microspheres. Journal of Controlled Release 106 (2005) 241–252
7王建欣.玻璃体内注射用苦参碱聚乳酸缓释亚微球的研制.[硕士论文]2008 -河北医科大学:药剂学
1 Yi Sun, JianCheng Wang , Qiang Zhang.Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: In vitro and in vivo studies. Journal of Controlled Release 129 (2008) 192-199
2韩永涛,黄桂华,席延卫.阿奇霉素聚乳酸微球的制备及其体外释药特性的研究. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES). 671-7554(2006)08-0853-04
3 Guo Ai ,Xing-Guo Mei. An accelerated method to evaluate thymopentin release from microspheres in vitro. G.Ai et a1./Journal of Chinese Pharmaceutical Sciences 17(2008)4l-45
4 WU zhen-zhen ,YANG Zhuo-li, Li Xin-ru.Accelerated release of simvastatin polylactic acid microspheres in vitro.Chinese Journal of New Drugs 2006,Vol.15 No.7
5杨亚兰.依托泊苷鼻用壳聚糖微球的研制[.硕士论文].河北医科大学,2005
6王建欣.玻璃体内注射用苦参碱聚乳酸缓释亚微球的研制. [硕士论文]2008 -河北医科大学:药剂学
1张建维.XG-07长效缓释微球的研制.[硕士论文].河北医科大学,2009
2赵颖.甲磺酸多沙唑嗪控释制剂的研究.[硕士论文].沈阳药科大学, 2004
3梁文权主编.生物药剂学与药物动力学[M].第二版,北京:人民卫生出版社,2003:328～344
1 Anderson JM,Shive MS. Biodegradation and biocompatibility of PLA and PLGA microsphere. Adv Drug Del REV,1997,28: 5
2 Liaz RV,Labres M Evora C. One-month sustained release microspheres of 1251-bovine calcitonin:In vivo syudies,【J】. Controlled Release, 1999,59(1):55-62
3 Chung T W:Huang Y Y Liu Y Z.Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres【J】.International Journal of Pharmaeeutics,2001,212(2):161-169
4 Roland B,Omlaksana R. Drug release from laminated p olymeric films prepared from aqueous latexe【J】.Journal of Pharmaceutical Sciences,1 990,79(1):32-36
5 McGinityJ W, O’Donnell P B. Preparation of microspheres by the solvent evaporation technique [J ]. Adv Drug DelivRev, 1997 ,28 1 :25-42
6扬帆,韩芸,赵耀明,旺朝阳,等.环丙沙星聚乳酸微球制备工艺的研究[s1.中国药科大学学报,2004,35(3):207-210
7王建欣.玻璃体内注射用苦参碱聚乳酸缓释亚微的研制[硕士论文].2008 -河北医科大学:药剂学
8 Jain R A. The manufacturing techniques of various drug loaded biodegradable poly( lactide-co-glycolide) (PLGA ) de vices [J]. Biomaterials ,2000,21(23):2475-2490
9 Akihiro Matsumoto , Takeo Kitazawa, Junichi Murata. A novel preparation method for PLGA microspheres using non-halogenated solvents. Journal of Controlled Release 129 (2008) 223–227
10 Chung T W,Huang Y Y,LiuY2.Effects of the rate of solvent evaporation on the characteristics of drug loaded PLLA and PDLLA microspheres[J].International Journal of Pharmaceutics,2001 ,212(2):161-169
11 ZhuKJ,ZhangJX,WangC,etal.Preparation and in vitro release behavioro 5-fluorouracil-loaded microspheres based on Poly(L-lactate) and itscarbonate eoPolymers[J].J Microeneencapsul,2003,6:731~739
12 R. Bodemier, H. Chen, P. Tyle, P. Jarosz,Pseudoephedrin HCl microspheres formulated into and oral suspension dosage form, J. Control. Release 15 (1991) 65–71
13 Kun Han, Kyu-Don Lee, Zhong-Gao Gao. Preparation and evaluation of poly(L-lactic acid) microspheres containing rhEGF for chronic gastric ulcer healing. Journal of Controlled Release 75 (2001) 259–269
14 UchidaT,YoshidaK,NinomiyaA,etal.Optimization of preparative conditions for polylactide microspheres containing ovalbumin. Chem Pharm Bull,1995,43(9): 1569-1573
15 Neelesh K. Varde, Daniel W. Pack. Influence of particle size and antacid on release and stability of plasmid DNA from uniform PLGA microspheres. Journal of Controlled Release 124 (2007) 172–180
16 Palmieri G F, Bonacucina G, Di Martino P, et al. Spraydrying as a methodfor microparticulate controlled release systems preparation: advantages and limits. I. Water-soluble drugs[J]. Drug Dev Ind Pharm, 2001 ,27 (3) :195-204
17 Pavan Kumar Naraharisetti, Magdeleine Duan Ning Lew, Yin-Chih Fu,Duu-Jong Lee. Gentamicin-loaded discs and microspheres and their modifications:characterization and in vitro release. Journal of Controlled Release 102 (2005) 345–359
18廖戎.聚乳酸微球制备的初步研究闭.西南民族大学学报·自然科学版2006,32(l):84-87
19 WiehertB,RohdewaldP.A new method for the Preparation of drug containing Polylactic acid microparticles without using organic solvents[J]. J Controlled Release,1990,14:269·283
20 Shirui Mao, Yi Shi, Luk Li, Jing Xu. Effects of process and formulation parameters on characteristics and internal morphology of poly(D,L-lactide-co-glycolide) microspheres formed by the solvent evaporation method. European Journal of Pharmaceutics and Biopharmaceutics 68 (2008) 214–223
21 Yi Sun , JianCheng Wang , Xuan Zhang. Synchronic release of two hormonal contraceptives for about one month from the PLGA microspheres: In vitro and in vivo studies. Journal of Controlled Release 129 (2008) 192–199
22 Mohamed Abbas Ibrahim, Ahmed Ismail, Mohamed Ihab Fetouh. Stability of insulin during the erosion of poly(lactic acid) and poly(lactic-co-glycolic acid) microspheres. Journal of Controlled Release 106 (2005) 241–252
23吴伟,崔光华.聚乳酸或乳酸/羟乙酸共聚物的制备方法研究进展[J].国外医药一合成药生化药制剂分册,2000,21(6):367.369
24 Cory Berkland , Martin King , Amanda Cox . Precise control of PLG microsphere size provides enhanced control of drug release rate。Journal of Controlled Release 82 (2002) 137–147
25 Banu S. Zolnik , Diane J. Burgess. Evaluation of in vivo–in vitro release of dexamethasone from PLGA microspheres. Journal of Controlled Release 127 (2008) 137–145
26程国华,罗佳波.汉防己甲素肺靶向聚乳酸微球兔体内药动学的研究.China Pharmacy 2005 Vol.16.10
27 Okada H , Doken Y, Ogawa Y, et al. Preparation of three-month depot injectable microspheres of leuprorelin acetate using biodegradable polymers [J ]. Pharm Res , 1994 , 11(8):1143
28 anusz WK. Patrick PD1A novel in vitro release technique for peptide containing biodegradable microspheres [EB/OL]. http://www.pharmscitech1.com/volumnlissue/111/manuscript.htm, 2000 - 01– 01
29冼远芳,程凤梅,陈鸿玉.阿司匹林聚乳酸微球的体外加速释放试验.中国医院药学杂志2008 28(16) :1364-1367