CN1194688C - 石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法 - Google Patents
石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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Abstract
本发明提供了一种石杉碱甲及其衍生物或其盐的新剂型注射用缓释微球，它是由微球重量的0.2-50%的石杉碱甲或其衍生物和微球重量的50-99.8%的可生物降解的分子量为5,000一1,000,000道尔顿的药用高分子辅料组成。它可以采用乳化分散法、溶剂挥发法和喷雾干燥法制备。该缓释微球能够延长药物作用时间、减少用药次数、提高石杉碱甲及其衍生物的生物利用度，降低该药物的毒副作用。
Description
本发明涉及石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法。
石杉碱甲(Huperzine A)，化学名为(5R，9R，11E)-5-氨基-11-亚乙基-5，6，9，10-四氢-7-甲基-5，9-亚甲环芳辛并-2(1H)-吡啶酮，是从中草药千层塔[Huperzia serrata(Thunb)Thev]中提取得到的酚性部分中获得的生物碱，是一种高效、低毒和可逆性的乙酰胆碱酯酶抑制剂(AChEI)。1993年美国FDA批准其作为类胆碱能剂。据报导，它可以用来治疗老年性痴呆病，科研人员并对其结构进行改造，发现它的一些衍生物也具有相似的功效。在本发明中它们分别是如下结构：
其中，结构式(I)即为石杉碱甲，经过检索发现石杉碱甲的制剂有片剂、胶囊剂、透皮吸收剂、注射剂、透皮控释帖片等，但至今没有发现它的缓释微球。现有的石杉碱甲剂型，不管是口服制剂、注射剂还是透皮吸收剂，因为石杉碱甲其生物半衰期较短，故其在血液中的生物利用度偏低且副作用较大。副作用主要表现为：头昏、恶心、多汗、便秘、口干、静坐不能、焦虑。呕吐。肌肉震颤、心率变化、瞳孔变化等。当剂量超过有效剂量时，副作用随剂量增大而增多。因此，迫切需要开发一种新型制剂，从而降低石杉碱甲毒副作用，提高其生物利用度，同时减少给药次数，方便患者用药。
本发明的目的就是提供一种如通式(1)所表述的石杉碱甲及其衍生物或其盐的注射用缓释微球，这种新剂型能够延长药物作用时间、减少用药次数、提高石杉碱甲及其衍生物的生物利用度，降低该药物的毒副作用。
本发明的另一个目的是提供上述石杉碱甲及其衍生物或其盐的注射用缓释微球的制备方法。
本发明所述的石杉碱甲及其衍生物的缓释微球直径为1-250μm，是由微球总重量0.2-50％(w/w)的石杉碱甲及其衍生物和微球总重量50-99.8％(w/w)的分子量在5000-1000000道尔顿的可生物降解的高分子药用辅料组成。其中所述的可生物降解的高分子药用辅料选自于聚丙交酯-乙交酯、聚乳酸、聚乙醇酸、聚-3-羟基丁酸酯、聚乳酸-聚羟乙酸、聚乳酸-乙醇酸、聚邻酯、聚内酯、聚酐、聚羟基丁酸酯-羟基戊酸酯共聚物、聚乙醇酸、聚丙烯葡聚糖、羟基乙酸、聚乳酸-聚乙二醇、聚羟乙酸-聚乙二醇其中的一种；优选聚丙交酯-乙交酯、聚乳酸、聚乳酸-聚羟乙酸、聚乳酸-乙醇酸、聚羟基丁酸酯-羟基戊酸酯共聚物，最佳为聚丙交酯-乙交酯，分子量为12000-15000道尔顿；丙交酯-乙交酯的聚合比例为40∶60-60∶40。
另外本发明所述的石杉碱甲及其衍生物也包括它们的盐，如盐酸盐、醋酸盐、乳酸盐、磷酸盐、柠檬酸盐、硫酸盐等。
本发明所述的微球可以采用微球的常规制备方法制得，如采用乳化分散法、喷雾干燥法和溶剂挥发法，优选喷雾干燥法。当用乳化分散法制备本发明的微球时，用二氯甲烷、氯仿、乙酸乙酯、二氧六环、乙醚、丙酮、四氢呋喃、冰醋酸以及由它们所组成的混合酸把石杉碱甲及其衍生物和可生物降解的药用辅料溶解配制成有机相，其中药用辅料在有机溶剂中的重量体积百分数为1-30％，有机相采用的乳化剂为HLB＝4.5～6.0的非离子型乳化剂，用量为有机相的0.01-12％；另外用聚乙烯醇、聚乙烯基吡咯烷酮、聚甲基丙烯酸钠、聚丙烯酸钠、羧甲基纤维素钠水溶液配制连续水相，其中它们在水相中的重量百分数为0.01-10.0％，水相中的乳化剂为HLB＝14.0-155的非离子型乳化剂，用量为水相的0.01-12％；有机相与水相的体积比为1∶4-100；将有机相通过细管慢慢注入到连续相中，充分乳化后，过筛分离所形成的微球，干燥即得。当采用溶剂挥发法时，是在分散相通过细管慢慢注入到连续相中充分乳化后，减压挥发溶剂，离心分离得到所形成的微球，干燥即得。
当采用喷雾干燥法制备石杉碱甲及其衍生物的缓释微球时，是用二氯甲烷、氯仿、乙酸乙酯、二氧六环、乙醚、丙酮、四氢呋喃、冰醋酸以及由它们所组成的混合酸把石杉碱甲及其衍生物和可生物降解的药用辅料充分溶解配制成有机溶液；过滤，喷雾干燥制成微球。
本发明所述的石杉碱甲及其衍生物的微球是将制好的微球无菌粉末先在无菌的0.9％的生理盐水溶剂中混悬，均匀后肌注来给药的。以石杉碱甲A剂量为400μg/kg给兔子肌肉注射，28天内，血药浓度至少为0.3ng/ml，最大量不超过20ng/ml。以石杉碱甲A剂量为200μg/kg给狗作肌肉注射，42天内，血药浓度至少为0.3ng/ml，最大量不超过20ng/ml。
以下将通过实施例来进一步说明本发明所述的石杉碱甲及其衍生物的微球的制备方法和缓释效果。
实施例1
将100mg石杉碱甲A、200mg聚丙交酯-乙交酯溶于3ml二氯甲烷中，用针筒在激烈搅拌下将其滴至装有300ml内含3.5Ghlb＝14乳化剂的10％PVA的三颈瓶中，充分乳化1小时后，在30℃0.03MPa的压力下，挥发溶剂1.5小时，离心分离，用蒸馏水洗反应物三次，在30℃真空烘箱内烘干，用环氧乙烷在30℃灭菌48小时，确保残留环氧乙烷含量在5ppm以下，灌装。
实施例2
称取石杉碱甲A100mg，聚丙交酯-乙交酯(丙交酯∶乙交酯＝50∶50)，2.0g于小烧杯中，加二氯甲烷31.5ml，电磁搅拌至充分溶解，用微孔滤膜过滤，采用喷雾干燥法制备微球，测得粒径5-80μm，灭菌，分装，进行动物体内释放试验，试验对象为家兔，剂量为400μg/kg，微球混悬于生理盐水中，肌注给药，在1到28日内，取血，HPLC-MS检测，血浓为1-5ng/ml。
实施例3
称取石杉碱甲100mg，聚丙交酯-乙交酯(丙交酯∶乙交酯＝60∶40)，4.0g于小烧杯中，加二氯甲烷41ml，电磁搅拌至充分溶解，采用喷雾干燥法制备微球，测得粒径1-50μm，平均粒径13.26μm，灭菌，分装，对狗进行体内释放试验，石杉碱甲A剂量为200μg/kg，微球混悬于生理盐水中，肌注给药，在1到42日内，取血，HPLC-MS检测，血浓为0.5-5ng/ml。
实施例4
将石杉碱甲100mg，聚丙交酯-乙交酯(丙交酯∶乙交酯＝50∶50)1.0g共置于小烧杯中，加冰醋酸22ml，电磁搅拌至充分溶解，采用喷雾干燥法制备微球，测得粒径1-100μm，灭菌，分装，体外模拟释放试验20天。
实施例5
将石杉碱甲500mg及1000mg的聚丙交酯-乙交酯(丙交酯∶乙交酯＝50∶50)溶于10ml二氯甲烷并冷却至15℃，另以400ml内含0.01mol/L三羟甲基氨基甲烷和0.01％聚乙烯醇的水溶液(pH＝8.0)作为连续水相，将分散相通过细管慢慢注入到连续相中，在15摄氏度用乳化器乳化15分钟，然后加1600ml，15℃的蒸馏水，用磁力搅拌器搅拌20分钟，再在抽真空状态下搅拌15分钟，过筛，低压冻干即得1-10微米的微球。
实施例6
称取石杉碱甲100mg，聚乳酸-聚羟乙酸，4.0g于小烧杯中，加二氯甲烷41ml，电磁搅拌至充分溶解，采用喷雾干燥法制备微球，测得粒径1-50μm，平均粒径13.26μm，灭菌，分装，
实施例7
将石杉碱甲100mg，聚乳酸1.0g共置于小烧杯中，加冰醋酸22ml，电磁搅拌至充分溶解，采用喷雾干燥法制备微球，测得粒径1-100μm，灭菌，分装。
实施例8
将100mg石杉碱甲A、聚羟基丁酸酯-羟基戊酸酯200mg溶于3ml二氯甲烷中，用针筒在激烈搅拌下将其滴至装有300ml内含3.5Ghlb＝14乳化剂的10％PVA的三颈瓶中，充分乳化1小时后，在30℃0.03MPa的压力下，挥发溶剂1.5小时，离心分离，用蒸馏水洗反应物三次，在30℃真空烘箱内烘干，用环氧乙烷在30℃灭菌48小时，确保残留环氧乙烷含量在5ppm以下，灌装。
实验例1石杉碱甲微球的体外释放试验。
实验样品：根据本发明实施例2、3、4所述的方法制备的微球。
实验试剂：一定PH值的缓冲溶液(4.0、5.5)。
实验仪器：恒温振荡器、离心机。
实验条件：温度：37±1℃，转速：30rp/分钟。
实验方法：精密称取实验样品约10mg置于容积为15ml的具盖塑料离心管中，加5ml释放介质(PH＝4和5.5磷酸缓冲溶液)置于恒温振荡器中，保持一定的温度和转速按时取样。
取样方法：3600转条件下离心50min，精取3ml溶液，再补加3ml的释放介质，取出液用HPLC检测。
取样时间点(天)：0、1、2、4、6、8、10、12、14、16、18、20。
其中、按实施例2、3、4所述的方法制备的微球在不同PH值的条件下体外释放效果图分别见附图1、2、3
试验结果：
石杉碱甲控释微球体外释放试验结果表
| 样品编号 | 含药量μg/mg | pH值 | 取值方式 | 释 放 百 分 数 ％ | |||||||||||
| 0 | 1 | 2 | 4 | 6 | 8 | 10 | 12 | 14 | 16 | 18 | 20 | ||||
| 实施例2 | 18.5 | 4.0 | 当天 | 0 | 26.6 | 4.0 | 0 | 1.5 | 1.15 | 14.0 | 11.95 | 3.0 | 0 | 6.5 | |
| 累积 | 0 | 26.6 | 30.6 | 30.6 | 33.6 | 35.9 | 63.9 | 87.8 | 93.8 | 93.8 | 106.8 | 106.8 | |||
| 5.5 | 当天 | 0 | 28.0 | 2.0 | 0 | 1.5 | 1.7 | 29.5 | 16.4 | 1.0 | 0 | 0.5 | |||
| 累积 | 0 | 28.0 | 30.0 | 30 | 33 | 36.4 | 95.4 | 128.2 | 130.2 | 130.2 | 131.2 | 131.2 | |||
| 实施例3 | 18.3 | 4.0 | 当天 | 0 | 28.3 | 0.3 | 0.95 | 1.1 | 2.1 | 9.0 | 12.35 | 4.8 | 2.8 | 0.85 | 0.5 |
| 累积 | 0 | 28.3 | 28.6 | 30.5 | 32.7 | 36.9 | 54.9 | 79.6 | 89.2 | 94.8 | 96.5 | 97.5 | |||
| 5.5 | 当天 | 0 | 18.1 | 0.9 | 3.5 | 0.05 | 2.65 | 8.6 | 10.5 | 12.7 | 2.05 | 1.2 | 0.6 | ||
| 累积 | 0 | 18.1 | 19.0 | 26.0 | 26.1 | 31.4 | 48.6 | 69.6 | 95.0 | 99.1 | 101.5 | 102.7 | |||
| 实施例4 | 23.96 | 4.0 | 当天 | 0 | 33.8 | 2.1 | 1.3 | 2.5 | 3.0 | 5.95 | 11.65 | 5.05 | 1.2 | 0.45 | 0.35 |
| 累积 | 0 | 33.8 | 35.9 | 38.5 | 43.5 | 49.5 | 61.4 | 84.7 | 94.8 | 97.2 | 98.1 | 98.8 | |||
| 5.5 | 当天 | 0 | 31.7 | 1.7 | 1.95 | 1.3 | 2.35 | 17.65 | 4.2 | 5.75 | 1.15 | 0.55 | 0.2 | ||
| 累积 | 0 | 31.7 | 33.4 | 37.3 | 39.9 | 44.6 | 79.9 | 88.3 | 99.8 | 102.1 | 103.2 | 103.6 | |||
结论：由上表可以看出，本发明石杉碱甲的缓释微球的释放可以长达20天，可以大大减少给药次数，同时有效控制了剂量，避免了副作用的出现。
Claims (10)
1.一种如通式(1)的石杉碱甲及其衍生物或其盐的缓释微球，其特征在于它由微球重量的0.2-50％的石杉碱甲及其衍生物或其盐和微球重量的50-99.8％的分子量范围在5,000-1,000,000之间的可生物降解的药用高分子辅料组成，其中和其成盐的酸为盐酸、醋酸、磷酸、硫酸、乳酸、柠檬酸。
2.按照权利要求1所述的缓释微球，其中所述的石杉碱甲及其衍生物或其盐为式(I)、式(II)、式(III)、式(IV)、式(V)化合物或其盐，其中与其成盐的酸为盐酸、醋酸、磷酸、硫酸、乳酸、柠檬酸。
3.按照权利要求1或2所述的缓释微球，其中所述的药用高分子辅料选自于聚丙交酯-乙交酯、聚乳酸、聚乙醇酸、聚-3-羟基丁酸酯、聚乳酸-聚羟乙酸、聚乳酸-乙醇酸、聚邻酯、聚内酯、聚酐、聚羟基丁酸酯-羟基戊酸酯共聚物、聚乙醇酸、聚丙烯葡聚糖、羟基乙酸、聚乳酸-聚乙二醇、聚羟乙酸-聚乙二醇其中的一种或其中的两种或两种以上混合。
4、按照权利要求3所述的缓释微球，其中所述的药用高分子辅料选自于聚丙交酯-乙交酯、聚乳酸、聚乳酸-聚羟乙酸、聚乳酸-乙醇酸、聚羟基丁酸酯-羟基戊酸酯共聚物其中的一种或其中的两种或两种以上的混合。
5、根据权利要求4所述的缓释微球，其中药用高分子辅料为聚丙交酯-乙交酯。
6.按照权利要求5所述的缓释微球，其中所述聚丙交酯-乙交酯其分子量在12000-15000道尔顿之间。
7.按照权利要求5或6所述的缓释微球，其中聚丙交酯-乙交酯中丙交酯和乙交酯聚合比例在40∶60-60∶40之间。
8.如权利要求1所述的缓释微球的制备方法，它是采用乳化分散法制成，其特征在于用二氯甲烷、氯仿、乙酸乙酯、二氧六环、乙醚、丙酮、四氢呋喃、冰醋酸以及由它们所组成的混合酸把石杉碱甲及其衍生物和可生物降解的药用辅料溶解，其中药用辅料在有机溶剂中的重量体积百分数为1-30％，有机相采用的乳化剂为HLB＝4.5～6.0的非离子型乳化剂，用量为有机相的0.01-12％；另外用聚乙烯醇、聚乙烯基吡咯烷酮、聚甲基丙烯酸钠、聚丙烯酸钠、羧甲基纤维素钠水溶液，配制连续水相，其中它们在水相中的重量百分数为0.01-10.0，水相中的乳化剂为HLB＝14.0-15.5的非离子型乳化剂，用量为水相的0.01-12％；有机相与水相的体积比为1∶4-100，将分散相通过细管慢慢注入到连续相中，乳化，然后过筛，干燥即得。
9.如权利要求1所述的缓释微球的制备方法，它是采用溶剂挥发法制成，其特征在于用二氯甲烷、氯仿、乙酸乙酯、二氧六环、乙醚、丙酮、四氢呋喃、冰醋酸以及由它们所组成的混合酸把石杉碱甲及其衍生物和可生物降解的药用辅料溶解，其中药用辅料在有机溶剂中的重量体积百分数为1-30％，有机相采用的乳化剂为HLB＝4.5～6.0的非离子型乳化剂，用量为有机相的0.01-12％；另外用聚乙烯醇、聚乙烯基吡咯烷酮、聚甲基丙烯酸钠、聚丙烯酸钠、羧甲基纤维素钠水溶液，配制连续水相，其中它们在水相中的重量百分数为0.01-10.0，水相中的乳化剂为HLB＝14.0-15.5的非离子型乳化剂，用量为水相的0.01-12％，有机相与水相的体积比为1∶4-100，将分散相通过细管慢慢注入到连续相中，充分乳化，然后减压挥发溶剂，离心分离，干燥即得。
10.如权利要求1所述的缓释微球的制备方法，它是采用喷雾干燥法制成，其特征在于用二氯甲烷、氯仿、乙酸乙酯、二氧六环、乙醚、丙酮、四氢呋喃、冰醋酸以及由它们所组成的混合酸溶解0.2-50％石杉碱甲及其衍生物和50-99.8％的分子量在5000-1000000道尔顿的可生物降解的高分子药用辅料，搅拌充分溶解后，过滤，采用喷雾干燥法制得微球。
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| CN1965839B (zh) * | 2005-11-15 | 2010-11-10 | 上海医药工业研究院 | 非那雄胺及其类似物的注射用缓释微球、其制备方法及其应用 |
| CN1981744B (zh) * | 2005-12-12 | 2011-09-07 | 上海医药工业研究院 | 石杉碱及其衍生物的注射用缓释微球的制备方法 |
| CN101264058B (zh) * | 2007-03-13 | 2010-09-01 | 中国科学院上海药物研究所 | 石杉碱甲及其衍生物或其盐的缓释纳米粒、和它的制造方法 |
| CN100528844C (zh) * | 2007-04-20 | 2009-08-19 | 中国科学院昆明植物研究所 | 石杉碱甲衍生物,其制备方法和其应用 |
| CA2743600C (en) * | 2008-11-14 | 2016-11-08 | Ewha University-Industry Collaboration Foundation | Method for preparing microspheres and microspheres produced thereby |
| US20130040982A1 (en) * | 2010-04-22 | 2013-02-14 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Oral sustained release formulation of huperzine a |
| CN101961318A (zh) * | 2010-09-17 | 2011-02-02 | 南昌大学 | 高乌甲素的注射用缓释微球及其制备方法 |
| EP2793865B1 (en) * | 2011-12-22 | 2018-01-31 | Shandong Luye Pharmaceutical Co., Ltd. | Pharmaceutical compositions of triptorelin microspheres |
| CN103505413B (zh) * | 2012-06-28 | 2015-07-08 | 上海现代药物制剂工程研究中心有限公司 | 石杉碱甲微粒长效注射剂及其制备方法 |
| WO2015043404A1 (zh) * | 2013-09-24 | 2015-04-02 | 万邦德制药集团股份有限公司 | (-)-石杉碱甲盐 |
| CN105586304B (zh) * | 2014-11-18 | 2019-03-05 | 北京化工大学 | 一种生产乙醇酸基聚合物的重组菌及其应用 |
| CN106511348B (zh) * | 2016-11-02 | 2019-04-19 | 中山大学 | 石杉碱甲骨架微粒、口崩片及其制备方法 |
| CN107149595B (zh) * | 2017-05-10 | 2019-11-12 | 烟台大学 | 一种载有石杉碱甲明胶纳米粒微球的制备方法和用途 |
| CN109662954B (zh) * | 2019-02-25 | 2021-07-06 | 福建中医药大学 | 石杉碱甲分子印迹水凝胶微球的制备方法 |
| CN112402380A (zh) * | 2020-11-19 | 2021-02-26 | 上海应用技术大学 | 一种含石杉碱甲微胶囊的缓释微丸及其制备方法 |
| CN113456640A (zh) * | 2021-08-26 | 2021-10-01 | 烟台大学 | 石杉碱甲在心肌缺血损伤预防中的应用 |
| CN113476446A (zh) * | 2021-08-26 | 2021-10-08 | 烟台大学 | 石杉碱甲在急性肝损伤预防中的应用 |
| CN114796132B (zh) * | 2022-05-13 | 2023-08-22 | 海南灵康制药有限公司 | 一种石杉碱甲冻干粉针剂及其制备方法 |
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| US4344431A (en) * | 1969-03-24 | 1982-08-17 | University Of Delaware | Polymeric article for dispensing drugs |
| US3773919A (en) * | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
| JPS63122620A (ja) * | 1986-11-12 | 1988-05-26 | Sanraku Inc | ポリ乳酸マイクロスフエア及びその製造方法 |
| US5106979A (en) * | 1989-02-21 | 1992-04-21 | University Of Pittsburgh | Method for the synthesis of huperzine A and analogs thereof and compounds useful therein |
| US5547960A (en) * | 1994-09-07 | 1996-08-20 | Mayo Foundation For Medical Education And Research | C-10 analogs of huperzine a |
| CN1047732C (zh) * | 1995-04-10 | 1999-12-29 | 浙江省医学科学院 | 石杉碱透皮吸收贴片 |
| US5759583A (en) * | 1995-08-30 | 1998-06-02 | Syntex (U.S.A.) Inc. | Sustained release poly (lactic/glycolic) matrices |
| US5665428A (en) * | 1995-10-25 | 1997-09-09 | Macromed, Inc. | Preparation of peptide containing biodegradable microspheres by melt process |
| SE9504537D0 (sv) * | 1995-12-19 | 1995-12-19 | Jan Hedner | Sätt att behandla och diagnosticera andningsstörningar under sömn och medel för utförande av sättet |
| US6663899B2 (en) * | 1997-06-13 | 2003-12-16 | Genentech, Inc. | Controlled release microencapsulated NGF formulation |
| CN1279065A (zh) * | 1999-07-06 | 2001-01-10 | 青岛科达生物工程有限公司 | 一种治疗记忆障碍和老年痴呆的药物组合物 |
| AR023940A1 (es) * | 2000-05-03 | 2002-09-04 | Eriochem Sa | Procedimiento para la produccion de microcapsulas de liberacion prolongada de peptidos solubles en agua |
| US6369052B1 (en) * | 2000-08-07 | 2002-04-09 | Georgetown University | Combination of huperzine and nicotinic compounds as a neuroprotective agent |
| US6558702B2 (en) * | 2001-04-13 | 2003-05-06 | Alkermes Controlled Therapeutics, Inc. | Method of modifying the release profile of sustained release compositions |
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2002
- 2002-07-03 US US10/482,631 patent/US20040266813A1/en not_active Abandoned
- 2002-07-03 WO PCT/CN2002/000472 patent/WO2003004024A1/zh not_active Ceased
- 2002-07-03 DE DE10297018T patent/DE10297018B4/de not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1393220A (zh) | 2003-01-29 |
| WO2003004024A1 (en) | 2003-01-16 |
| US20040266813A1 (en) | 2004-12-30 |
| DE10297018B4 (de) | 2010-01-28 |
| DE10297018T5 (de) | 2004-09-16 |
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