CN1109754A - 阿尔加特罗邦浓缩水溶液 - Google Patents

阿尔加特罗邦浓缩水溶液 Download PDF

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CN1109754A
CN1109754A CN95101782A CN95101782A CN1109754A CN 1109754 A CN1109754 A CN 1109754A CN 95101782 A CN95101782 A CN 95101782A CN 95101782 A CN95101782 A CN 95101782A CN 1109754 A CN1109754 A CN 1109754A
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argatroban
arbitrary
described solution
micelle
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CN1054743C (zh
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F·安德烈
V·阿夫里尔
J·蒙特尔
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SYNTHETIC LABORATORY CORP
Synthelabo SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

浓缩的argatroban水溶液，其中含argatroban、 胶粒生成剂和类脂物。

Description

本发明的内容是关于新的阿尔加特罗邦（argatroban）盖伦医学配方。
argatroban、凝血酶的合成抑制剂，是一种不太溶于水的化合物（约1mg/ml）。然而，对于某些适应症，当argatroban只是一种单一含水溶液形式时，服用量必需达到每天几百毫升。
为了限制服用体积，可以使用能提高溶液浓度的某些制剂。
例如，曾研究使用低量乙醇、丙（撑）二醇或聚乙二醇或表面活性剂，诸如山梨糖醇酐酯或蓖麻油聚氧乙烯化衍生物的可能性。
这些试剂中某些试剂能提高argatroban溶解度。然而，对于任何制得的溶液，都存在着局部耐药量和/或一般过敏性反应等严重问题。
通过修改混合胶粒技术可以调整出argatroban新的盖伦医学配方，改善了它在水中的溶解度。
这种配方与argatroban、胶粒生成剂和类脂物质（如磷脂）相关。
这种配方还可含有在制备液体药物时通常使用的添加剂，如渗透剂、缓冲剂、抗氧化剂和抗氧剂（防腐剂），或制备干剂型所必需的添加剂（通过低温干燥、雾化、粉化……而得到的），在重新制作后可得到液体剂型。
作为胶粒生成剂，例如可以使用具有下述通式（Ⅰ）的胆酸衍生物：
Figure 951017829_IMG2
式中，R1、R2和R3各自分别代表氢原子、羟基或酮基（氧代）环外基，R4代表羧基或由酰胺链与氨基酸的氨基相连的羧基，并且在类固醇骨架中可含一或二个双链，例如于7-8位、11-12位或9-11位。
更具体地说可以使用化学式（Ⅰ）的化合物，其中R1、R2、R3和R4如下：
R1、R2、R3=OH，R4=COOH，
R1、R2、R3=OH，R4=CONH-CH2-COOH，
R1、R2、R3=OH，R4=CONH-CH2-CH2-SO3H，
R1、R3=OH，R2=H，R4=COOH，
R1、R3=OH，R2=H，R4=CONH-CH2-COOH
R1、R3=OH，R2=H，R4=CONH-CH2-CH2-SO3H
R1、R3=OH，R3=H，R4=COOH，
R1、R2=OH，R3=H，R4=CONH-CH2-COOH
R1、R2=OH，R3=H，R4=CONH-CH2-CH2-SO3
还可以使用化学式（Ⅰ）的化合物盐，尤其是碱金属盐，优选为钠盐。
作为类脂物，尤其可以使用下述化合物：
-磷脂酰胆碱
-磷脂酰乙醇胺
-磷脂酰肌醇
-磷脂酰丝氨酸
-二磷脂酰丙三醇
-丙三醇醚-磷脂
-缩醛磷脂
-鞘磷脂
-硫脂和单酸甘油酯
优选为磷脂，更优选为磷脂酰胆碱。
胶粒生成剂可以是二种或多种胆酸衍生物的混合物。还可使用二种或多种类脂物的混合物。
胶粒类脂部分（纯的或混合的化合物）与生成剂部分（纯的或混合的化合物）之间摩尔比可以是0.1/1至2/1，这个比优选为0.5/1至1.5/1。
本发明药物配方中胶粒生成剂最终浓度随所要求argatroban浓度而改变。所述最终浓度一般是0.01-0.5M。
本发明argatroban溶液可采用下述方法制备：
1.在剧烈搅拌下将所有组分溶于水中。
2.将混合的胶粒组分溶于或多或少已稀释的有机溶剂中，然后蒸发溶剂，用水溶解其残留物，往其中添加对于调节PH、渗透性所必需的和/或溶液稳定性所必需的赋形剂，最后在搅拌下加入argatroban。
3.将argatroban和胶粒组分溶于有机溶剂中，然后蒸发其溶剂，用水溶解其残留物，往其中可以加入如（2）中所述的其它赋形剂。
这样得到的溶液argatroban浓度超过1mg/ml，优选为1mg/ml至21mg/ml。
在采用上述一种方法制得的溶液中，可加入一种或多种物质，如糖、低聚糖、多元醇、氨基酸、聚合物如聚乙烯吡咯烷酮、明胶、葡聚糖、蛋白质…，浓度为0.1-20%。
然后，采用雾化或冷冻法干燥其制剂。
这样得到的固体物质保存在控制气氛的密封容器中，在使用时加入适于可注射制剂的溶剂使之溶解。
如此制得了一种浓度为1-21mg/ml的透明溶液。
下面的实施例说明了本发明：
实施例1
在75mg    95%乙醇中，在磁搅拌下溶解已纯化的1.2克卵磷脂、0.7克甘胆酸钠和0.125克argatroban。然后在减压下蒸发乙醇，再在室温下用25ml    0.06M磷酸盐缓冲液（PH=6）搅拌溶解残留物。得到透明的溶液、浓度为5mg/ml。
这种溶液保存在4℃，在数星期里都是稳定的。
实施例2
在10ml    95%乙醇中溶解0.750克已纯化的卵磷脂和0.490克甘胆酸钠。在减压蒸发溶剂之后，将残留物溶于15ml    0.06M磷酸盐缓冲液（PH=6）中，并在剧烈搅拌下加入0.100克argatroban。采用氮鼓泡搅拌几个小时后，加入磷酸盐缓冲液将其体积调整到20ml。得到的溶液浓度为5mg/ml。
实施例3
按照实施例2的方法，制备一种溶液含0.1M甘胆酸钠和0.1M磷脂酰胆碱，然后加入过量的argatroban，搅拌悬浮液达48小时，并在孔隙为0.22μm的膜上过滤。得到的溶液浓度为11.3mg/ml。
实施例4
按照实施例3的方法，但使用的溶液含0.075M甘胆酸钠，得到的溶液浓度为9mg/ml。
实施例5
按照实施例3的方法，但使用的溶液含0.15M甘胆酸钠和0.15M磷脂酰胆碱，得到的溶液浓度为16.9mg/ml。
实施例6
按照实施例3的方法，但使用的溶液含0.15M磷脂胆碱和0.15M牛磺胆酸钠，得到的溶液浓度为13mg/ml。
实施例7
按照实施例3的方法，但使用0.15M混合物，其中含65%牛磺胆酸钠、35%甘胆酸钠，还使用0.15M磷脂酰胆碱，得到的溶液浓度为20.6mg/ml。
实施例8
按照实施例3的方法，但使用0.15M牛磺胆酸钠和0.15M磷脂酰胆碱与磷脂酰乙醇胺混合物（比例为8.5/1），得到的溶液浓度为20.1mg/ml。
本发明argatroban溶液可以由肠道外、口、鼻、眼或眼球后部位用药。

Claims (10)

1、浓缩的argatroban水溶液，其特征在于它含有argatroban，一种或多种胶粒生成剂和一种或多种类脂物。
2、根据权利要求1所述的溶液，其特征在于：胶粒生成剂选自于具有下述通式（Ⅰ）的胆酸衍生物；
式中R1、R2和R3分别各自代表氢原子、羟基或酮基（氧代）环外基，而R4代表羧基或由酯胺链与氨基酸的氨基相连的羧基，并且在类固醇骨架中可含一个或二个双键。
3、根据权利要求2所述的溶液，其特征在于胆酸衍生物呈碱金属盐形式。
4、根据权利要求1-3中任一权利要求所述的溶液，其特征在于类脂物是磷脂。
5、根据权利要求4所述的溶液，其特征在于磷脂是磷脂酰胆碱。
6、根据权利要求1-5中任一权利要求所述的溶液，其特征在于：它含有在液体药品制剂或干的药物制剂的配制中（这种干的药物制剂在重制后得到液体制剂）所通常使用的赋形剂。
7、根据权利要求1-6中任一权利要求所述的溶液，其特征在于：类脂物与胶粒生成剂之间的摩尔比为0.1/1至2/1。
8、根据权利要求1-7中任一权利要求所述的溶液，其特征在于胶粒生成剂浓度为0.01-0.5M。
9、根据权利要求1-8中任一权利要求所述的溶液，其特征在于：argatroban浓度为1mg/ml至21mg/ml。
10、溶液，其特征在于，它是由根据权利要求1-9中任一权利要求所述溶液组分全部或部分经雾化或冷冻干燥得到的固体物质即时制备的。
CN95101782A 1994-02-03 1995-01-28 阿加曲班浓缩水溶液 Expired - Fee Related CN1054743C (zh)

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FR9401195A FR2715566B1 (fr) 1994-02-03 1994-02-03 Solutions aqueuses concentrées d'argatroban.
FR9401195 1994-02-03

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CN110478471B (zh) * 2019-09-17 2020-04-10 鲁南制药集团股份有限公司 一种阿加曲班注射液及其制备方法
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ATE179327T1 (de) 1999-05-15
KR950031042A (ko) 1995-12-18
EP0669131B1 (fr) 1999-04-28
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EP0669131A1 (fr) 1995-08-30
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CN1054743C (zh) 2000-07-26
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