CN1069408A - 球状药用制剂 - Google Patents

球状药用制剂 Download PDF

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CN1069408A
CN1069408A CN92105698A CN92105698A CN1069408A CN 1069408 A CN1069408 A CN 1069408A CN 92105698 A CN92105698 A CN 92105698A CN 92105698 A CN92105698 A CN 92105698A CN 1069408 A CN1069408 A CN 1069408A
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I·R·巴克斯顿
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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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

一种受控释放组合物，包括由硫氮酮或其药学 上可接受的盐和可选的成球剂组成的球状核，所述核 被一种受控释放材料涂覆。如果加入成球剂的话，最 好选用微晶纤维素。乙基纤维素是优选的受控释放 涂层。受控释放涂层最好包含增塑剂、表面活性剂和 胶粘改性剂。

Description

本发明涉及一种受控释放制剂及其制备方法，尤其涉及含硫氮
Figure 921056982_IMG6
酮的控制释放制剂。
硫氮
Figure 921056982_IMG7
酮是一种钙拮抗剂，可用来治疗心脏病，例如心胶病和高血压。
本发明的目的是提供一种受控释放硫氮
Figure 921056982_IMG8
酮制剂，适于每日一次给药，治疗高血压和心绞痛。
因此，本发明提供包含球状核的受控释放制剂，该核由硫氮
Figure 921056982_IMG9
酮或其药学上可接受的盐组成，还可含有成球剂，并覆有受控释放层。
本发明所用的适当的药学上可接受的盐包括药学上可接受的酸加成盐。特别优选盐酸盐。
本发明的受控释放药用组合物能够在较长时间内缓慢释放药物，并且在该时间内延长药物作用时间以达到常规药物传送的效果。
“球状”一词是药学领域的常用词，它是指直径为0.1mm～2.5mm;尤其是0.5mm～2mm的球状粒子。
本发明球状核最好含40%～98%，含60%～85%更好，尤其含70%～85%（重量）硫氮
Figure 921056982_IMG10
酮或其药学上可接受的盐。
成球剂可以是任何适当的药学上可接受的材料。它可以与活性成分一起成球以形成球状核。优选的成球剂是微晶纤维素，所用的微晶纤维素可以是，例如阿维塞尔PH107或阿维塞尔PH102（商品名，FMC公司）。一般来说，当存在成球剂时，它占球状核的1%～60%（重量），最好药15%～40%（重量）。
球状核还可含有其它药学上可接受赋形剂和稀释剂。使之易于成球，例如用糖（如蔗糖、右旋糖、麦芽糖或乳糖）或糖醇（例如甘露醇、木糖醇或山梨糖醇）。在球状核中还可含有着色剂。
球状核最好是涂覆允许硫氮
Figure 921056982_IMG11
酮在水性介质中控制速率释放的膜，适宜的涂膜材料可包括水不溶蜡和聚合物，例如聚甲基丙烯酸酯（例如商标为Eudragit的聚合物）或优选水不溶纤维素，特别是乙基纤维素。这膜涂层还可含水溶性聚合物，例如聚乙烯吡咯烷酮或最好是水溶性纤维素，例如羟丙基甲基纤维素和羟丙基纤维素。应当理解，水不溶材料与水溶性材料的比率取决于所要求的释放速度和所选村料的溶解度，水溶性聚合物与水不溶聚合物的比率以1∶20至1∶2为佳。受控释放涂层优选包括一种或多种本领域的常规增塑剂，例如酞酸二乙酯，但最好是癸二酸二丁酯;表面活性剂，例如山梨聚糖三油酸酯、山梨聚糖单月桂酸酯或优选多乙氧基醚80（商标为Tween80）和胶粘改性剂，例如滑石粉或优选胶质无水硅石。
当存在增塑剂时，其含量将取决于所选的特定增塑剂，一般，增塑剂的量为受控释放膜涂层的1%至25%（重量）。当存在表面活性剂时，其适宜存在量为受控膜涂层的1%至25%（重量）当存在胶粘改性剂时，其存在量也以受控释放膜涂层的1%至25%（重量）为宜。
优选的受控释放膜涂层包括50%至95%乙基纤维素，5%至15%胶质无水硅石，5%至15%癸二酸二丁酯和5%至15%多乙氧基醚80（商标为Tween  80）。
采用传统涂覆方法例如流化床或槽式涂覆，可在含硫氮
Figure 921056982_IMG12
酮的球状核的表面形成受控释放涂膜层。该涂层材料可应用溶液或悬浮液，适宜的溶剂系统包括水、二氯甲烷、乙醇、甲醇、异丙醇和丙酮及其混合物。涂覆溶液或悬浮液优选含2%至60%（重量）、最好含2%至20%（重量）涂覆材料。
受控释放涂覆材料的用量取决于所要求的释放速率，但是一般为受控释放涂覆球体的1%至25%（重量），最好为2%至8%（重量）。
本发明含硫氮
Figure 921056982_IMG13
酮球体的制备方法包括以下步骤：
（a）将包括硫氮
Figure 921056982_IMG14
酮或其药学上可接受的盐、水和可选的成球剂的混合物成粒;
（b）挤压成粒混合物，得到挤出物;
（c）将挤出物成球，直至形成球状核;
（d）干燥球状核;并且
（e）膜涂覆球状核。
采用传统制药技术可将本发明组合物填充制成胶囊或压制成片剂。
本发明组合物的可适当地每日一次给药。一般每日一次给药，剂型中硫氮）酮或其药学上可接受的盐（优选硫氮
Figure 921056982_IMG15
酮盐酸盐）的含量为120mg～300mg。
为了更好地理解本发明，给出下述实施例，仅为说明而已。
实施例1
制备了具有下述配方的胶囊
硫氮
Figure 921056982_IMG16
酮球状核
材料  毫克
硫氮
Figure 921056982_IMG17
酮盐酸盐U.S.P 120
微晶纤维素E.P（Avicel  PH  101）  30.0
蒸馏水E.P  适量
150
受控释放膜涂层
材料  毫克
硫氮
Figure 921056982_IMG18
酮盐酸盐球状核 150
乙基纤维素N10  U.S.N.F  7.38
胶质无水硅石E.P.（Aerosil  130）  0.988
癸二酸二丁酯U.S.N.F.  0.742
多乙氧基醚80  E.P.（Tween80）  0.791
二氯甲烷BS  1994  适量
甲醇B.P.1973  适量
160
胶囊制剂  mg
硫氮
Figure 921056982_IMG19
酮受控释放球状体 160
硬酯酸镁  EP  0.480
明胶囊壳3号（Size  3）
采用高剪切混合器混合硫氮
Figure 921056982_IMG20
酮和微晶纤维素，该混合是湿式成粒，挤压后得到挤出物，成粒并置于流化床干燥器中干燥，所得球体过筛，得到粒径为0.85-1.7毫米。
将受控释放涂膜成分分散在二氯甲烷/甲醇溶剂体系中，应用到流化床涂敷器内的硫氮
Figure 921056982_IMG21
酮球状核上，得到的涂膜球体过筛，然后，在流化床涂覆器中，将含硫氮
Figure 921056982_IMG22
酮受控释放球体用双氢氯噻嗪和羟丙基甲基纤维素的分散体涂膜。
通过EP篮式装置（100转/分），用PH4.5EP磷酸盐缓冲液测定所得产品的溶解度。所得结果如下：
硫氮 酮溶解度
时间（小时） 硫氮 酮受控释放
                  球状体
1  9
2  23
3  37
4  48
5  57
6  63
8  72
10  77
12  81
15  86
20  90

Claims (12)

1、一种受控释放组合物，包括由硫氮
Figure 921056982_IMG2
酮或其药学上可接受的盐和可选的成球剂组成的球状核，所述核被一种受控释放材料涂覆。
2、按照权利要求1的组合物，其中，球状核包含40%～98%（重量）的硫氮
Figure 921056982_IMG3
酮或其药学上可接受的盐。
3、按照权利要求2的组合物，其中，球状核包含70%～85%（重量）的硫氮 酮或其药学上可接受的盐。
4、接照权利要求1至3的组合物，其中，成球剂的含量为球状核重量的15%～40%。
5、按照权利要求4的组合物，其中，成球剂包括微晶纤维素。
6、按照权利要求1至5任一项的组合物，其中，受控释放涂覆材料包括水不溶性聚合物。
7、按照权利要求6的组合物，其中，涂覆材料包括乙基纤维素。
8、按照权利要求1至7任一项的组合物，其中，受控释放涂覆材料还包括一种或多种增塑剂、表面活性剂和胶粘改性剂。
9、按照权利要求8的组合物，其中，受控释放涂层包括50%～95%乙基纤维素、5%～15%胶状无水硅石、5%～15%癸二酸二丁酯和5%～15%多乙氧基醚80。
10、按照权利要求1至9任一项的组合物，其中，受控释放涂覆材料的用量为组合物重量的2%～8%。
11、一种胶囊，它包含权利要求1至10任一项的受控释放涂覆的球状核。
12、一种制备权利要求1至10任一项的组合物的方法，包括：
（a）将包括硫氮
Figure 921056982_IMG5
酮或其在药学上可接受盐、水和可选的成球剂的混合物成粒;
（b）挤压成粒混合物，得到挤出物;
（c）将挤出物成球，直至形成球状核;
（d）干燥球状核;并且
（e）用受控释放材料涂覆球状核。
CN92105698A 1991-08-12 1992-08-12 球状药用制剂 Expired - Lifetime CN1052398C (zh)

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GB919117361A GB9117361D0 (en) 1991-08-12 1991-08-12 Oral dosage form
GB9122967.4 1991-10-29
GB919122967A GB9122967D0 (en) 1991-10-29 1991-10-29 Pharmaceutical composition
GB9117361.7 1991-10-29

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CN1052398C CN1052398C (zh) 2000-05-17

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NO304406B1 (no) 1998-12-14
ATE165513T1 (de) 1998-05-15

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