CN1355694A - 美沙拉秦控释口服药物组合物 - Google Patents
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Abstract
含有5－氨基水杨酸作为活性成分的控释口服药物组合物,包含:a)内部亲脂性基质,由熔点低于90℃的物质组成,其中至少部分包容有活性成分;b)外部亲水性基质,其中分散有亲脂性基质;c)可选的其他赋形剂。
Description
本发明涉及控释口服药物组合物，含有5-氨基水杨酸(也称美沙拉秦)作为活性成分。
发明背景
由于其对肠黏膜的抗炎活性，美沙拉秦用于克罗恩氏(Chron′s)病和溃疡性结肠炎的治疗。美沙拉秦的控释制剂公开在WO95/16451、EP 0 453 001、EP 0 377 477中。
持续、控制、延迟或至少有所改变的释放剂型可以按照不同的已知工艺进行制备：
1、惰性基质的使用，其中该基质结构的主要组分由于对水性液体的亲合性差，对溶剂渗入具有一定的抵抗性；这样的性质已知是亲脂性。
2、亲水性基质的使用，其中该基质结构的主要组分对溶剂前进具有较高的抵抗性，因为在其链中、主要在支链中存在强亲水性基团，显著增加了水合层内部的黏度。
3、生物可腐蚀基质的使用，它能够被一些生物腔内的酶所降解。
不过，所有上述操作都面临着缺点和瑕疵。
惰性基质：例如一般赋予活性成分以非线性、而是指数性(esponential)释放。
亲水性基质：具有线性行为，直至某些部分的活性成分已经被释放，然后它们显著偏离线性释放。
生物可腐蚀基质：是进行所谓“就地释放”所理想的，但是它们牵涉找到适合的酶或或者对降解呈反应性的问题。此外，它们经常就地(in situ)释放代谢产物，后者在毒理学上并不是完全惰性的。
人们已经描述了大量基于惰性亲脂性基质的制剂：《Drug Dev.Ind.Pharm.》13(6)，1001-1022，(1987)公开了利用不同量胶体二氧化硅作为亲脂性惰性基质的微孔化成分的方法，在该基质中掺有活性成分。
US 4,608,248描述了相同的惰性基质成管作用构思，其中将少量亲水性聚合物与各物质按不同基质材料的非连续共同渗入(compenetration)方式混合形成惰性基质。
EP 375,063公开了用于活性成分控制释放的多粒子颗粒剂的制备工艺，包括将聚合物或适合的物质与活性成分共溶，形成惰性基质，随后使所述溶液沉积在充当药具核心的惰性载体上。作为替代选择，将惰性载体与含有惰性聚合物和活性成分的溶液捏和，然后蒸发除去其溶解所用的有机溶剂，得到固体残余物。所得结构是一种“药库”，也就是沿最终形状的所有对称轴都不是宏观均匀的。
《化学与药学通报》(Chem.Pharm.Bull.)46(3)，531-533也描述了相同的“药库”结构，通过沉积在丸粒表面上的惰性聚合物层的退火工艺，提高了实用性。
根据WO 93/00889所述工艺所得产品也属于“药库”结构，其中公开了亲水性基质中的丸粒的制备方法，包括：
-将活性成分与胃耐受性亲水性聚合物溶于有机溶剂；
-干燥所述悬液；
-随后在亲水性或亲脂性基质中捏和和配制丸粒，在两种类型应用之间没有有效性上的区别。
EP 0 453 001公开了在亲水性基质中插入“药库”结构的多粒子。基本的多粒子采用两层包衣膜，以降低活性成分的释放速率，pH-依赖性膜的目的是对胃的保护作用，pH-独立性甲基丙烯酸膜的目的是减缓水性流体的渗入。
WO 95/16451公开了仅由被胃耐受性膜包衣的亲水性基质所形成的组合物，用于控制美沙拉秦的溶解速率。
在制备通常对胃肠道具有活性的药物的、持续、控制释放剂型时，确保从给药后第一阶段的控制释放是很重要的，此时惰性基质在对数期内具有最大释放速率，也就是更高地偏离线性释放。
本发明已经达到了所述目标，并且还可以制备以活性成分含量高为特征的组合物。
发明的公开
本发明提供了含有5-氨基水杨酸作为活性成分的控释口服药物组合物，包含：
a)内部亲脂性基质，由熔点低于90℃的物质组成，其中至少部分包容(inglobate)有活性成分；
b)外部亲水性基质，其中分散有亲脂性基质；
c)可选的其他赋形剂。
发明的详细说明
利用包括下列步骤的方法可以得到本发明的组合物：
a)首先将活性成分包容在一种低熔点赋形剂或赋形剂混合物中，同时加热至使赋形剂本身软化和/或熔化，从而通过简单的分散作用掺入活性成分。
在室温下冷却后，惰性基质成型，其体积可被减小，得到含有活性成分粒子的基质颗粒。
b)随后将惰性基质颗粒与一种或多种亲水性水可溶胀的赋形剂混合在一起。
以这种方式，当片剂与生物液体接触时，形成高黏度溶胀层，它协调溶剂分子，充当水性液体本身渗入新结构内部的屏障。所述屏障拮抗由包容在惰性基质内的药物的溶解作用所致起始“爆发效应”，这也出现在亲水性基质内部。
亲脂性基质由选自如下的物质组成：不饱和和/或氢化的脂肪酸、它的盐、酯或酰胺，脂肪酸单-、二-或三-甘油酯，蜡，神经酰胺，胆固醇衍生物或其混合物，它们的熔点在40至90℃的范围内。
如果需要的话，可以将脂肪酸钙盐掺入亲脂性基质，随后将其分散在由藻酸制成的亲水性基质中，因而在前面的溶剂渗入之后直至与分散其中的亲脂性基质颗粒接触，显著增加亲水性基质的黏度。
亲脂性基质中活性成分的重量含量通常为5至95％。
通过挤出和/或造粒方法或任意其他已知保留起始混合物的均匀分散性和基质结构的方法，可以将惰性亲脂性基质缩小为颗粒。
亲水性基质由已知为水凝胶的赋形剂组成，也就是这样的物质，它从干燥状态到水合状态经历所谓的“分子松弛”，也就是在赋形剂本身聚合链中存在的极性基团与大量水分子的协调作用之后，质量和重量有显著增加。
按照本发明可以使用的水凝胶实例是选自如下的化合物：丙烯酸或甲基丙烯酸的聚合物或共聚物、烷基乙烯基聚合物、羟基烷基纤维素、羧基烷基纤维素、多糖、糊精、果胶、淀粉与衍生物、天然或合成的树胶、藻酸。
将含有活性成分的亲脂性基质颗粒与上述亲水性化合物混合，二者的重量比通常为100∶0.5至100∶20(亲脂性基质∶亲水性基质)。可选地可以将一部分美沙拉秦与亲水性物质混合，得到其中活性成分既分散在亲脂性基质中、也分散在亲水性基质中的组合物，所述组合物优选地是片剂、胶囊剂和/或微型片剂。
亲脂性基质、形成水凝胶的化合物与可选的未包容在亲脂性基质中的活性成分的混合物经过压制，得到宏观上全体均匀的结构，也就是含有亲脂性颗粒在亲水性基质中的分散系的基质。
可根据本发明得到的片剂、胶囊剂和/或微型片剂可以可选地用胃耐受性膜进行已知的包衣过程，膜例如由甲基丙烯酸聚合物(Eudragit)或纤维素衍生物、例如纤维素乙酰邻苯二甲酸酯组成。
本发明的组合物可以含有相对全体组合物重量而言高达95％的活性成分，这对美沙拉秦来说是有利的，因为后者要求相当高的单元剂量。
从溶解特征上来说，本发明组合物使活性成分的释放比传统系统更均匀。事实上，水立即渗入亲水性基质表面层内部和随后因水凝胶聚合链膨胀而溶胀，引起前面水合的黏度增高，这防止水的进一步渗入，线性减缓溶解过程至既定的点，可以位于厚度的大约一半，直至水的进一步渗入将导致亲水层的崩解和内容物的释放，不过，由亲脂性颗粒组成的内容物诱发这些结构特有的扩散机理，因此进一步减缓活性成分的溶解。
下列实施例更详细地阐述发明。
实施例1
在捏和机内加入770g 5-氨基水杨酸、20g巴西棕榈蜡和50g硬脂酸，加热直至均匀分散，然后挤成小颗粒，冷却。
将惰性基质颗粒装入混合机，向其中按顺序加入30g Carbopol971P和65g羟丙基甲基纤维素。
在均匀分散粉末的第一个混合步骤之后，加入60g微晶纤维素和5g硬脂酸镁。混合后，将最终的混合物压制成单重649mg/片或510mg/片，分别得到500和400mg剂量。
将所得片剂用纤维素乙酰邻苯二甲酸酯或聚甲基丙烯酸酯和增塑剂进行膜包衣，以提供胃耐受性，防止产品在胃内过早释放。
这些片剂的溶解情况显示，活性成分在模拟肠液中的释放量在第一小时内低于30％，在第四小时低于60％，在第八小时低于90％，因而证实双基质有效控制溶解。
实施例2
在捏和机内加入1000g 5-氨基水杨酸、10g巴西棕榈蜡和20g硬脂酸，加热直至均匀分散，然后挤成小颗粒，冷却，或者直接在高速率混合机内造粒。
将所得颗粒装入混合机，向其中按顺序加入80g羟丙基甲基纤维素和12g淀粉羟乙酸钠。在第一个混合步骤之后，加入11g胶体二氧化硅和11g硬脂酸镁。将最终的混合物匀化，然后压制成单重1144mg/片。
然后将所得片剂用聚甲基丙烯酸酯或纤维素乙酰邻苯二甲酸酯和增塑剂进行膜包衣，以提供胃耐受性。
这些片剂在胃内和部分在肠内持续一定时间之后的溶解情况提供如下释放：在第一小时内不超过30％，在两小时内不超过55％，在四小时内不超过70％，在八小时内不超过90％。
实施例3
在造粒/捏和机内加入850g 5-氨基水杨酸、9g蜂蜡和22g棕榈酸，加热直至均匀分散；然后在高剪切造粒设备中加工成颗粒。然后将所得颗粒装入混合机，连续加入45.5g羟丙基甲基纤维素、45.5g微晶纤维素、20g淀粉羟乙酸钠、22g胶体二氧化硅和22g硬脂酸镁。匀化后，将最终的混合物压制成单重975mg/片。
然后将所得片剂用聚甲基丙烯酸酯或纤维素乙酰邻苯二甲酸酯和增塑剂进行膜包衣，以提供胃耐受性。
这些片剂在胃内和部分在肠内持续一定时间之后的溶解情况提供如下释放：在第一小时内不超过30％，在两小时内不超过50％，在四小时内不超过70％，在八小时内不超过90％。
实施例4
在造粒/捏和机内加入1100g 5-氨基水杨酸、10g巴西棕榈蜡和20g硬脂酸。
分别向匀化/造粒机内装入10g聚丙烯酰胺、39.5g微晶纤维素和22g胶体二氧化硅，得到均匀的固体混合物，将其放置在混合机内，其中活性成分已被造粒和匀化。将49.5g羟丙基甲基纤维素与12g藻酸钠充分混合，然后加入5g碳酸钙、34.5g微晶纤维素和11g硬脂酸镁。将混合物匀化，然后压制成最终单重1194mg/片。然后将所得片剂用聚甲基丙烯酸酯或纤维素乙酰邻苯二甲酸酯和增塑剂进行膜包衣，以提供胃耐受性。
这些片剂在胃内和部分在肠内持续一定时间之后的溶解情况提供如下释放：在第一小时内不超过35％，在两小时内不超过50％，在四小时内不超过70％，在八小时内不超过90％。
实施例5
在混合机内加入1200g 5-氨基水杨酸、10g巴西棕榈蜡和20g硬脂酸，加热直至均匀分散，然后冷挤压成小的颗粒或者直接在高速率混合机内造粒。
将所得颗粒装入混合机，然后按顺序加入70g羟丙基甲基纤维素和20g淀粉羟乙酸钠。
在第一个混合步骤之后，加入80g碳酸钠和5g硬脂酸镁。将最终混合物匀化，然后压制成单重1375mg/片。
然后将所得片剂用聚甲基丙烯酸酯或纤维素乙酰邻苯二甲酸酯和增塑剂进行膜包衣，以提供胃耐受性。
这些片剂在胃内和部分在肠内持续一定时间之后的溶解情况提供如下释放：在第一小时内不超过30％，在两小时内不超过50％，在四小时内不超过70％，在八小时内不超过90％。
Claims (11)
1、含有5-氨基水杨酸作为活性成分的控释口服药物组合物，包含：
a)内部亲脂性基质，由熔点低于90℃的物质组成，其中至少部分包容有活性成分；
b)外部亲水性基质，其中分散有亲脂性基质；
c)可选的其他赋形剂。
2、如权利要求1所要求保护的组合物，其中该亲脂性基质由选自如下的化合物组成：不饱和和/或氢化的脂肪酸、它的盐、酯或酰胺，脂肪酸单-、二-或三-甘油酯，蜡，神经酰胺，胆固醇衍生物。
3、如权利要求1或2所要求保护的组合物，其中5-氨基水杨酸通过捏和、挤出和/或造粒作用而包容在熔化的亲脂性基质中。
4、如上述权利要求任意一项所要求保护的组合物，其中该亲水性基质由形成水凝胶的化合物组成。
5、如权利要求4所要求保护的组合物，其中该亲水性基质由选自如下的化合物组成：丙烯酸或甲基丙烯酸的聚合物或共聚物、烷基乙烯基聚合物、羟基烷基纤维素、羧基烷基纤维素、多糖、糊精、果胶、淀粉与衍生物、藻酸、天然或合成的树胶。
6、如上述权利要求任意一项所要求保护的组合物，包含胃耐受性外部包衣。
7、如权利要求6所要求保护的组合物，其中该胃耐受性包衣由甲基丙烯酸聚合物或纤维素衍生物组成。
8、如上述权利要求任意一项所要求保护的组合物，呈片剂、胶囊剂、微型片剂的形式，其中该活性成分被完全包含在该亲脂性基质内部。
9、如权利要求1至7任意一项所要求保护的组合物，呈片剂、胶囊剂、微型片剂的形式，其中该活性成分被分散在该亲水性基质与该亲脂性基质中。
10、如上述权利要求任意一项所要求保护的组合物，其中该活性成分占全体组合物重量的百分比为80至95％。
11、权利要求1-10组合物的制备方法，包括：
a)至少一部分活性成分与熔点低于90℃的亲脂性赋形剂的熔化造粒；
b)将步骤a)颗粒与亲水性赋形剂混合，随后制片或压制。
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| JP2829794B2 (ja) * | 1991-02-08 | 1998-12-02 | エスエス製薬 株式会社 | 徐放性経口投与型プラノプロフェン製剤 |
| JPH0624962A (ja) * | 1992-07-09 | 1994-02-01 | Green Cross Corp:The | 腸溶徐放性製剤 |
| EP0665010B1 (en) * | 1992-10-16 | 2002-09-11 | Nippon Shinyaku Company, Limited | Method of manufacturing wax matrices |
| US5911980A (en) * | 1996-06-27 | 1999-06-15 | Macrochem Corporation | Lipophilic and amphiphilic or hydrophilic film-forming polymer compositions, and use thereof in topical agent delivery system and method of delivering agents to the skin |
| AU5775398A (en) * | 1996-12-17 | 1998-07-15 | Poli Industria Chimica S.P.A. | Site-specific controlled release dosage formulation for mesalamine |
| US5851555A (en) | 1997-08-15 | 1998-12-22 | Fuisz Technologies Ltd. | Controlled release dosage forms containing water soluble drugs |
| DK1183014T3 (da) * | 1999-06-14 | 2004-02-09 | Cosmo Spa | Smagsmaskerede orale farmaceutiske sammensætninger med kontrolleret frigivelse |
-
1999
- 1999-06-14 IT IT1999MI001316A patent/ITMI991316A1/it unknown
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2000
- 2000-06-08 JP JP2001502815A patent/JP4727875B2/ja not_active Expired - Lifetime
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2001
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2002
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112587506A (zh) * | 2020-12-09 | 2021-04-02 | 南京森博医药研发有限公司 | 一种用于制备美沙拉嗪肠溶缓释胶囊的方法 |
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