CN1305371A - 程序化和随时间释放的多颗粒药物剂型及其制备方法 - Google Patents
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Abstract
本发明涉及延迟和计时释放的多种颗粒的药物剂型,该剂型能够在吸收后4到8小时内使得活性成分开始有效,然后在以后的8到20小时逐渐释放全部活性成分。该发明的特征在于它不含有机酸并且它是含药球体形式,该球体由中性球状载体组成,该球状载体含有的第一层包衣是以至少一种水溶性聚合物和至少一种不溶于水的聚合物的混合物为主,在整个混合物中都均匀分布了活性成分组成的颗粒,它们整个含有的第二层包衣是以至少两种不依赖于pH的聚合物为主,这些聚合物对不同的胃肠环境具有不同程度的渗透性,任选在该包衣中分布有至少一种依赖pH的聚合物、至少一种增塑剂和至少一种惰性填充剂。
Description
本发明涉及一种用于口服的程序化和随时间释放的多颗粒药物剂型。本发明也涉及该药物剂型的制备方法。
目前可以得到许多用于口服的延迟释放的药物剂型。由于治疗目的和活性成分的药理特性的缘故，必须控制活性成分的释放。结果，不是总要求血浆速率是恒定的。相反，为了避免任何习性的形成和为了限制由活性成分引起的副作用，血浆速率符合代谢规律和患者在特定昼夜期间的特殊需要是绝对有益的。例如，在些慢性疾病如局部缺血性心脏病、哮喘和关节炎的情况中，为了除去夜间症状或者醒来时的症状，应当按照这样一种方式给药，即仅在需要的时刻，也就是说在睡觉中或刚刚清醒时，达到理想的血浆治疗水平。
在文章“一种用于口服控制释放制剂的有机酸诱发的乙状结肠释放系统”药学研究，第11卷，No.1(1994)中公开了一种药物剂型其中活性成分的释放是乙状结肠型的。但是，在该文章中暗示了只要把有机酸加入药物剂型就能够获得活性成分的乙状结肠的释放。但是，由于有有机酸的存在，这类药物剂型会有刺激作用，这种刺激作用带来了许多缺点，尤其在长期持续治疗中。
所以，目前没有一种不含有机酸的多颗粒的药物剂型能够实现在患者需要的时候达到活性成分的高浓度，同时在整天维持血浆的最小治疗浓度。
申请人现已出人意料地发现获得容易给药并没有刺激作用的药物剂型是可能的。
这样，本发明的药物剂型释放活性成分是延迟的和随时间性的并且能够在吸收后4到8小时内使得活性成分开始有效，然后在以后的8到20小时逐渐释放全部活性成分，本发明的药物剂型特征在于它不含有机酸并且是微颗粒或药物球体形式，该球体由中性球芯组成，该球芯含有的第一层包衣是以至少一种水溶性聚合物和至少一种不溶于水的聚合物的混合物为主，在该混合物中均匀分布活性成分组成的颗粒，整个含有的第二层包衣是以至少两种pH独立的聚合物为主，该聚合物就不同的胃肠环境来说具有一定程度的渗透性，任选在该包衣中分布有至少一种依赖pH的聚合物、至少一种可塑剂和至少一种惰性填充剂。
在包裹中性球芯的包衣中活性成分的浓度是非常高的，该中性球芯使得能够得到体积减小了的含药球体并且由此确定小体积的药物剂型，这种药物剂型更容易和更乐于被患者吸收并且使每个给药单位可给予较高剂量。
按照优选的技术方案，本发明药物剂型的特征在于：活性成分是以包裹中性球芯的包衣重量的20到100％存在的，优选60到90％，并且更优选80到90％。
包裹中性球芯和含有活性成分的包衣部分组分是水溶性聚合物，其选自于下组，尤其是聚乙烯吡咯烷酮、羟丙基甲基纤维素及其混合物，而不溶于水的聚合物选自于下组，尤其是丙烯酸和/或甲基丙烯酸树脂、纤维素聚合物及其混合物。
水溶性聚合物与不溶于水的聚合物的重量比为0.1到0.9，优选0.3到0.7，更优选0.45到0.55。
本发明的第二层包衣是以至少两种不依赖于pH的聚合物为主，就胃肠介质而言，这两种聚合物的渗透速率是相互不同的，任选在该包衣中完全均匀地分布有至少一种依赖pH的聚合物、至少一种增塑剂和至少一种惰性载体。
在第二层包衣中，渗透性最低的聚合物与渗透性最高的聚合物之间的比例为97/3到80/20。
在不同渗透性速率的聚合物之间必需注意这些比例。实际上，当低渗透性的聚合物高于97％时，活性成分的释放太迟缓；相反，当低渗透性的聚合物低于80％时，活性成分的释放不足以延迟。
第二层包衣中的聚合物选自于下组，尤其是丙烯酸和/或甲基丙烯酸树脂、纤维素聚合物及其混合物。
在整个第二层包衣中均匀分布的惰性载体选自于下组，尤其是滑石、无水胶体二氧化硅、硬脂酸镁、甘油单硬脂酸酯及其混合物。
作为第二层包衣部分组分的增塑剂必须是药学上可接受的；它选自于下组，尤其是邻苯二甲酸乙酯、枸橼酸三乙酯、癸二酸二丁酯、甘油三醋酸酯及其混合物。
按照本发明的优选技术方案，活性成分选自于下组，尤其是对心血管系统有活性的分子，更具体地说，是地尔硫和维拉帕米、抗炎药、抗过敏药和抗组胺药。
在睡觉时间服用本发明的药物剂型。
这样，因为在吸收后4到8小时有效成分起效，也就是说，是在患者清醒的时刻，即在心血管意外危险最高的某些症状时刻。
在随后8-20小时规律性地持续释放。
在活性成分全部释放完后几个小时进行下一次给药，患者在整个昼夜中有最小治疗血浆浓度。
按照本发明药物剂型的制备方法，它的特征在于包括下面步骤：
-根据流化床原理，把中性球芯放入正在工作的反应容器中；
-在有机和/或含水溶剂中把悬浮于至少一种水溶性聚合物和至少一种不溶于水聚合物的溶液中的活性成分颗粒喷涂在中性球芯上；
-把包衣悬浮液喷涂在上述步骤获得的包衣颗粒上，其中包衣悬浮液含有至少一种惰性载体，其悬浮于至少两种具有就胃肠介质而言相互不同渗透性的聚合物的混合物溶液中；
-任选干燥所得该含药球体。
实施例
在下列实施例中，使用下列药用赋形剂：-EUDRAGIT RS 100:RHM出售的低渗透性的聚丙烯酸-聚甲基丙烯酸树脂，-EUDRAGIT RL 100:RHM出售的可渗透的聚丙烯酸-聚甲基丙烯酸树脂，-PVP K 90:BASF生产的聚乙烯吡咯烷酮，-AEROSLL:DEGUSSA生产的硅胶，-药用醇，-药用滑石，-SOLVAY生产的邻苯二甲酸乙酯，-由WERNER公司出品的由蔗糖和淀粉组成的中性球芯，-INWITOR 900:由UHLS公司出品的甘油单硬脂酸酯，-EUDRAGIT L 100:RHM生产的以甲基丙烯酸和甲基丙烯酸甲酯为主的树脂。
实施例1
构成本发明药物剂型的含药球体的制备其中活性成分为地尔硫。
把0.7g直径为300到400μm的中性球芯装入GPCG1型空气流化床反应容器中并在这里给该球芯上喷涂含下列组分的悬浮液：
EUDRAGIT RS 100 0.525kg
PVP K90 0.525kg
地尔硫 7.000kg
药用醇 18.760kg。
然后，把包衣混悬液喷涂在由此得到的颗粒上，混悬液含下列组分：
EUDRAGIT RS 100 2.000kg
EUDRAGIT RL 100 0.100kg
邻苯二甲酸乙酯 0.192kg
AEROSIL 0.320kg
药用滑石 0.400kg
药用醇 10.500kg
丙酮 4.500kg。
把这样得到的400到500个含药球体装入传统组成的明胶硬胶囊中。
如下进行活性成分的体外释放试验：
使用带有栏栅的常用溶解测定仪；使用纯化水作溶解介质；溶解测定仪的使用条件是900ml纯化水和100rpm；装入胶囊的量相当于一个治疗单位。
如下测定相对于含在所装胶囊中的活性成分总量所释放的活性成分量(用重量百分比表示)：
从0到第4小时期间每隔1小时进行溶液取样，然后从第4到第16小时每隔2小时进行溶液取样。用带有240nm的UV测定仪的HPLC装置测定样本溶液中释放的地尔硫。
表1中收集了所获得的结果。
表1
实施例2
| 小时 | 溶解的％ |
| 0 | 0 |
| 1 | 0.8 |
| 2 | 2.0 |
| 3 | 3.4 |
| 4 | 5.1 |
| 6 | 11.7 |
| 8 | 40.4 |
| 10 | 88.0 |
| 12 | 99.4 |
| 14 | 100.9 |
构成本发明药物剂型的含药球体的制备其中活性成分为地尔硫
使用含有下列组分的包衣混悬液按照实施例1所述的方法制备含药球体：
EUDRAGIT RS 100 3.060kg
EUDRAGIT RL 100 0.340kg
邻苯二甲酸乙酯 0.340kg
INWITOR 900 0.170kg
异丙醇 14.28kg
丙酮 9.52kg。
按照与实施例1相同的方法，测定溶解度。结果收集在下列表2中。
表2
实施例3
| 小时 | 溶解的％ |
| 0 | 0 |
| 1 | 2.8 |
| 2 | 6.4 |
| 3 | 11.6 |
| 4 | 18.4 |
| 6 | 32.3 |
| 8 | 49.1 |
| 10 | 68.7 |
| 12 | 85.3 |
| 16 | 103.6 |
构成本发明药物剂型的含药球体的制备并且活性成分为地尔硫
使用含有下列组分的包衣混悬液按照实施例1所述的方法制备含药球体：
EUDRAGIT RS 100 3.612kg
EUDRAGIT RL 100 0.638kg
邻苯二甲酸乙酯 0.425kg
INWITOR 900 0.213kg
异丙醇 17.850kg
丙酮 11.900kg。
按照与实施例1相同的方法，测定溶解度。结果收集在下列表3中。
表3
实施例4构成本发明药物剂型的含药球体的制备并且活性成分为维拉帕米
| 小时 | 溶解的％ |
| 0 | 0 |
| 1 | 1.1 |
| 2 | 7.2 |
| 3 | 84.3 |
| 4 | 90 |
| 6 | 92.7 |
| 8 | 94.8 |
| 10 | 94 |
| 12 | 95.1 |
| 14 | 95.1 |
| 16 | 96 |
使用含有下列组分的包衣混悬液用维拉帕米替代地尔硫作活性成分，按照与实施例1相同的方法制备含药球体：
EUDRAGIT RS 100 1.650kg
EUDRAGIT RL 100 0.87kg
EUDRAGIT L 100 0.063kg
邻苯二甲酸乙酯 0.165kg
AEROSIL 0.274kg
滑石 0.343kg
药用醇 9.000kg
丙酮 3.857kg。
按照与实施例1相同的方法，测定溶解度，使用色谱仪在278nm的UV测定释放的维拉帕米。结果收集在下列表4中。
表4
| 小时 | 溶解的％ |
| 0 | 0 |
| 1 | 1.9 |
| 2 | 6.1 |
| 3 | 12.3 |
| 4 | 21.2 |
| 6 | 49.6 |
| 8 | 82.1 |
| 10 | 94.7 |
| 12 | 97.4 |
| 14 | 97.8 |
| 16 | 98.6 |
Claims (9)
1．一种延迟和计时释放的多颗粒的药物剂型，它能够在药物剂型吸收后4到8小时内使得活性成分的药效起作用，然后在之后的8到20小时逐渐释放全部活性成分，其中它不含有机酸并且是含药球体形式，该球体由中性球芯组成，该球芯含有的第一层包衣是以至少一种水溶性聚合物和至少一种不溶于水的聚合物的混合物为主，在整个混合物中都均匀分布了活性成分组成的颗粒，它们整个含有的第二层包衣是以至少两种不依赖于pH的聚合物为主，对胃肠介质来说这些聚合物的渗透率是不相同的，任选在整个包衣中均匀地分布至少一种依赖pH的聚合物、至少一种增塑剂和至少一种惰性载体。
2．按照权利要求1所述的药物剂型，其中活性成分是以包裹中性球芯的包衣重量的20-100％，优选60-90％，更优选80-90％存在的。
3．按照权利要求1所述的药物剂型，其中水溶性聚合物和不溶于水的聚合物重量比是0.1到0.9，优选0.3到0.7，更优选为0.45到0.55。
4．按照权利要求1-3的任何一种所述的药物剂型，其中水溶性聚合物选自于下组，特别是聚乙烯吡咯烷酮、羟丙基甲基纤维素及其混合物，而不溶于水的聚合物选自于下组，特别是丙烯酸和/或甲基丙烯酸树脂、纤维素聚合物及其混合物。
5．按照权利要求1-4的任何一种所述的药物剂型，其中渗透性最低的聚合物与渗透性最高的聚合物之间的比例为97/3到80/20。
6．按照权利要求1到5中任何一个所述的药物剂型，其中第二层包衣的聚合物选自于下组，特别是丙烯酸和/或甲基丙烯酸树脂、纤维素聚合物及其混合物。
7．按照权利要求1到6中任何一个所述的药物剂型，其中均匀分布在整个第二层包衣中的惰性载体选自于下组，特别是滑石、无水胶状二氧化硅、硬脂酸镁、单硬脂酸甘油酯及其混合物。
8．按照权利要求1到7中任何一个所述的药物剂型，其中活性成分选自于下组，特别是对心血管系统具有活性的分子，更具体地说是地尔硫和维拉帕米、消炎药、抗过敏药和抗组胺药。
9．制备权利要求1-8中任何一个所述的药物剂型的方法，它包括：
-根据流化床的原理，把中性球芯到入反应容器中；
-在有机和/或含水溶剂中把悬浮于至少一种水溶性聚合物和至少一种不溶于水的聚合物溶液中的活性成分颗粒喷涂在该中性球芯上；
-在上述步骤得到的包衣颗粒上喷涂包衣混悬液，该包衣混悬液含有悬浮于由至少两种对胃肠介质具有相互不同渗透性的聚合物组成的混合物溶液中的至少一种惰性载体；
-任选干燥所得含药球体。
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| FR98/06384 | 1998-05-20 | ||
| FR9806384A FR2778848B1 (fr) | 1998-05-20 | 1998-05-20 | Forme pharmaceutique multiparticulaire a liberation programmee et pulsee et son procede de preparation |
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| US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
| US9358214B2 (en) | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
| US8367111B2 (en) | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
| EP2112920B1 (en) | 2003-06-26 | 2018-07-25 | Intellipharmaceutics Corp. | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient |
| US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
| US8747895B2 (en) | 2004-09-13 | 2014-06-10 | Aptalis Pharmatech, Inc. | Orally disintegrating tablets of atomoxetine |
| US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
| CA2584957C (en) | 2004-10-21 | 2015-08-25 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
| AU2013273835B2 (en) * | 2005-05-02 | 2016-07-07 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| US9161918B2 (en) * | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
| US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
| WO2008136016A1 (en) * | 2007-05-08 | 2008-11-13 | Medreich Limited | A stable controlled release oral solid dosage form composition and a process thereof |
| SG10201407965XA (en) | 2009-12-02 | 2015-02-27 | Aptalis Pharma Ltd | Fexofenadine microcapsules and compositions containing them |
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| US5567441A (en) * | 1995-03-24 | 1996-10-22 | Andrx Pharmaceuticals Inc. | Diltiazem controlled release formulation |
| FR2754710B1 (fr) * | 1996-10-22 | 1998-12-31 | Prographarm Lab | Procede de preparation d'une forme pharmaceutique multiparticulaire a liberation controlee plurisequentielle |
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