CN108366971A - 具有不依赖于pH释放的软胶囊 - Google Patents
具有不依赖于pH释放的软胶囊 Download PDFInfo
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- CN108366971A CN108366971A CN201680071964.2A CN201680071964A CN108366971A CN 108366971 A CN108366971 A CN 108366971A CN 201680071964 A CN201680071964 A CN 201680071964A CN 108366971 A CN108366971 A CN 108366971A
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- gelatin
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- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
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- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol hydrochloride Natural products C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
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- 239000008158 vegetable oil Substances 0.000 description 1
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular 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
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
公开了软胶囊，其包含明胶壳、增塑剂、水和任选的钙盐和含有分散或溶解的药物的填充剂，其包含具有胶凝力的明胶、水解明胶、甘油、水、果胶和吉兰糖胶。本发明的制剂能够逐步释放活性组分，与pH无关。
Description
本发明涉及用于软胶囊的新制剂，该软胶囊允许以不依赖于pH的方式调节难溶性和水溶性活性组分或其复合物的释放，所述复合物被设计为增加难溶或不溶于水的活性组分的溶解度。
本领域的状态
由软胶囊组成的药物形式用于非结晶、难溶于水的活性组分的施用(主要是口服)。例如，在市场上存在软胶囊形式的孕酮和维生素复合物。
软胶囊由包含增塑的包封填充材料的明胶的壳组成，其通常由液体或半液体亲脂性活性组分、亲脂性活性组分溶液或糊状物组成，所具有的特征使得所述壳不溶。
从EP1315479中已知，在具有胶凝力的明胶壳中包含果胶、吉兰糖胶和氯化钙的硬胶囊在酸性pH下(例如pH 1.2)无法释放活性组分，而在接近中性的pH值(例如pH 6.8)下，它们在几分钟内释放胶囊的全部内容物。EP1315479由此描述了胃保护性胶囊，但未教导具有胶凝力的明胶、果胶、吉兰糖胶和氯化钙的组合能够导致不依赖于pH的可调节的缓释。
发明描述
目前令人惊奇地发现，与来源于现有技术中的教导相反，根据本发明的第一个方面，可以得到新的软胶囊，其允许通过将药物的溶液或混悬液分散于亲水性填充剂中调节和延长活性组分的释放，所述亲水性填充剂由具有凝胶力的明胶、水解明胶、甘油、水、果胶和吉兰糖胶组成。将由此配制的填充剂包封在由明胶、无水甘油、水和任选的氯化钙制成的壳中。
因此，本发明的目的在于软胶囊形式的药物制剂，其包含明胶壳、增塑剂例如无水甘油或其它多元醇、水和任选的钙盐，所述壳包含分散于或溶于亲水性填充剂的药物，所述亲水性填充剂包含具有胶凝力的明胶、水解明胶、甘油、水、果胶和吉兰糖胶。
本发明的制剂有利地适合于难溶性活性组分和水溶性活性组分，并且还适合于难溶或不溶、复合以增加其溶解度的活性组分。例如，所述药物可以为用环糊精包合的形式。
本发明可用的活性组分的实例包括非类固醇抗炎药、甲状腺激素类(左甲状腺素、三碘甲状腺氨酸)、他汀类药物、支气管扩张药、抗组胺药、类固醇及其衍生物、麻醉镇痛药、抗菌药/抗病毒药、维生素、各种类型的油(鱼油、甲壳类动物油、植物油和精油)、糖胺聚糖类、抗真菌剂、质子泵抑制剂、生育激素(FSH、HCG、HMG、LH)、皮质类固醇、勃起功能障碍药物和抗凝血药。
本发明可用的可溶性药物的实例包括盐酸二甲双胍、盐酸普萘洛尔、盐酸雷尼替丁和盐酸地尔硫而本发明可用的一般水溶性的药物(1-100mg/ml)的非限制性实例包括对乙酰氨基酚、帕罗西汀、度洛西汀、坦索罗辛、阿托西汀、氟西汀及其盐。
本发明的制剂中任何情况下都适合于为口服施用设计的任意化合物。
可以将所述药物导入填充剂“照此”，为溶液或乙醇混悬液的形式。
本文的“具有胶凝力的明胶”是指具有Bloom值为60-360、优选60-120的明胶。
本文的“水解明胶”是指已经进行酶消化的明胶。水解明胶可以从商品市场的不同来源得到，并且富含甘氨酸、脯氨酸、羟脯氨酸、赖氨酸和羟赖氨酸。
吉兰糖胶是细菌来源的由重复四糖单元葡萄糖-鼠李糖-葡萄糖-葡糖醛酸形成的无支链聚合物。其用作食品添加剂、化妆品添加剂和药物添加剂，作为乳化剂、增稠剂和稳定剂，并且可以得自不同商品来源。
果胶是包含通过α(1-4)键连接的半乳糖醛酸单元的杂多糖，其羧基部分地为甲酯的形式。将果胶的酯化度定义为酯化基团与总羧基基团之比。
胶囊的壳优选包含20-45％的具有110-300的Bloom值的明胶、15-30％的增塑剂、30-40％的水和任选0.5-5％、优选1-2％的钙盐，优选氯化钙。
所述增塑剂可以优选自多羟基醇，优选自甘油、山梨醇、山梨醇/脱水山梨糖醇混合物、1，2-丙二醇、聚乙二醇200-600及其混合物。
百分比以占总壳重的重量表示。
胶囊填充剂优选包含具有60-150的Bloom值的1-5％的明胶、10-30％的水解明胶、10-30％的85％甘油、1-5％的果胶、至多5％的吉兰糖胶、20-60％的水和0.1％-10％的醇。所述百分比以基于总壳重的重量计。活性组分百分比显然取决于所选择的单位剂量。
本发明允许活性组分以不依赖于pH的方式释放；释放可以通过增加或减少果胶的量及其酯化度并且在水解明胶存在下改变吉兰糖胶的量来调节。释放可以通过向壳中加入氯化钙而得到进一步延长。正如从如下举出的实施例中显而易见的，通过使用在百分比上接近上述指定的区间的最高值的果胶和吉兰糖胶得到更为逐步的释放。
下文的实施例更详细地示例本发明。
实施例1：壳中CaCl2的作用
图1比较了实施例1的制剂与专利EP1315479的实施例1。
图2和3分别显示了在pH 6.8和1.2下在CaCl2存在或不存在下的释放特性。
实施例2：果胶和吉兰糖胶对释放的影响
释放特性比较显示，具有最高果胶和吉兰糖胶含量的制剂导致较为缓慢的释放。结果如图4中所示。
Claims (11)
1.软胶囊，其包含明胶壳、增塑剂、水和任选的钙盐和包含分散的或溶解的药物的填充剂，该填充剂包含具有胶凝力的明胶、水解明胶、甘油、水、果胶和吉兰糖胶。
2.根据权利要求1的胶囊，其中所述活性组分可以通过乙醇或其它亲水性或亲脂性溶剂分散或溶解和/或用环糊精包合。
3.根据权利要求1或2的胶囊，其中所述壳包含氯化钙。
4.根据权利要求1-3的一项或多项的胶囊，其中亲水性填充剂中的明胶具有60-150的Bloom值。
5.根据权利要求1-4的一项或多项的胶囊，其中所述活性组分选自非类固醇抗炎药、甲状腺激素类、他汀类药物、支气管扩张药、抗组胺药、类固醇及其衍生物、麻醉镇痛药、抗菌药/抗病毒药、维生素、各种类型的油、糖胺聚糖类、抗真菌剂、质子泵抑制剂、生育激素、皮质类固醇、勃起功能障碍药物和抗凝血药。
6.根据权利要求1-5的一项或多项的胶囊，其中所述壳包含20-45％的具有110-300的Bloom值的明胶、15-30％的增塑剂、30-40％的水和任选的钙盐，所述百分比基于总壳重。
7.根据权利要求6的胶囊，其中所述钙盐为氯化钙。
8.根据权利要求7的胶囊，其中氯化钙以占总壳重0.5-5％的重量百分比存在。
9.根据权利要求1-8的一项或多项的胶囊，其中所述增塑剂选自甘油、山梨醇、山梨醇/脱水山梨糖醇混合物、1，2-丙二醇、聚乙二醇200-600及其混合物。
10.根据权利要求9的胶囊，其中所述增塑剂为无水甘油。
11.根据权利要求1-10的一项或多项的胶囊，其中所述填充剂包含具有60-150的Bloom值的百分比为1-5％的明胶、10-30％的水解明胶、10-30％的85％甘油、1-5％的果胶、至多5％的吉兰糖胶和20-60％的水，所述百分比以基于总填充剂重量的重量计。
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| PCT/EP2016/078913 WO2017097612A1 (en) | 2015-12-09 | 2016-11-25 | SOFT GELATIN CAPSULES WITH pH-INDEPENDENT RELEASE |
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| CN112826807A (zh) * | 2021-01-29 | 2021-05-25 | 北京航洋健康科技有限公司 | 一种软胶囊囊壳及由其制备的软胶囊及其制备方法 |
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| EP3311844A1 (en) | 2016-10-18 | 2018-04-25 | Altergon S.A. | High-stability packaged solutions of t4 thyroid hormone |
| US11241382B2 (en) | 2019-03-01 | 2022-02-08 | Altergon Sa | Administration regimen of compositions of T4 thyroid hormone with high oral absorption |
| KR20220088898A (ko) * | 2019-10-28 | 2022-06-28 | 알.피.쉐러 테크놀러지즈 엘엘씨 | 더 높은 pH 환경에서의 지연 방출 소프트젤 캡슐 |
| WO2023167803A1 (en) * | 2022-03-01 | 2023-09-07 | Sittner Edward Oscar | Method of manufacture of active ingredient infused gelatin capsule |
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| RU2018120693A (ru) | 2020-01-10 |
| US20180353432A1 (en) | 2018-12-13 |
| US11304910B2 (en) | 2022-04-19 |
| RU2018120693A3 (zh) | 2020-03-04 |
| HK1255969A1 (zh) | 2019-09-06 |
| CA3007592A1 (en) | 2017-06-15 |
| EP3386489A1 (en) | 2018-10-17 |
| ITUB20156821A1 (it) | 2017-06-09 |
| RU2738933C2 (ru) | 2020-12-18 |
| WO2017097612A1 (en) | 2017-06-15 |
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