CN1280492A - 作为药物载体的多孔羟基磷灰石颗粒 - Google Patents
作为药物载体的多孔羟基磷灰石颗粒 Download PDFInfo
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Abstract
一种用于口服给予油脂/油性/粘稠物质和药用活性物质或本身油脂/油性/粘稠的药用活性物质的固体干燥形式的药物传递系统,其特征在于具有大量多孔无机的小颗粒并混合有大量油脂/油性/粘稠物质,具有快速释放的特征,并且涉及制备这种含有油脂/油性/粘性物质的多孔无机颗粒的方法。
Description
发明领域
本发明涉及一种新的口服剂型，它含有多孔无机颗粒并混合有大量油脂、油性或粘性(油脂／油性／粘性)物质，并且其中新剂形具有干燥的特征并且易于制备和具有释放快的特性。
发明背景
在很多治疗区域，需要将吸收促进剂(如Pharmacia在WO95／00152中所描述的用于增加肝素或肝素片段或衍生物吸收的甘油酯)，加溶剂(如AB Hassle在EP 0249587中所描述的用于非洛地平的聚乙氧基化的氢化蓖麻油)，悬浮剂(如Sanofi在美国专利5，597，582中所描述的用于1，2，4-苯并三嗪氧化物的豆油或分馏的椰子油)等加到药物剂型中用于改善药物释放。
很久以来就已经知道，将大量这类物质加到药物剂量形式中引起技术问题。获得可药用的容易处理和应用或在以后步骤中应用的干燥物质是其中的一个问题。
早期解决该问题的方法包括将油脂、油性或粘性物质填充到软明胶胶囊中，如US 5 589 455(Han Mi Pharm．)中所描述的，其中公开了软明胶胶囊充填物的精选，包括环孢菌素和用于改善生物利用度的油性组分。
这些年来，很多研究者描述了使用很多小颗粒(多单位)作为剂型时，其体内行为，特别是它们在胃排空性方面的好处，例如，参见Bogentoft等人，J．Clin．Pharmacol．1978，14，351-5。
在上述发现的思路上，解决该问题的另一种方法是使用微囊化技术。然而，这种方法是昂贵的，因为其中包括许多步骤并且也常常存在扩大规模的问题。如Luzzi在J．Pharm．Sci．，1970，59(10)，1367-76中描述了该方法。
现有技术
WO 94／23703(Kabi Pharmacia AB)公开了制备多孔纤维素基料的方法和包含多孔纤维素基料颗粒的含有生物活性物质的多单位制剂。
然而，该文献中既没有涉及油脂、油性或粘性物质的操作问题也没有涉及无机基料。
EP 294206(Unilever NV)公开了多孔球状二氧化硅，它具有某些特性，即含有高至50％重量的二氧化硅，其中包括诸如治疗剂的材料。然而，该文献既没有涉及油脂、油性或粘性物质的操作问题也没有表明具有快速释放的特性。
发明描述
已经发现了一种以固体干燥形式给予油脂、油性或粘稠物质和药用活性物质或者本身是油脂、油性或粘稠的药用活性物质的药物传递系统，其特征在于具有与大量油脂、油性或粘稠物质混合的小粒径的多孔无机颗粒并且具有可克服现有技术缺陷的快速释放特性。
因此，本发明提供一种新的将油脂、油性或粘稠的材料混合在小颗粒中的剂型制备方法，使得制备多单位系统成为可能。为了实现该发明目的，已经发现使用高度多孔的无机颗粒是有利的。
本发明的一个特征是小粒径的多孔颗粒。粒径在5-150μm之间，优选为20-100μm。
本发明的另一特征是大量的油脂、油性或粘稠物质。本说明书中的大量意指15％w／w到40％w／w，优选20％w／w到40％w／w，最优选30％w／w到40％w／w。
混合的油脂、油性或粘稠物质可以是但不限于药用活性物质，如阿莫兰特或维生素A；本身不油脂、油性或粘稠但与油脂、油性或粘稠物质在一起的特别适于混入制剂的药用活性物质如非洛地平、melagatran或inogatran；吸收增强剂是油脂、油性或粘稠的并且选自单、二或三甘油酯或其混合物，如AkolineMCM、Imvitor 308，Imvitor 742，Imvitor 928，Imvitor 988，辛酸甘油酯；加溶剂如半固体或液体的非离子表面活性剂，如含有作为酯或醚形式的聚乙二醇的，并且选自聚氧乙基化的脂肪酸、羟基化的脂肪酸和脂肪醇并且特别是选自聚氧乙基化的蓖麻油、聚氧乙基化的氢化蓖麻油(Cremophors)、来自蓖麻油的聚氧乙基化的脂肪酸或来自氢化蓖麻油的聚氧乙基化的脂肪酸并且商品名称作Cremophor、Myrj、Polyoxol40硬脂酸酯、Emerest2675、Lipal395和HCO50。
本发明的药物传递系统也具有快速释放的特征，在体外进行溶出试验时，30分钟或更短的时间内，释放不低于药用活性物质和油脂／油性／粘稠物质或药物(药物为油脂、油性或粘稠的物质时)的60％(优选70％w／w)。
对于油脂、油性或粘稠的物质来说，用USA设备No．2(桨式装置)测定溶出速度，在100rpm转速下操作。溶出介质的温度为37℃。对溶出介质的量和溶出技术还有要求，即对于所试验的整个剂量来说，要求能够将所释放的油脂、油性或粘稠的物质非延迟性均匀地分布在介质中。
对实施例所显示的具体的油脂、油性或粘稠的物质来说，各实施例中所公开的介质是适宜的。
对于药物来说，用USA设备No．2(桨式装置)测定溶出速度，在100rpm转速下操作。溶出介质的温度为37℃。对溶出介质的量和溶出技术还有要求，即对于所试验的整个剂量来说，要求能够将所释放的药物非延迟性均匀地分布在介质中(分布条件)。
对实施例所显示的具体药物来说，各实施例中所公开的介质是适宜的。
应该注意到，对于一种和相同的制剂来说，可根据所测试物质的性质，即在制剂中是否含有油脂、油性或粘稠的物质和药学活性物质并根据测试这些物质中的哪一个来选择不同的溶出介质。
本发明所用的无机多孔颗粒是无机非金属的羟基磷灰石。
无机非金属羟基磷灰石具有颗粒直径范围在5-150μm之间，优选20-80μm、正常孔径在5-100μm之间，优选50-100μm并且表面积在40-50m2／g之间的特征。如从BIO-RAD实验室以Macro-Prep为商品名称可购得无机非金属羟基磷灰石。
多孔颗粒的装载
可通过常规的已知方法完成油脂、油性或粘稠材料与颗粒的混合。一种方法是将油状物质溶于合适的溶剂，然后与多孔颗粒材料混合并干燥。另一种方法是，将油状物直接与多孔颗粒材料混合。再一种方法是通过非溶剂的加入来使含有颗粒的溶液产生相分离。
颗粒的孔隙率为50-70％(v／v)，优选62％(v／v)。
在用于药物传递系统时，装载的多孔颗粒可被直接使用或填充在胶囊中、压成片剂或通过本领域已知的方法包衣。应当以快速释放特征基本上不被改变的方式进行胶囊的填充、压片或包衣。如果需要在小肠中快速释放，装载的多孔颗粒可进行肠包衣。
操作实施例
实施例1
含非洛地平和19．5％CremophorRH40的羟基磷灰石颗粒。将油脂／油性物质CremophorRH40(312mg)在大约30℃温度下熔化并将非洛地平(88mg)溶解在其中。在轻轻手工搅拌下，将所得溶液倾倒在1200mg的具有平均直径80μm的羟基磷灰石颗粒(Macro-Prep无机非金属羟基磷灰石；BIO-RAD实验室)上，并且混合继续进行直到均匀。
利用USP溶出装置No．2(桨式装置)，在100rpm转速下操作，分析所得颗粒中非洛地平的溶出情况。所使用的温度为37℃的溶出介质是含0．4％溴化十六烷基三甲基铵的磷酸盐缓冲液，pH 6．5。通过UV-光谱测定法测定释放的非洛地平的量。
30分钟后，所溶出的非洛地平的量为实测含量的84％(平均值，n=2)。
实施例2
含melagatran和37％Akoline的羟基磷灰石颗粒。
将油脂／油性物质Akoline(779mg)在大约30℃温度下熔化并将melagatran(21mg)溶解在其中。在轻轻手工搅拌下，将所得溶液倾倒在1200mg的具有平均直径80μm的羟基磷灰石颗粒(Macro-Prep无机非金属羟基磷灰石；BIO-RAD实验室)上，并且混合继续进行直到均匀。
利用USP溶出装置No．2(桨式装置)，在100rpm转速下操作，分析所得颗粒中AkolineMCM和melagatran的溶出情况。所使用的温度为37℃的溶出介质是加有2mM卵磷脂和5mM牛磺胆酸盐使样品均匀溶出的磷酸盐缓冲液，pH 6．8。通过液相色谱层析分离样品成分。使用光散射检测器测定Akoline的释放量并通过UV-光谱测定法测定melagatran的释放量。
20分钟后，所溶出的AkolineMCM的量为实测含量的71％(平均值，n=2)。所溶出的melagatran的量为实测含量的94％(平均值，n=2)。
实施例3
含17．4％阿莫兰特的羟基磷灰石颗粒。
将油脂／油性物质阿莫兰特(0．6g，室温)在轻轻手工搅拌下，倾倒在1200mg的具有平均直径80μm的羟基磷灰石颗粒(Macro-Prep无机非金属羟基磷灰石；BIO-RAD实验室)上，并且混合继续进行直到均匀。
利用USP溶出装置No．2(桨式装置)，在100rpm转速下操作，分析所得颗粒中阿莫兰特的溶出情况。所使用的温度为37℃的溶出介质是磷酸盐缓冲液，pH 6．8。通过UV-光谱测定法测定阿莫兰特的释放量。
30分钟后，所溶出的阿莫兰特的量为实测含量的100％(平均值，n=2)。
实施例4
含17．4％阿莫兰特的羟基磷灰石颗粒。
将油脂／油性物质阿莫兰特(0．35g，室温)在轻轻手工搅拌下，倾倒在1．7g的具有平均直径80μm的羟基磷灰石颗粒(Macro-Prep无机非金属羟基磷灰石；BIO-RAD实验室)上，并且混合继续进行直到均匀。
利用USP溶出装置No．2(桨式装置)，在100rpm转速下操作，分析所得颗粒中阿莫兰特的溶出情况。所使用的温度为37℃的溶出介质是磷酸盐缓冲液，pH 6．8。通过UV-光谱测定法测定阿莫兰特的释放量。
30分钟后，所溶出的阿莫兰特的量为实测含量的80％(平均值，n=2)。
实施例5
将实施例1所得颗粒填充在3号大小的硬明胶胶囊中。每个胶囊填充190mg的非洛地平／羟基磷灰石颗粒。
Claims (9)
1、一种干燥的固体药物传递组合物，该组合物含有：
(ⅰ)至少一种油脂、油性或粘稠的物质和至少一种药用活性物质，或者
(ⅱ)至少一种油脂、油性或粘稠的药用活性物质，
其特征在于所述组合物为大量多孔无机颗粒的形式，所述颗粒包含直径为5-150μm的无机非金属羟基磷灰石，所述组合物具有快速释放的特征并且混合有15wt％-40wt％的组分(ⅰ)或(ⅱ)。
2、权利要求2的药物传递系统，其中羟基磷灰石的直径为20-80μm。
3、上述任一权利要求的药物传递系统，其中药用活性物质的分子量小于1000道尔顿。
4、上述任一权利要求的药物传递系统，其中药用活性物质是凝血酶抑制肽药物。
5、上述任一权利要求的药物传递系统，其中药用活性物质是melagatran。
6、权利要求1-3的药物传递系统，其中药用活性物质为非洛地平。
7、权利要求1-3的药物传递系统，其中药用活性物质为阿莫兰特。
8、一种制备干燥的固体药物传递组合物的方法，该方法包括：
(ⅰ)至少一种油脂、油性或粘稠的物质和至少一种药用活性物质，或者
(ⅱ)至少一种油脂、油性或粘稠的药用活性物质，
其特征在于将15wt％-40wt％的组分(ⅰ)或(ⅱ)和包含直径为5-150μm的无机非金属羟基磷灰石的大量多孔无机颗粒混合。
9、大量多孔无机颗粒在制备具有快速释放特征的干燥的固体药物传递组合物中的用途，所述颗粒包含直径为5-150μm的无机非金属羟基磷灰石，并且混合有15wt％-40wt％的下列组分：
(ⅰ)至少一种油脂、油性或粘稠的物质和至少一种药用活性物质，或者
(ⅱ)至少一种油脂、油性或粘稠的药用活性物质。
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| GB9924334D0 (en) * | 1999-10-15 | 1999-12-15 | Secr Defence | Pharmaceutical products and methods of fabrication therefor |
| CN100450483C (zh) * | 2000-04-11 | 2009-01-14 | 三共株式会社 | 含有钙阻滞剂的稳定药物组合物 |
| IT1319202B1 (it) | 2000-10-12 | 2003-09-26 | Nicox Sa | Farmaci per le malattie a base infiammatoria. |
| US6462021B1 (en) | 2000-11-06 | 2002-10-08 | Astrazeneca Ab | Use of low molecular weight thrombin inhibitor |
| US7479502B2 (en) | 2002-12-03 | 2009-01-20 | Pharmacyclics, Inc. | 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors |
| KR101207553B1 (ko) | 2005-06-02 | 2012-12-03 | (주)씨앤팜 | 금속 이중층 수산화물을 포함하는 생체 주사제용 약물 담체 |
| TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
| TW200806648A (en) * | 2005-11-29 | 2008-02-01 | Sankyo Co | Acid addition salts of dihydropyridine derivatives |
| JP5027410B2 (ja) * | 2005-12-13 | 2012-09-19 | 株式会社サンギ | ユビキノン含有組成物 |
| US8287914B2 (en) * | 2006-01-12 | 2012-10-16 | Rutgers, The State University Of New Jersey | Biomimetic hydroxyapatite synthesis |
| US20100040668A1 (en) * | 2006-01-12 | 2010-02-18 | Rutgers, The State University Of New Jersey | Biomimetic Hydroxyapatite Composite Materials and Methods for the Preparation Thereof |
| GB0909460D0 (en) | 2009-06-02 | 2009-07-15 | Intrinsiq Materials Global Ltd | Mesoporus material |
| ES2908958T3 (es) | 2013-02-01 | 2022-05-04 | Grace W R & Co | Gel de sílice porosa como portador para tecnologías líquidas |
| AU2014322985B2 (en) * | 2013-09-20 | 2019-05-16 | Tillotts Pharma Ag | Delayed release pharmaceutical formulation |
| CN104133014B (zh) * | 2014-07-16 | 2015-09-16 | 广州法尔麦兰药物技术有限公司 | 一种考察布洛伪麻缓释制剂释放度的方法 |
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| GB8413191D0 (en) | 1984-05-23 | 1984-06-27 | Beecham Group Plc | Pharmaceutical composition |
| GB8713263D0 (en) | 1987-06-05 | 1987-07-08 | Unilever Plc | Spheroidal silica |
| EP0376331A3 (en) | 1988-12-29 | 1991-03-13 | Asahi Kogaku Kogyo Kabushiki Kaisha | Slow release drug delivery granules and process for production thereof |
| US5149523A (en) * | 1989-06-20 | 1992-09-22 | Aktiebolaget Hassle | Polystyrenesulfonate-drug complex and solid dosage forms thereof |
| NL9100105A (nl) * | 1991-01-23 | 1992-08-17 | Kuil R A Holding | Voedingssupplement. |
| US5443459A (en) * | 1991-01-30 | 1995-08-22 | Alza Corporation | Osmotic device for delayed delivery of agent |
| US5834496A (en) * | 1991-12-02 | 1998-11-10 | Sepracor, Inc. | Methods for treating hypertension using optically pure S(-) felodipine |
| US5947893A (en) * | 1994-04-27 | 1999-09-07 | Board Of Regents, The University Of Texas System | Method of making a porous prothesis with biodegradable coatings |
| US6096324A (en) * | 1995-06-13 | 2000-08-01 | Laboratory Skin Care | Methods of delivering materials into the skin, and compositions used therein |
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| ID24700A (id) | 2000-08-03 |
| AU752044B2 (en) | 2002-09-05 |
| EP1032370B1 (en) | 2003-12-17 |
| WO1999027912A1 (en) | 1999-06-10 |
| ES2210840T3 (es) | 2004-07-01 |
| US6558703B1 (en) | 2003-05-06 |
| AU1356399A (en) | 1999-06-16 |
| IL136146A0 (en) | 2001-05-20 |
| NZ504353A (en) | 2001-10-26 |
| SK6602000A3 (en) | 2001-01-18 |
| DK1032370T3 (da) | 2004-03-15 |
| DE69820674T2 (de) | 2004-09-30 |
| JP2001524513A (ja) | 2001-12-04 |
| EP1032370A1 (en) | 2000-09-06 |
| BR9814751A (pt) | 2000-10-03 |
| HUP0100303A2 (hu) | 2001-08-28 |
| SE9704400D0 (sv) | 1997-11-28 |
| PT1032370E (pt) | 2004-05-31 |
| NO20002719L (no) | 2000-07-28 |
| TW524694B (en) | 2003-03-21 |
| NO20002719D0 (no) | 2000-05-26 |
| DE69820674D1 (de) | 2004-01-29 |
| RU2219907C2 (ru) | 2003-12-27 |
| KR20010032557A (ko) | 2001-04-25 |
| HUP0100303A3 (en) | 2004-03-29 |
| CA2311780A1 (en) | 1999-06-10 |
| PL340927A1 (en) | 2001-03-12 |
| AR016683A1 (es) | 2001-07-25 |
| ZA9810463B (en) | 1999-05-21 |
| ATE256453T1 (de) | 2004-01-15 |
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