CN101137351A - 阿夫唑嗪控释制剂 - Google Patents

阿夫唑嗪控释制剂 Download PDF

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CN101137351A
CN101137351A CNA200680007656XA CN200680007656A CN101137351A CN 101137351 A CN101137351 A CN 101137351A CN A200680007656X A CNA200680007656X A CN A200680007656XA CN 200680007656 A CN200680007656 A CN 200680007656A CN 101137351 A CN101137351 A CN 101137351A
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hpmc
compositions
mixture
alfuzosin
tablet
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V·拉韦利
F·尼克莱
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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
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  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

含有盐酸阿夫唑嗪的固体控释药物制剂及其用于治疗前列腺肥大的用途。

Description

阿夫唑嗪控释制剂
本发明涉及含阿夫唑嗪的控释片形式的固体制剂、其制备方法和其治疗前列腺肥大的用途。
阿夫唑嗪(盐酸盐)是能够对抗α-肾上腺收缩的分子。特别是，阿夫唑嗪及其盐是已知的α-肾上腺受体的强效阻断剂，其选择性作用于尿道。因为阿夫唑嗪作用持续时间短，有必要提供允许一日一次施用确保24h活性成分有效血浆浓度的口服药物形式。
现有技术
已提出了不同的技术解决方案用于解决这一问题，其中之一是
Figure A20068000765600041
技术，由三层片组成，阿夫唑嗪分布在两层中。速释层含有阿夫唑嗪总量中的一部分，第二层含有剩余部分的药物用于提供延长部分的释放，同时第三层作为阻滞阿夫唑嗪释放的屏障层(EP938318)。这一技术允许灵活调控释放动力学，但是有诸如生产成本高、释放动力学难以重现并导致药物血浆水平难于重现的问题，而这是由于制剂中的单个亚成分是由不同机制所确定造成的。
显示“波动”性质的阿夫唑嗪延长释放制剂报道于WO02/06231；所述性质允许较长的胃滞留时间，且因此可能获得释放药物延长时间的体内吸收。
此方法被人们了解已有一段时间，但这一方法不能确保血浆水平的重现性，损害药物的有效性和安全性。这是由于胃排空情况是高度不稳定的，并且依赖于生理-病理状况，即便在同一患者可能亦有所不同。
WO2004/037228涉及仅一层含阿夫唑嗪的一层或多层阿夫唑嗪延长释放制剂。
其他专利申请涉及阿夫唑嗪固体控释制剂，在多数情况下包括具有差异释放和不同的空间分布的多层(参阅例如EP673650和HU9903428)。
发明的公开
现已发现，阿夫唑嗪以药理活性量的每日恒速释放可以通过包含活性成分连同亲水聚合物、聚维酮和乳糖的混合物的片剂的方法获得。
根据发明的亲水聚合物是羟丙基甲基纤维素混合物。所述化合物在水存在下形成溶出/溶蚀速率随着粘度增加而降低的凝胶。有不同粘度的这些聚合物的混合物使调控药物释放速率成为可能，并由穿过水化骨架的扩散和骨架进一步的溶出/溶蚀机制所决定。
根据优选的实施方案，有不同粘度的羟丙基甲基纤维素(HPMC)混合物包含片剂最终重量的5～10％(w/w)HPMC K100(USP定义：Hypromellose型2208；标示粘度100,000cP)、20～35％HPMC K15M(USP定义：Hypromellose型2208；标示粘度15,000c P)和15～25％HPMCK100M(Hypromellose型2910；标示粘度100cP)。含7.87％HPMC K100、19.68％HPMC K100M和27.56％HPMC K15M的制剂是特别优选的。
除了羟丙甲纤维素混合物和阿夫唑嗪以外，本发明的片剂可以包含对调节活性成分释放有贡献的成分，优选地，包含片剂总重1～4％的聚维酮和15～25％的乳糖。
聚维酮允许维持水化骨架内部溶液中高梯度的药物浓度。乳糖因其高水溶度可促进水或消化液迅速进入片剂内部，提供片芯的迅速水合作用，因此在非水化骨架、水化合骨架和周边环境之间形成药物浓度梯度。
在制备步骤期间制剂中还可以加入其他成分，例如稀释剂、润滑剂和膜形成成分。
在本发明的另一个实施方案中，片剂用水不溶的膜形成聚合物包衣，优选乙基纤维素(如，N10和N100)和聚甲基丙烯酸甲酯(如，Eudragit RS)，用量范围为片重的0.5～10％。
依照发明的固体制剂优选地是通过包含以下步骤的方法制备的：
(a)将亲水聚合物、阿夫唑嗪和聚维酮混合；
(b)将(a)步制备的混合物通过14目金属网挤出制粒机湿法制粒；
(c)加入乳糖和特别是稀释剂和润滑剂的任何其他赋形剂至(b)步制备的颗粒混合物；
(d)将(c)步制备的产物压片；且，任选地，
(e)将制得的片剂以用量范围为片重的0.5～10％的水不溶聚合物膜包衣。
使用符合标准的粒度的颗粒能够在骨架内产生阿夫唑嗪浓度梯度，借此浓度梯度在整个溶出过程的持续期间产生渗透压差。
尽管盐酸阿夫唑嗪的溶解度是pH-依赖的，但本发明的片剂显示不依赖于溶出介质pH的溶出特性。
再者，本发明片剂通过易获得的方法和不昂贵的装置易于生产。
本发明的更进一步的方面涉及所述片剂在治疗良性前列腺肥大中的用途。
实施例
将100g盐酸阿夫唑嗪与200g羟丙基甲基纤维素K100、700g羟丙基甲基纤维素K15M和500g羟丙基甲基纤维素K100M混合。
所得混合物与聚维酮溶液捏合，用符合标准的孔径的金属网挤出制粒机制粒，干燥。
所得颗粒与500g乳糖一水合物、500g微晶纤维素、4g微粉硅胶和6g硬脂酸镁混合。
所得混合物用10mm直径圆形冲压制成每片含盐酸阿夫唑嗪10mg的片剂。
片剂可任选用各种膜形成成分包衣用以改善脆碎度和流动性。
片剂可任选用用量范围在片重的0.5～10％的水不溶性聚合物包衣，用以进一步调控体内的溶出模式。

Claims (12)

1.片剂形式的固体药物组合物，其含有盐酸阿夫唑嗪、亲水聚合物、聚维酮和乳糖。
2.根据权利要求1的药物组合物，其中的片剂用不溶性膜形成性聚合物包衣。
3.根据权利要求2的组合物，其中的不溶性膜形成性聚合物以片剂重量的0.5％至10％的量存在。
4.如权利要求1的组合物，其中所述的亲水性聚合物是具有不同粘度等级的羟丙基甲基纤维素(HPMC)。
5.如权利要求4所述的组合物，其含有HPMC K100、HPMC K100M和HPMC K15M的混合物。
6.如权利要求5所述的组合物，其中所述的混合物由5至10％的HPMC K100、15至25％的HPMC K100M和20至35％的HPMC K15M组成。
7.如权利要求6所述的组合物，其中所述的混合物由7.87％的HPMCK100、19.68％的HPMC K100M和27.56％的HPMC K15M组成。
8.如权利要求1所述的组合物，其含有1至4％的聚维酮。
9.如权利要求1所述的组合物，其含有15至25％的乳糖。
10.如权利要求1所述的组合物，还含有选自稀释剂、润滑剂和膜形成剂的赋形剂。
11.根据上述权利要求制备固体组合物的方法，其包含下列步骤：
(a)制备含有亲水性聚合物、阿夫唑嗪和聚维酮的混合物；
(b)将(a)步制备的混合物通过14目金属网挤出制粒机湿法制粒；
(c)加入乳糖和特别是稀释剂和润滑剂的任何其他赋形剂至(b)步制备的颗粒混合物；
(d)将(c)步制备的产物压片；
且，任选地，
(e)将制得的片剂用水不溶、水可渗透性聚合物膜包衣。
12.如权利要求1至10所述的固体制剂用于制备治疗前列腺肥大的药物的用途。
CNA200680007656XA 2005-03-11 2006-03-06 阿夫唑嗪控释制剂 Pending CN101137351A (zh)

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IT000391A ITMI20050391A1 (it) 2005-03-11 2005-03-11 Formulazioni a rilascio controllato di alfuzosin
ITMI2005A000391 2005-03-11

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CN (1) CN101137351A (zh)
IT (1) ITMI20050391A1 (zh)
RU (1) RU2423107C2 (zh)
TR (1) TR200706209T1 (zh)
WO (1) WO2006094736A2 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080095844A1 (en) * 2006-10-23 2008-04-24 Rajhans Sujay Kamalakar Sustained release pharmaceutical compositions of alfuzosin and process for preparation thereof
US20080160081A1 (en) * 2006-12-11 2008-07-03 Mutual Pharmaceutical Company, Inc. Alfuzosin formulations, methods of making, and methods of use
CN101095681B (zh) * 2007-07-13 2011-04-20 沈阳药大制剂新技术有限公司 盐酸阿夫唑嗪渗透泵型控释制剂及其制备方法
CN105287422A (zh) * 2015-12-07 2016-02-03 黑龙江省智诚医药科技有限公司 一种盐酸阿夫唑嗪缓释片及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69704712T2 (de) * 1996-08-29 2001-11-29 Jagotec Ag, Hergiswil Tablette mit gesteuerter freisetzung von alfuzosinhydrochlorid
FR2752737B1 (fr) * 1996-08-29 1998-10-02 Synthelabo Comprime a liberation controlee de chlorhydrate d'alfuzosine
FR2820319B3 (fr) * 2001-02-08 2003-12-05 Ellipse Pharmaceuticals Procede de fabrication d'un comprime flottant incluant de l'alfuzosine et comprime obtenu

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TR200706209T1 (tr) 2007-12-24
RU2423107C2 (ru) 2011-07-10
WO2006094736A2 (en) 2006-09-14
ITMI20050391A1 (it) 2006-09-12
KR20070110068A (ko) 2007-11-15
WO2006094736A3 (en) 2007-01-04

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