CN1480218A - 缓慢释放生物活性物质的药物制剂及其制备方法与应用 - Google Patents
缓慢释放生物活性物质的药物制剂及其制备方法与应用 Download PDFInfo
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- CN1480218A CN1480218A CNA03148624XA CN03148624A CN1480218A CN 1480218 A CN1480218 A CN 1480218A CN A03148624X A CNA03148624X A CN A03148624XA CN 03148624 A CN03148624 A CN 03148624A CN 1480218 A CN1480218 A CN 1480218A
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Classifications
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明涉及一种缓慢释放生物活性物质的药物制剂，该药物制剂由粉末状替考拉宁同至少一种选自庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星的粉末状水溶性盐以及一种无机辅料及/或有机辅料的混合物组成。该药物制剂以片剂、模压制剂、丝状制剂和颗粒剂用作永久植入剂或暂时植入剂。
Description
技术领域
本发明涉及一种缓慢释放生物活性物质的药物制剂，该药物制剂在人类医学及兽医学上可以以可吸收植入体或不可吸收植入体使用，并用于治疗硬组织和软组织中严重局部细菌感染。这种药物制剂尤其可以用来治疗那些由于仅以一种抗生素进行简单局部抗生素治疗而导致产生抗药性的细菌性感染。此外，本发明还涉及该药物制剂的制备方法和应用。
背景技术
人类医学及兽医学中，治疗软组织及硬组织微生物局部感染，要求在感染组织区域内具有高局部抗生素浓度。人们久已悉知，全身使用抗生素会出现一些问题。全身用药时，往往需要使用很大剂量的抗生素，才能使受感染组织中达到有效抗菌的抗生素浓度，尤其在使用氨基甙类抗生素时会由于抗生素所致肾中毒和耳中毒而发生严重机体损伤。因此，比较容易理解的想法是，将抗生素用在局部可采用的输送系统中，或者将其转化成适宜的长效制剂。此外，还可以采用的输送方法是，使局部可采用的输送系统先释放较多的生物活性物质，随后在数天内连续放出较少量的生物活性物质，从而能尽可能地杀灭细菌性病原体。
替考拉宁是一种对革兰氏阳性病原菌有效的糖肽类抗生素。它抑制细胞壁质的合成，从而抑制细菌胞壁横向交联。替考拉宁具有的显著优点是，它与β-内酰胺类抗生素相比，贮藏稳定性显著，而且可用于有青霉素过敏反应的病人。氨基甙类抗生素，例如庆大霉素、卡那霉素及克林霉素，它们都影响细菌的蛋白质合成，因此对许多革兰氏阳性菌、厌氧菌以及部分革兰氏阴性菌都有抑制作用。4-喹诺酮类抗生素，例如环丙沙星和莫西沙星是广谱抗生素，是许多革兰氏阳性菌的拓扑异构酶抑制剂和螺旋酶抑制剂。因此，在治疗上述病原菌所致疾病时，有意义的是将两种在细菌物质代谢中具有不同作用的抗生素联合使用，从而提高有效防治这种病原菌的可能性。
EP 0 611 571公开了一种以干燥状态的形式或者悬浮液形式用于局部用药的缓释药物，其中在一种惰性液态载体中含有水难溶活性物质，其由替考拉宁和另一种具有碱性的药物结合而成的组合物。其中所述的碱性药物有氨基甙类庆大霉素、奈替米星和妥布霉素。该公开说明书要求保护的是替考拉宁与庆大霉素、替考拉宁与奈替米星的难溶混合物，它们以局部可使用的干燥的药物形式或者悬浮液的药物形式来使用。
迄今为止，尚无出版物记载由粉末替考拉宁(Teicoplanin)和选自庆大霉素(Gentamicin)、克林霉素(Clindamycins)、卡那霉素(Kanamycins)、丁氨卡那霉素(Amikacins)、妥布霉素(Tobramycins)、万古霉素(Vancomycins)、莫西沙星(Moxifloxacins)和环丙沙星(Ciprofloxacins)的粉末状水溶性盐和适宜的无机辅料和/或有机辅料组成的混合物制成的药物制剂在含水环境中作为一种缓慢释放生物活性物质的制剂。
发明内容
本发明所要解决的技术问题是要研制一种药物制剂，该药物制剂中含有替考拉宁和其他抗生素，并且该制剂在含水介质中，例如在生理条例下，抗生素可以被缓释数天。
本发明所要解决的技术问题通过各独立权利要求中的必要技术特征来体现，各从属权利要求则给出了更有利的技术特征描述。
本发明赖以为基础的意外发现是，由粉末状替考拉宁和至少一种粉末状庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星的水溶性盐组成的混合物，在适宜的无机辅料及/或有机辅料存在下，在含水环境中为一种缓慢释放生物活性物质的制剂。出乎意料的是，与将替考拉宁和其他抗生素的水微溶加合物用作药物的EP 0 611 571相反，本发明提供的药物制剂不必合成难溶替考拉宁抗生素加合物，而在含水环境中仍然可以延缓抗生素的释放。本发明提供的药物制剂可用药物学常规方法来制造，不必象EP 0 611 571中那样用耗大费用的合成法制造水微溶抗生素盐。此外，本发明提供的药物制剂还适用于替考拉宁和其他抗生素的多重合用。该药物制剂还可用不同于常用的片剂辅料来制造。
本发明优选的是，用碳酸钙、硫酸钙二水合物(石膏)、磷酸三钙和羟磷灰石作无机辅料。
另外，按照本发明，本药物制剂优选的有机辅料是乳酸、羟基乙酸、5-羟基戊酸以及6-羟基己酸及其共聚物的聚酯。
本发明优选的是，该混合物经压制、挤压、纺丝和造粒制成片剂、模压制剂(Formkrper)、丝状制剂和颗粒剂。
此外，还优选的是，将可聚合的甲基丙烯酸酯和由粉末状替考拉宁和至少一种选自庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星的粉末状水溶性盐组成的组合物混合，并聚合成一种模压制剂。按照本发明，可将由甲基丙烯酸酯聚合物构成、含有本发明的由粉末状替考拉宁和至少一种庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星粉末状水溶性盐所组成混合物的球状体、辊状体或者相似于塞透派勒链(Septopal链)的可植入生物活性物质的载体式制剂用于治疗局部感染。除此之外，按照本发明，所述由粉末状替考拉宁及至少一种粉末状庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星以及环丙沙星的水溶性盐组成的混合物可包含骨胶，骨胶固化而成模压制剂。
按照本发明，这种由粉末状替考拉宁同至少一种选自庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星的粉末状水溶性盐构成的混合物，在其固化之前，混入无机磷酸钙-骨胶。按照本发明，加入硫酸钙的上述混合物在硬化后也用于充填骨质缺损。
相宜的是，该混合物是涂布在非金属植入物和金属植入物上的可吸收及/或不可吸收的涂层组分。
本发明提供的缓慢释放生物活性物质的药物制剂可以以片剂、模压制剂、丝状制剂和颗粒剂的形式作为永久植入剂或暂时植入剂而应用。
具体实施方式
下面通过非限定性实施例1至3对本发明作进一步阐明。
实施例1
研磨一种由500.0mg硫酸钙二水合物(Fluka公司产)、125.0mg聚-L-丙交酯(M10000g/Mol)、18.7mg硫酸庆大霉素(AK 628)以及18.7mg替考拉宁组成的混合物。
在5吨压力下，用压力机在2分钟内将各200mg该混合物压制成直径为13mm的圆片形的模压制剂。
实施例2
研磨一种由500.0mg硫酸钙二水合物(Fluka公司产)、125.0mg聚-L-丙交酯(M10000g/Mol)、18.7mg盐酸克林霉素以及18.7mg替考拉宁组成的混合物。在5吨压力下，用压力机在2分钟内将各200mg该混合物压制成直径为13mm的圆片形的模压制剂。
实施例3
研磨一种由1000.0mg硫酸钙二水合物(Fluka公司产)、250.0mg聚-L-丙交酯(M～10000g/Mol)、18.7mg硫酸卡那霉素以及18.7mg替考拉宁组成的混合物。在5吨压力下，用压力机在2分钟内将各200mg该混合物压制成直径为13mm的圆片形的模压制剂。
抗生素释放试验
将实施例1-3中所制的模压制剂置入PH7.4的泽伦森氏缓冲液(Srensen-Puffer)中，并在该缓冲剂中于37℃下放置12天。每天进行取样，并且更换释放介质。用枯草芽胞杆菌(Bacillus subtilis)ATCC6633作试验菌进行的琼脂扩散试验来跟踪模压制剂中的抗生素的释放。用扫描仪和专门结果分析软件计算出抑菌圈直径。结果示如下表。
表：实施例1～3所用试验体中抗生素释放量的微生物琼脂扩散试验结果与37℃泽伦森氏缓冲剂中放置时间的关系。
| 时间[天] | 实施例1 | 实施例2 | 实施例3 | |||
| 稀释 | 抑菌圈直径[mm] | 稀释 | 抑菌圈直径[mm] | 稀释 | 抑菌圈直径[mm] | |
| 1 | 1∶100 | 22.40 | 1∶100 | 20.00 | 1∶70 | 20.35 |
| 2 | 1∶15 | 20.85 | 1∶30 | 20.80 | 1∶5 | 21.15 |
| 3 | 1∶3 | 20.28 | 1∶14 | 19.80 | 未稀释 | 21.45 |
| 6 | 未稀释 | 18.25 | 未稀释 | 21.55 | 未稀释 | 14.20 |
| 9 | 未稀释 | 15.63 | 未稀释 | 18.35 | 未稀释 | 不确定 |
| 12 | 未稀释 | 17.70 | 未稀释 | 21.30 | 未稀释 | 15.25 |
Claims (8)
1.一种缓慢释放生物活性物质的药物制剂，其特征在于，该药物制剂包括由粉末状替考拉宁和至少一种选自庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星的粉末状水溶性抗生素盐以及一种无机辅料及/或有机辅料组成的混合物。
2.如权利要求1所述的缓慢释放生物活性物质的药物制剂，其特征在于，该制剂含有的无机辅料为碳酸钙、硫酸钙二水合物、磷酸三钙及/或羟磷灰石。
3.如权利要求1或2所述的缓慢释放生物活性物质的药物制剂，其特征在于，该药物制剂含有的有机辅料为乳酸、羟基乙酸、5-羟基戊酸和/或6-羟基己酸及其共聚物的聚酯。
4.如权利要求1至3中任何一种所述的缓慢释放生物活性物质的药物制剂，其特征在于，该制剂的剂型为片剂、模压制剂、丝状制剂以及颗粒剂。
5.如权利要求1所述的缓慢释放生物活性物质的药物制剂，其特征在于，将可聚合的甲基丙烯酸酯和由粉末状替考拉宁同至少一种选自庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星和环丙沙星的粉末状水溶性盐组成的混合物混合，并聚合成一种模压制剂。
6.如权利要求1至4中所述的任何一种缓慢释放生物活性物质的的药物制剂，其特征在于，该混合物是涂布在非金属植入物和金属植入物上的可吸收和/或不可吸收的涂层组分。
7.如权利要求1所述的缓慢释放生物活性物质的药物制剂，其特征在于，无机磷酸钙-骨胶和石膏混合物在其固化之前，添加由粉末状替考拉宁和至少一种选自庆大霉素、克林霉素、卡那霉素、丁氨卡那霉素、妥布霉素、万古霉素、莫西沙星及/或环丙沙星的粉末状水溶性盐构成的混合物。
8.如权利要求1至5中所述的缓慢释放生物活性物质的药物制剂以片剂、模压制剂、丝状制剂和颗粒剂的形式作为永久植入剂或暂时植入剂的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006015545A1 (fr) * | 2004-08-11 | 2006-02-16 | Shenzhen Tys R & D Co., Ltd. | Capsule de gelatine de moxifloxacin et procede pour sa preparation |
| CN103977456A (zh) * | 2014-06-05 | 2014-08-13 | 赵全明 | 一种载万古霉素/羟基磷灰石人工关节假体的制备工艺 |
| CN104910259A (zh) * | 2015-06-02 | 2015-09-16 | 苏州纳微科技有限公司 | 一种替考拉宁的层析纯化方法 |
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| US7144857B2 (en) * | 2004-01-15 | 2006-12-05 | Murali Dharan | Vancomycin haemostatic paste composition |
| DE102004060666B3 (de) * | 2004-12-15 | 2006-03-30 | Heraeus Kulzer Gmbh | Antibiotikum/Antibiotika enthaltendes Knochenersatzmaterial mit retardierender Wirkstofffreisetzung |
| GB0618963D0 (en) * | 2006-09-26 | 2006-11-08 | Ucl Business Plc | Formulations and composites with reactive fillers |
| WO2008042228A2 (en) * | 2006-09-28 | 2008-04-10 | Med Institute, Inc. | Medical devices incorporating a bioactive and methods of preparing such devices |
| WO2008042227A1 (en) * | 2006-09-28 | 2008-04-10 | Med Institute, Inc. | Medical device including an anesthetic and method of preparation thereof |
| US20080082038A1 (en) * | 2006-09-28 | 2008-04-03 | Vance Products Incorporated, D/B/A/ Cook Urological Incorporated | Medical Device including a Bioactive in a Non-ionic and an Ionic Form and Methods of Preparation Thereof |
| DE102007063613B4 (de) * | 2007-04-24 | 2010-01-07 | Heraeus Kulzer Gmbh | Verwendung eines Spacer-Polymethylmethacrylat-Knochenzement |
| DE102007029098B4 (de) * | 2007-04-24 | 2010-12-09 | Heraeus Kulzer Gmbh | Spacer-Polymethylmethacrylat-Knochenzement und seine Verwendung |
| US9492374B2 (en) | 2015-03-25 | 2016-11-15 | Jose Rafael Salinas Andrade | Composition and method for treatment of ulcers |
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| US4283799A (en) * | 1979-09-10 | 1981-08-18 | Massachusetts Institute Of Technology | Pre-coated body implant |
| DE3245956A1 (de) * | 1982-12-11 | 1984-06-14 | Beiersdorf Ag, 2000 Hamburg | Chirurgisches material |
| DE4304716A1 (de) * | 1993-02-16 | 1994-08-18 | Melzer Wolfgang | Lokal applizierbares Arzneimittel mit verzögerter Freisetzung |
| DE4433201A1 (de) * | 1994-09-17 | 1996-03-21 | Merck Patent Gmbh | Verfahren zur Herstellung von wirkstoffhaltigen Knochenzementen |
| US6375982B1 (en) * | 2000-07-05 | 2002-04-23 | Capricorn Pharma, Inc. | Rapid-melt semi-solid compositions, methods of making same and method of using same |
| ES2219386T3 (es) | 2000-08-01 | 2004-12-01 | CORIPHARM MEDIZINPRODUKTE GMBH & CO. KG. | Sistema modular de implante que contiene substancia activa y procedimiento para su fabricacion. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006015545A1 (fr) * | 2004-08-11 | 2006-02-16 | Shenzhen Tys R & D Co., Ltd. | Capsule de gelatine de moxifloxacin et procede pour sa preparation |
| CN103977456A (zh) * | 2014-06-05 | 2014-08-13 | 赵全明 | 一种载万古霉素/羟基磷灰石人工关节假体的制备工艺 |
| CN104910259A (zh) * | 2015-06-02 | 2015-09-16 | 苏州纳微科技有限公司 | 一种替考拉宁的层析纯化方法 |
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| CA2432006A1 (en) | 2003-12-21 |
| ES2264505T3 (es) | 2007-01-01 |
| AU2003204859B2 (en) | 2005-08-25 |
| BR0301708A (pt) | 2004-08-24 |
| CA2432006C (en) | 2010-03-16 |
| AU2003204859A1 (en) | 2004-01-15 |
| EP1374854A1 (de) | 2004-01-02 |
| ZA200304799B (en) | 2004-04-29 |
| DE50304336D1 (de) | 2006-09-07 |
| JP2004026827A (ja) | 2004-01-29 |
| DE10227914A1 (de) | 2004-01-15 |
| US7264825B2 (en) | 2007-09-04 |
| EP1374854B1 (de) | 2006-07-26 |
| ATE333865T1 (de) | 2006-08-15 |
| DK1374854T3 (da) | 2006-09-11 |
| PT1374854E (pt) | 2006-11-30 |
| US20040052841A1 (en) | 2004-03-18 |
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