CN1188122C - 新制剂 - Google Patents
新制剂 Download PDFInfo
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- CN1188122C CN1188122C CNB008168830A CN00816883A CN1188122C CN 1188122 C CN1188122 C CN 1188122C CN B008168830 A CNB008168830 A CN B008168830A CN 00816883 A CN00816883 A CN 00816883A CN 1188122 C CN1188122 C CN 1188122C
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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
- A61K9/10—Dispersions; Emulsions
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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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
本发明描述了喔尼妙林的改善的盖伦给药形式的制备，该给药形式的特点在于其耐受性良好并且存放稳定。所述的新的给药形式是非水或油性的注射制剂，可以通过就地制备相对不稳定的活性成分的游离碱并随后使其稳定制得。本发明的另一方面涉及所述注射制剂在治疗生产性牲畜或家畜传染病的方法中的用途。
Description
本发明涉及喔尼妙林(valnemulin)的改善的盖伦给药形式的制备方法，该给药形式的特点在于其耐受性良好并且存放稳定。所述的新的给药形式是非水或油性的注射制剂，可以通过就地制备相对不稳定的活性成分的游离碱并随后使其稳定制得。本发明的另一方面涉及所述的油性注射制剂及其在治疗生产性牲畜或家畜传染病的方法中的用途。
在本发明中，喔尼妙林应理解为是指下式I所示的化合物
喔尼妙林记载于EP-0153277中，并在其中的实施例12中做了具体描述。喔尼妙林的商标名为Econor。
已知该化合物在例如口服或胃肠外给药后具有抗菌特性，可在动物卫生领域用于预防或治疗一系列细菌感染。其广谱活性包括Streptococcusaronson、金黄色葡萄球菌、关节炎枝原体、牛生殖道枝原体、公牛枝原体、牛鼻枝原体、枝原体种、犬枝原体、狸猫枝原体、发酵枝原体、鸡枝原体、鸡败血枝原体、A.granularum、人型枝原体、猪鼻枝原体、Actinobacilluslaidlawii、火鸡枝原体、溶神经枝原体、肺炎枝原体和猪肺炎枝原体。
WO98/01127记载了其对于在将动物关在非常狭小的空间中(放养密度增加，例如为了运输的目的，在该情况下动物会处于很高的紧张状态)时可能出现的疾病综合征的优良活性。在该情况下起决定作用的最常见的病原体是猪肺炎枝原体、猪痢疾小蛇菌(以前称为猪痢疾密螺旋体)、Serpulinapilosicoli、Lawsonia intracellularis、鸡败血枝原体、多杀巴斯德氏菌、大叶性肺炎放线杆菌(大叶性肺炎嗜血菌)和副猪嗜血菌，从而呼吸道疾病和其它感染经常一起出现并导致复杂的临床表现。所有的群居动物例如牛、绵羊和猪以及家禽均会感染。
游离形式的喔尼妙林(喔尼妙林碱)相对不稳定，因此主要以其盐、特别是盐酸盐的形式使用。目前在动物卫生领域采用的施用抗生素的方法是注射，因其适于施用控制的单个剂量，从而可以施用针对个体需要而确定的量。这在动物医学领域对于成功地控制多种传染性疾病通常是非常重要。相反，口服给药则不能控制的如此之好，因此在人用药中更为常用。
但是，已经证实大部分家畜、特别是猪对于喔尼妙林盐的含水注射溶液、甚至是油性注射混悬液的耐受性非常差。已经观察到了从轻度皮肤刺激到难以愈合的坏死的损伤。这也是喔尼妙林迄今为止仍主要通过口服应用的原因之一。此外，水溶液通常不能表现出所需的储库作用。另一个问题是喔尼妙林不能以所谓的喔尼妙林碱的游离形式以工业量生产，而是以盐的形式生产，因此一直以盐的形式用于治疗。
但是，对于商业应用，极为需要稳定的、可储存的、油性的并且可耐受的注射制剂。
现已出人意料地发现，可以就地生产喔尼妙林的化学稳定的非水注射制剂并且可以在非水和油性溶剂中稳定。
根据本发明，用于就地生产喔尼妙林游离碱的适宜非水或油性溶剂(i)是肉豆蔻酸异丙酯、甘油或乙二醇或丙二醇与短链至中链的单或二元羧酸的半合成以及合成的酯，例如单、二和三甘油酯(例如中性油或三甘油辛-酸酯)。
为了稳定游离碱，可以向这些溶剂(i)中加入其它的溶剂(ii)，例如中链至长链羧酸(例如乳酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸和油酸等)和一元醇(例如乙醇、正丙醇、2-丙醇等)的酯、1，2-O-异丙叉甘油、甘油、乙醇、N，N-二甲基乙酰胺、苯甲酸苄酯或四甘醇，从而在最终产物中存在溶剂(i)和溶剂(ii)的混合物(iii)。加入溶剂(ii)可以改善盖伦特性。特别优选的溶剂(i)是肉豆蔻酸异丙酯并加入溶剂(ii)苯甲酸苄酯或乙醇。
本发明的一个优选实施方案的特点在于溶剂(i)和(ii)在最终产物中的比例约为70∶15。
如上所述，喔尼妙林的游离碱目前还不能大规模地得到。因此，在下文中描述了一种新的和出人意料的就地制备该游离碱并将其配制成稳定形式的方法。
为此，将0.5至30％(重量)、优选5至10％(重量)的喔尼妙林盐悬浮在浓度为50至99％(重量)的非水溶剂(i)中。向悬浮液中加入适宜的碱性赋形剂并在约50至80℃的温度下搅拌和温和地加热，以就地释放喔尼妙林碱，而游离碱立即溶于溶剂(i)中。
用于就地释放喔尼妙林游离碱的适宜碱性赋形剂是，例如碱金属和碱土金属碳酸盐、碳酸氢盐和氢氧化物或有机胺，例如三乙胺。
该过程完成后，将不互溶的两相(水相和非水相)在约50至80℃的温度下相互分离。该相分离可以借助离心来进行。将分离的非水相(现在含有(I)的游离碱)用水在室温下洗涤数次，然后再次在约50至80℃的温度下进行相分离。然后将非水相用例如真空进行干燥，以除去残余的水和挥发性物质例如有机胺，然后将其与第(ii)组的溶剂或溶剂混合物混和以使其稳定。(ii)的加入改善了制剂的盖伦特性。
为了防止氧化的影响，可向所得到的溶液中加入生理可接受的抗氧剂，例如抗坏血酸的酯、丁基羟基甲苯、丁基羟基苯甲醚、没食子酸丙酯、生育酚或生育酚衍生物等，为了防止微生物的感染，可以加入生理可接受的防腐剂，例如苄醇、氯甲酚、氯丁醇、对羟基苯甲酸的酯、苯氧基乙醇、苯酚和苯酚衍生物、山梨酸等。
将最终的溶液无菌过滤或在最终的容器例如安瓿中灭菌。
因此，本发明实质上包括如下优选的方面：
生产非水注射制剂的方法，所述制剂含有喔尼妙林游离碱作为活性成分，选择性地含有稳定剂以防止氧化的影响，还选择性地含有稳定剂以防止微生物感染，该方法的特征在于，在上述类型(i)的生理可接受的非水溶剂或溶剂混合物中从盐的形式就地生产喔尼妙林游离碱并加入选自上述类型(ii)的另一种溶剂进行稳定。
一个优选的实施方案的特征在于，使上述类型(i)的生理可接受的非水溶剂或溶剂混合物中的0.5至30％(重量)的喔尼妙林盐在温和地加热并加入适宜碱性赋形剂的同时就地释放。
优选使用一种或多种溶剂作为上述类型(i)的非水溶剂或溶剂混合物，它们选自肉豆蔻酸异丙酯、半合成和合成的甘油或乙二醇或丙二醇与短链至中链的单或二元羧酸的酯，中链至长链的羧酸与一元醇的酯。
另一个值得注意的实施方案的特征在于，将喔尼妙林的盐悬浮在浓度为50至99％(重量)的溶剂中，用适宜的碱性赋形剂在温和的加热和搅拌下就地生产喔尼妙林的游离碱。
在该方法的另一种优选形式中，为了在物理上稳定喔尼妙林碱，加入中链至长链的羧酸与一元醇的酯、1，2-O-异丙叉甘油、甘油、乙醇、N，N-二甲基乙酰胺、苯甲酸苄酯或四甘醇作为上述类型(ii)的稳定溶剂。
在优选的实施方案中，溶剂(i)和(ii)在最终产物中的比例约为70∶15。
该方法的一个特别优选的方式的特征在于，将喔尼妙林的盐悬浮在溶剂或溶剂混合物(i)中，向悬浮液中加入适宜的碱性赋形剂并在约50至约80℃的温度下进行搅拌和温和地加热以就地释放喔尼妙林碱，所形成的游离碱被该溶剂(i)吸收；该过程结束后，将不互溶的两相(水相和非水相)在约50至约80℃的温度下相互分离；将分离出的非水相(现在含有(I)的游离碱)用水在室温下洗涤数次，然后再次在约50至80℃的温度下进行相分离；然后将非水相干燥并除去挥发性成分，然后将其与第(ii)组的溶剂或溶剂混合物混和以使其稳定。
本发明的另一个目的是含有喔尼妙林游离碱作为活性成分的油性的、稳定的注射制剂，该制剂可以通过以上描述的释放和稳定方法之一制得。本发明还包括所述的油性注射制剂在治疗生产性牲畜或家畜传染病的方法中的用途。
制剂实施例
实施例1：注射制剂
每100mL制得的注射制剂含有5g喔尼妙林碱。在圆括号前给出的克数(制剂1：90.0g，制剂2：85.0g，制剂3：86.0g)是肉豆蔻酸异丙酯、乙醇和苯甲酸苄酯的混合物密度不同的结果。在制剂中给出两个数字的原因是成分以克来称量的，但测出的是体积的量(ml)。
| 制剂1 | g |
| 喔尼妙林 | 5.0 |
| 苯甲酸苄酯 | 15.1 |
| 肉豆蔻酸异丙酯 | 69.9 |
| 90.0(100.0mL) |
| 制剂2 | g |
| 喔尼妙林 | 5.0 |
| 乙醇 | 13.5 |
| 肉豆蔻酸异丙酯 | 66.5 |
| 85.0(100.0mL) |
| 制剂3 | g |
| 喔尼妙林 | 5.0 |
| 肉豆蔻酸异丙酯 | 81.0 |
| 86.0(100.0mL) |
化学稳定性数据
喔尼妙林油性注射液的稳定性(％)：
| 喔尼妙林的含量 | 25℃/60％相对湿度 | 40℃/75％相对湿度 | ||||
| 制剂1 | 制剂2 | 制剂3 | 制剂1 | 制剂2 | 制剂3 | |
| 0个月后 | 99.2 | 99.8 | 98.5 | 99.2 | 99.8 | 98.5 |
| 1个月后 | 99.9 | 99.2 | 98.9 | 99.7 | 100.4 | 98.4 |
| 2个月后 | 100.2 | 100.5 | 100.3 | 99.4 | 100.4 | 99.4 |
| 3个月后 | 101.2 | 102.0 | 99.6 | 100.2 | 101.2 | 100.8 |
| 6个月后 | 101.4 | 100.4 | n.a. | 98.9 | 99.2 | n.a. |
n.a.表示未测定。大于100％的值是由于分析方法的偏差引起的。
所有三种制剂均被证实是化学稳定的。
喔尼妙林盐酸盐的油性混悬液的稳定性(％)：
| 喔尼妙林的含量 | 25℃/60％相对湿度 | 40℃/75％相对湿度 |
| 0周后 | 102.0 | 102.0 |
| 8周后 | 104.8 | 102.8 |
大于100％的值是由于分析方法的偏差引起的。
耐受性数据
通过对猪肌肉内注射注射制剂并评估其对附近组织的影响来进行耐受性的研究。
| 坏死的直径(cm) | ||||
| 制剂1 | 安慰剂 | 制剂2 | 安慰剂 | |
| 颈部区域 | 1 | 0 | 4 | n.a. |
| 大腿 | 1 | n.a. | 3 | 5 |
将制剂与安慰剂进行了比较。结果证实两种制剂并未显示出明显比安慰剂差的耐受性。
Claims (9)
1.生产非水注射制剂的方法，该制剂含有
(a)喔尼妙林游离碱作为活性成分；
(b)选择性地含有一种稳定剂以防止氧化的影响，并且
(c)还选择性地含有一种稳定剂以防止微生物感染；
该方法包括在生理可接受的非水溶剂或溶剂混合物(i)中从盐的形式就地生产喔尼妙林游离碱并通过加入另一种溶剂(ii)使其稳定，其中所述溶剂(i)选自肉豆蔻酸异丙酯、半合成和合成的甘油或乙二醇或丙二醇与短链至中链的单或二元羧酸的酯、中链至长链的羧酸与一元醇的酯，所述溶剂(ii)选自中链至长链的羧酸与一元醇的酯、1，2-O-异丙叉甘油、甘油、乙醇、N，N-二甲基乙酰胺、苯甲酸苄酯或四甘醇。
2.权利要求1所述的制备方法，其中所述中链至长链的羧酸选自乳酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸和油酸。
3.权利要求1所述的制备方法，其中所述一元醇选自乙醇、正丙醇和2-丙醇。
4.权利要求1所述的制备方法，其中，使生理可接受的非水溶剂或溶剂混合物(i)中的0.5至30％(重量)的喔尼妙林盐在温和地加热并加入适宜碱性赋形剂的同时就地释放出所述游离碱。
5.权利要求1所述的制备方法，其中使用一种或多种溶剂作为非水溶剂或溶剂混合物(i)。
6.权利要求1至5中任意一项所述的制备方法，其中，将喔尼妙林的盐悬浮在浓度为50至99％(重量)的溶剂中，用适宜的碱性赋形剂在温和的加热和搅拌下就地生产喔尼妙林的游离碱。
7.权利要求1至5中任意一项所述的制备方法，其中，溶剂(i)和(ii)在最终产物中的比例约为70∶15。
8.权利要求1至5中任意一项所述的制备方法，其中，将喔尼妙林的盐悬浮在溶剂或溶剂混合物(i)中，向悬浮液中加入适宜的碱性赋形剂并在50至80℃的温度下进行搅拌和温和地加热以就地释放喔尼妙林碱，所形成的游离碱被该溶剂(i)吸收；该过程结束后，将不互溶的两相，水相和非水相，在50至80℃的温度下相互分离；将分离出的含有喔尼妙林的游离碱的非水相用水在室温下洗涤数次，然后再次在50至80℃的温度下进行相分离；然后将非水相干燥并除去挥发性成分，然后将其与第(ii)组的溶剂或溶剂混合物混和以使其稳定。
9.喔尼妙林游离碱在制备用于治疗生产性牲畜或家畜传染病的非水注射制剂中的用途。
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| CN101744799B (zh) * | 2008-12-12 | 2012-01-11 | 北京大北农科技集团股份有限公司 | 一种兽用沃尼妙林及其盐的脂质体新剂型及其制备方法 |
| CN101947203A (zh) * | 2010-10-14 | 2011-01-19 | 郑州后羿制药有限公司 | 一种兽用盐酸沃尼妙林乳剂及其制备方法 |
| CN103288694B (zh) * | 2013-06-28 | 2015-06-17 | 宁夏泰瑞制药股份有限公司 | 一种截短侧耳素类合成衍生物盐的晶体制备方法 |
| CN103483232B (zh) * | 2013-09-25 | 2015-05-13 | 宁夏泰瑞制药股份有限公司 | 一种盐酸沃尼妙林的精制方法 |
| CN103520099A (zh) * | 2013-10-30 | 2014-01-22 | 王玉万 | 含有效成份为沃尼妙林的长效注射剂 |
| CN103705454B (zh) * | 2014-01-07 | 2016-08-31 | 王玉万 | 含盐酸沃尼妙林/泊洛沙姆407的油质注射剂 |
| CN104689324A (zh) * | 2014-07-30 | 2015-06-10 | 王玉万 | 含亲水性治疗药物可乳化油质注射剂的制备方法 |
| CN104311464A (zh) * | 2014-09-15 | 2015-01-28 | 河北威远动物药业有限公司 | 一种兽用沃尼妙林的制备方法 |
| KR102098289B1 (ko) * | 2018-04-11 | 2020-04-07 | 경북대학교 산학협력단 | 발네물린을 유효성분으로 함유하는 골 질환 예방 또는 치료용 조성물 |
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| DK1235566T3 (da) | 2005-06-20 |
| EP1235566B1 (en) | 2005-03-23 |
| ES2240232T3 (es) | 2005-10-16 |
| AR029777A1 (es) | 2003-07-16 |
| US20010021693A1 (en) | 2001-09-13 |
| DE60018967D1 (de) | 2005-04-28 |
| ZA200204460B (en) | 2003-09-03 |
| EP1235566A2 (en) | 2002-09-04 |
| PT1235566E (pt) | 2005-08-31 |
| AU769857B2 (en) | 2004-02-05 |
| MXPA02005705A (es) | 2002-09-18 |
| ATE291422T1 (de) | 2005-04-15 |
| DE60018967T2 (de) | 2006-03-23 |
| CN1409631A (zh) | 2003-04-09 |
| WO2001041758A2 (en) | 2001-06-14 |
| KR20020064335A (ko) | 2002-08-07 |
| JP2003516352A (ja) | 2003-05-13 |
| BR0016262B1 (pt) | 2014-10-21 |
| CA2390047C (en) | 2010-03-16 |
| AU3007701A (en) | 2001-06-18 |
| WO2001041758A8 (en) | 2002-08-29 |
| KR100491464B1 (ko) | 2005-05-25 |
| RU2270676C2 (ru) | 2006-02-27 |
| CA2390047A1 (en) | 2001-06-14 |
| WO2001041758A3 (en) | 2002-03-07 |
| TWI228048B (en) | 2005-02-21 |
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