CN1248732C - 包含韩蛙皮素类似物的双羟萘酸盐的药物组合物 - Google Patents
包含韩蛙皮素类似物的双羟萘酸盐的药物组合物 Download PDFInfo
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- CN1248732C CN1248732C CNB021593949A CN02159394A CN1248732C CN 1248732 C CN1248732 C CN 1248732C CN B021593949 A CNB021593949 A CN B021593949A CN 02159394 A CN02159394 A CN 02159394A CN 1248732 C CN1248732 C CN 1248732C
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- Prior art keywords
- cetrorelix
- pamoate
- peptide
- acetate
- acid
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Abstract
本发明涉及一种包含韩蛙皮素类似物的双羟萘酸盐的药物组合物，其中盐颗粒大小约5μm到200μm，显示体内持续释放的效果。
Description
本申请是申请号为94194405.0的专利申请的分案申请，其母案的申请日为1994年11月25日，发明创造名称为“长效注射用混悬液及其制备方法”。
本发明涉及长效注射用混悬液，其中包含生理上可接受的，X-衍射呈无定形及结晶的低溶解性的盐类的具有治疗意义的活性肽类，及其制备方法。
在治疗中，肽类通常只能在经非胃肠道的注射给药时才能安全、高效，这是因为经口服给药它们会被酶降解而破坏，而且经鼻给药通常只有很少量的药物能被吸收，而经皮肤给药根本就不吸收。
由于在生物体内肽类仅有很短的半衰期，肽类的非肠道给药剂型，例如LHRH类似物，即所说的超兴奋剂和LHRH拮抗剂，必须被天天使用以达到所希望的疗效，其中包括对LH和FSH抑制剂的两组物质的使用。
其结果是使男性的睾酮生成量和女性的雌二醇生成量下降到一个特定的值之下。可使用术语化学阉割来表示这样的结果。
LHRH类似物被理解为超兴奋剂如戈舍瑞林(INN)或曲普瑞林(INN)，以及拮抗剂如cetrorelix(INN)antide(INN)或ganirelix(INN)。戈舍瑞林和戈舍瑞林的合成公开于Drug of the Future，5(4)1980，p191。布舍瑞林和布舍瑞林的合成公开于Drugs of theFuture，4(3)，1979，p173和Drugs of Today，21，(305)，(1985)。De-capeptyl以及decapeptyl的合成公开于Drugs of the Future，3，(9)，(1978)，p645。Leuprolide和Leuprolide的合成公开于Drugs of theFuture，7(12)，(1982)，p883。
Azaline B公开于GHRH-Analogues-The State ofthe Art(1993)，Parthenon Publishing Groups Ed.，B.Lunenfeld，V.Insler，Pages 13-26。
已有很多人在试图制备具有持续释放效果的长效LHRH类似物制剂。例如，GB2 052 258公开了由肽的锌盐，芝麻油和硬脂酸铝制备的含LHRH类似物质持续释放注射剂。
事实上超兴奋剂和拮抗剂的差异在于，对于超兴奋剂，反馈机理导致在前几周的治疗中与过高激素释放，即所说发作，有关的效果，它必须用另外的药物对抗。相反地，对于拮抗剂，例如，Cetrorelix(INN)，药理作用立即产生并不存在发作机理。持续降低血液中性激素水平通常用于前列腺癌和乳腺癌的缓和治疗中，以抑制依赖于性激素的肿瘤的生长，也可用于治疗子宫内膜异位。从化学的角度讲LHRH-超兴奋剂和拮抗剂为九肽或十肽。
上面提到的一个有效的LHRH拮抗剂是Cetrorelix，氨基酸序列为Ac-Dnal-PpcL-Phe-Dpal-Ser-Tyr-Dcit-Leu-Arg-Pro-D-Ala-NH2的十肽。它的合成和药理性质在EP299402中公开。Cetrorelix乙酸盐已被证明为一生理上可接受的盐。在临床前研究和临床研究中发现Cetrorelix乙酸盐水溶液必须被每日注射，以使睾酮和雌二醇激素水平降到适当范围，直至下次注射。虽然慢性病患者和不在医院治疗的患者设计的一星期给一次药代替每日给药已走出了第一步，但是，可达到阈剂量的作用持续时间却不能被延长。
目前使用的LHRH-类似物为每日使用的水溶性盐的溶液如注射溶液或者每日多次经鼻使用的布舍瑞林乙酸盐滴鼻剂(Supref-act nasal)或那法瑞林乙酸盐滴鼻剂，此剂型至今只在美国上市。如以上所述，这些药剂形式必须被经常地使用。注射剂只能由医生给药，而滴鼻剂一天得用药好几次。这两种药剂形式都很不适合于慢性病的治疗。
DE-05 42 23 282.1描述了通过微胶囊法制备Cetrorelix双羟萘酸盐的持续释放制剂的方法。植入剂是一种用于长时间间隔给药的药剂形式。例如，当植入皮下后，一个包含了戈舍瑞林乙酸盐的可生物降解的聚(乳酸—乙醇酸)共聚物圆柱可有效地降低睾酮水平(Zoladex depot)。每月注射一次含活性物质亮丙瑞林乙酸盐的可生物降解的聚合物颗粒的混悬液也可有效地降低这一时期的性激素水平(Enantone MonatsdepotR)。
两种持续释放剂型将在下面的专利或专利申请中描述。除用药间隔这一优点外，它们的明显的缺点将在下文中列出。
EP 0058 481描述了以ZoladexR商标上市的植入剂的组成与制备。这种剂型的缺点在于使用特需的挤压机和包装机生产此种圆柱体剂型的昂贵的工艺，这些机器将此圆柱体剂型插入到特殊设计的套管很厚的注射器中。这种圆柱体直径为1mm，长度为几个毫米。当植入患者时引起剧痛和淤血，所以需要一种无疼痛的剂型。
EP 0 05 2510描述了例如那法瑞林乙酸盐的微粒体的组成与制备。在氯化烃存在下将活性物质掺入到聚(乳酸，乙醇酸)共聚物中。因为所用的具有体内所需的生物降解性能的聚合物仅溶于氯化烃中，所以氯化烃在该组合物中的使用是不可避免的。用该方法制备的剂型中包含有大量残余溶剂，近似值＝1000ppm，这是其缺点。越来越多的最新研究结果表明，氯化烃有致癌性，根据现行的欧洲药典(Pharm Europe，Vol 4 No.1，March 1992)规定，现在将原料和剂型中的残余溶剂含量限制在＜50ppm。该方法另外的缺点是由于多肽在水相中的损失使实际加入微胶囊的活性物质含量偏低，而此步骤在生产中是必不可少的。
为了药物的安全性，只有用繁琐的后处理方法才能将残余溶剂含量降到该阈值以下。例如，Syntex提出了一种用次临界CO2降低残余溶剂的方法。
DE 4023 134 A1使用了一种如上所述的将肽类掺入聚(乳酸，乙醇酸)共聚物类型的可生物降解的聚合物中的相似方法。在该方法中，使用不溶于水的肽盐代替肽乙酸盐混入聚酯中以减少大量活性物质的损失。不溶于水的肽盐如双羟萘酸盐，硬脂盐和棕榈酸盐。如上面描述过的，这一方法存在必须使用致癌烃的缺点，并且存在含有氯代甲烷或氯仿溶剂这些生理上不接受的残余溶剂的问题。
EP 145 240包含了其它掺加水溶性肽盐的方法。在通过复合乳剂将活性物质水溶液混入可生物降解的聚(乳酸、乙醇酸)共聚物的复杂过程中，活性物质有显著的损失，其缺点还在于使用了氯化烃。
在EP 505 966中，通过含有氯化烃的活性物质一聚合物溶液的喷雾干燥将布舍瑞林乙酸盐嵌入聚(乳酸，乙醇酸)共聚物中。反过来说，此方法有使用致癌的氯化烃作溶剂的缺点。
当使用氯化烃时，不仅药剂中的高残留溶剂量是其缺点，而且，从生态学角度看，就使用这些溶剂本身而言，产生了氯化烃在生产地的处理问题，而且对工人有危险。
根据WO 921 4449，一些易溶解的肽，如生长激素也进行了混合法制备。例如，将活性物质混合入月桂酸中，熔化，并在冷却后将此混合物研磨成100μm的颗粒。US 5,137,669在制备LHRH兴奋剂持续释放剂型时使用了同样的方法，以使这些颗粒以混悬液的形式注射来延缓有效成分的释放。这两种制剂的共同因素是需要长时间释放有效成分的载体物质，并且只能使用繁琐的工艺生产注射剂。直到今天，检验脂肪沉积物的耐药性，及其可靠度和有效成份的再生释放还是不可能的。对于脂肪嵌入物，在以包封物形式给药的部位可产生副作用，这种副作用在长达数年以上的治疗中是无法被耐受的。
由于甲磺酸溴麦角环肽，一种活性成份，很难制成缓释剂型，DE3430852合成了一种新聚酯，如葡萄糖与乳酸和乙醇酸的聚酯，以便达到期望的活性物质的释放分布型。这种情况下需要进行综合的，高成本的开发和毒理学试验以便制备一种有着充足持续作用时间的缓释剂型，因为很明显，没有更简单，更便宜的剂型能达到同样的目的。
双羟萘酸(4，4’-亚甲基-双(3-羟基-2-萘酸)经常用于药物制型中以便制备药物的难溶盐。这些难溶盐在体内滞留时间长，可使药物缓慢释放(Rompps Chemie-Lexikon，Sttuttgart 1976，p.1007)。
根据权利要求1的本发明的制剂可令人惊奇地在不使用可生物降解的聚合物或脂肪时，产生意外的作用时间延长和疗效的提高。不仅仅是由激素抑制时间测得的作用时间的延长，而且还发现肿瘤的生长被抑制到超比例的范围内。
本发明的制剂也可以用于LHRH兴奋剂，如用于Lenprolide布舍瑞林，戈舍瑞林和曲普瑞林。本发明的制剂也可用于韩蛙皮素拮抗剂，生长抑素拮剂剂和GHRH类似物。
按下列程序进行实验：
对DM BA(7，12-二甲基苯并[a]-蒽)诱导的Spragne-Daw-ley大鼠乳腺癌的抑制作用
方法：
雌性Spragne-Dawley大鼠(动物饮食：Altromin R，任意给水)在50天龄，用胃管经口将溶于1ml橄榄油的20mg 7，12-二甲基苯并[a]-蒽给药。每星期触摸动物来监视肿瘤的发展。在诱导后第35天和第70天约90％的大鼠有肿瘤发展，它们适于进行实验。
用Druckry.H，Steinhoff.D.Nakayama，M，Preussmanp，R，Anger，K(1983)，Experimentelle Beitrage zum Dosis-Problem in derKrebs-Chemotherapia und zur Wirkung von Endoxan，[xperimental.Contributions to the doseproblem in cacer chemotherapy and to themode of action of Endoxan]，Dtsoh.Med.Wschr.88：651.的方法测定肿瘤的重量。通过比较触摸法测定的肿瘤重量和直接称重法(切除肿瘤之后)测定的肿瘤重量验证该方法。
相关系数为0.98。当肿瘤的总重量达到约1g后，将动物随机分组，每组7只，分为对照组和处理组。
立即对处理组皮下注射试验药物。
通过使用亚甲蓝染色的阴道细胞涂片的方法测定并通过Jones，T.C，Mohr.U，Hunt，K.D(1972)：The genital，System，in Mono-graphs on Pathology of lakaratory animals sponsored by the Interna-tional Life Science Institute(Springer，N.Y.，London)的方法评价动物的激素状况。
实验结果于图1中列出。未处理的对照组动物的肿瘤重量曲线呈现出无限制的增长。曲线1(*)和2(○)为给以在不同载体中的Cenorelix乙酸盐而处理的结果。拉长的曲线3显示双羟萘酸盐处理后肿瘤重量急剧降低。
由于在此实验中仅单剂量给药治疗，肿瘤继续生长是因为单方药物治疗不能杀死所有肿瘤细胞。
本发明的制剂为十肽Cetrorelix的双羟萘酸盐的X-衍射呈无定形的沉淀物。这种沉淀物的水混悬物，可有选择地含有一些等渗添加剂，比肽的水溶液在动物模型上显现出明显的作用延长。令人吃惊地发现，其作用持续时间大约和包含了肽双羟萘酸盐的沉淀物于如聚(乳酸，乙醇酸)共聚物的可生物降解的聚合物中的注射用混悬液的作用时间相同。此结果的特别意外在于，如上面提出的，直至今日，只有付出复杂劳动制备的将有效成份混合于可生物降解的聚合物中的缓释剂型，才能显现出足够持久的作用时间。
此发现另外使人惊奇的是，根据J.Pharm Phamavol 47，878-883(1985)，嘧啶甲胺，一种2，4-二氨基嘧啶衍生物，在给小鼠皮下注射后，与它的双羟萘酸盐比较，在药物动力学表现，血浆水平过程和AUC方面没有显示出不同。相似地，咪丙嗪盐酸盐在口服给药后没有显现出与咪丙嗪双羟萘酸盐有什么不同(Indian Journal ofPhysiology and Pharmacology 25，(4)，331-338(1989)。正如结晶胰岛素锌混悬液用于治疗糖尿病，非肽药物的结晶注射用混悬液，如强的松龙或去炎松，被认为是缓释剂型。胰岛素包含51个氨基酸。后来所述的这些剂型均为晶体。而X-射线衍射分析显示本发明的剂型为无定型。本发明制剂的粒度均在5μm到200μm之间。粒度在5μm以下的Cetrorelix双羟萘酚盐显示出比本发明制剂差的持续释放作用。类似地，粒度超过200μm的Cetrorelix双羟萘酸盐比本发明的制剂持续释放作用更差。
本发明的制剂的另一优点是：批产物有更高的一致性：用本发明的制剂生产出的药物的质量几乎没有改变。
实施例1
以肽(按游离碱计算)和双羟萘酸的等摩尔比，将含过量碱的双羟萘酸水溶液与Cetrorelix乙酸盐的乙酸溶液合并，出现黄色结晶状双羟萘酸沉淀。再加入稀氢氧化钠溶液使PH值为7-7.5，双羟萘酸溶解并与十肽成摩尔组成为肽∶双羟萘酸2∶1(Mol/Mol)的Cetrorelix双羟萘酸含水盐而沉淀。将该沉淀滤出，用水洗涤并干燥。
实施例2
以等摩尔比将Cetrorlix乙酸盐和双羟萘酸溶于二甲基乙酰胺并将该溶液滴入水中。将肽∶双羟萘酸盐为2∶1(Mol/Mol)的Cetrorelix双羟萘酸盐滤出并干燥。
实施例3
以摩尔比为1∶1.6的比率将Cetrorelix和双羟萘酸溶于二甲基乙酰胺或其含水混合物中，并将该溶液滴入水中。将黄色沉淀滤出并干燥。将所得沉淀用70％乙酸成糊，在35℃干燥并通过80到125μm的筛。
实施例4
以肽∶双羟萘酸为2∶1的摩尔比将碱性双羟萘酸盐溶液加入肽乙酸盐的含水乙醇溶液中。将白色沉淀滤出并干燥。将干燥的沉淀用50％乙醇润湿，在真空干燥箱中干燥并过筛。白色产物含2∶1肽双羟萘酸盐(Mol/Mol)。
实施例5
以肽∶双羟萘酸为1∶1.6的摩尔比将碱性双羟萘酸盐溶液加入肽乙酸盐的含水乙醇溶液中。将黄色沉淀滤出并干燥。将干燥的沉淀用50％乙醇润湿，在真空干燥箱中于35℃干燥并过筛。黄色产物含2∶1肽双羟萘酸盐(Mol/Mol)以及过量的双羟萘酸。
对动物作用期的实验：
以0.5mg cetrorelix/kg体重的剂量对雄性大鼠皮下注射沉淀物的混悬液，之后测量肽对睾酮血浆水平的影响。Cetrorelix的影响为降低睾酮水平。作为参考同时对按照DE 4023134 A1制备的含在聚(乳酸，乙醇酸)共聚物中的肽双羟萘酸盐的注射混悬液进行测试。通过检测Cetrorelix乙酸盐的水溶液确定Cetrorelix的非—持续释放剂型的作用期。
图3显示在对雄性大鼠施用Cetrorelix乙酸盐(D-20761)水溶液后测得的300小时睾酮水平变化过程。施用6小时后达到对睾酮抑制的效果。24小时后仍可在两只动物中测得低于1ng/ml的抑制效果，48小时或两天后仍可在另三只动物中测得同样的抑制效果。
图2显示在以相同剂量对四只动物11-14号施用按实施例1制备的没有粘性添加剂的Cetrorelix双羟萘酸盐(D-20762)混悬液后测得的300小时睾酮水平变化过程。使用6小时后也达到对睾酮抑制的效果，192小时(八天)后有一只动物睾酮水平升至1ng/ml以上，直到第九天其他三只动物仍保持抑制效果。
图4显示用本发明双羟萘酸盐(颗粒大小：80μm-125μm)处理后睾酮水平变化过程。
将图2-3与图4比较即可看出本发明制剂的优点。
Claims (1)
1.一种药物组合物，其包含西曲瑞克的双羟萘酸盐，其中盐颗粒的粒径在5到200μm之间，其特征在于所述的药物组合物不含可生物降解的聚合物或脂肪。
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| CN102665401A (zh) * | 2009-11-16 | 2012-09-12 | 益普生制药股份有限公司 | 黑皮质素受体配体的药物组合物 |
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| US6828415B2 (en) * | 1993-02-19 | 2004-12-07 | Zentaris Gmbh | Oligopeptide lyophilisate, their preparation and use |
| DE69434553T2 (de) * | 1993-12-09 | 2006-08-10 | Zentaris Gmbh | Lang wirkende injektionssuspensionen von lhrh-analogen und ein verfahren für ihre herstellung |
| WO1998032423A1 (en) * | 1997-01-29 | 1998-07-30 | Takeda Chemical Industries, Ltd. | Sustained-release microspheres, their production and use |
| DE10040700A1 (de) * | 2000-08-17 | 2002-02-28 | Asta Medica Ag | Salze von biologisch aktiven Peptiden, ihre Herstellung und Verwendung |
| WO2002047722A1 (fr) * | 2000-12-15 | 2002-06-20 | Takeda Chemical Industries, Ltd. | Compositions medicinales agoniste ou antagoniste de la gonadoliberine non peptidyl, methode de production et utilisation desdites compositions |
| TWI332407B (en) | 2001-06-29 | 2010-11-01 | Takeda Chemical Industries Ltd | Controlled release composition and method of producting the same |
| US7098305B2 (en) * | 2001-09-06 | 2006-08-29 | Ardana Bioscience Limited | Sustained release of microcrystalline peptide suspensions |
| EP1674082A1 (de) | 2004-12-22 | 2006-06-28 | Zentaris GmbH | Verfahren zur Herstellung von sterilen Suspensionen oder Lyophilisaten schwerlöslicher basischer Peptidkomplexe, diese enthaltende pharmazeutische Formulierungen sowie ihre Verwendung als Arzneimittel |
| EP2094246B1 (en) | 2006-12-18 | 2020-04-01 | Takeda Pharmaceutical Company Limited | Sustained-release composition and method for producing the same |
| CN102504018A (zh) * | 2011-10-28 | 2012-06-20 | 沈阳药科大学 | 可持续释放的蜂毒肽帕莫酸盐及其制剂 |
| JP6669932B2 (ja) * | 2016-03-29 | 2020-03-18 | シャンハイ・シナジー・ファーマシューティカル・サイエンシーズ・カンパニー・リミテッド | ボルチオキセチンのパモ酸塩及びその結晶形 |
| CN108969478A (zh) * | 2018-08-29 | 2018-12-11 | 江南大学 | 一种美金刚难溶盐缓释注射剂及其制备方法 |
| CN110003195B (zh) * | 2019-05-21 | 2020-05-26 | 湖北中医药大学 | 鲁拉西酮晶体及其制备方法和在注射给药系统中的应用 |
| CN112569340A (zh) * | 2020-12-31 | 2021-03-30 | 苏州素仕生物科技有限公司 | 一种无菌布舍瑞林注射液及其制备方法和应用 |
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| NZ181036A (en) * | 1975-06-12 | 1978-12-18 | A Schally | Luteinising hormone releasing hormone analogues and intermediates therefor |
| GB2209937B (en) * | 1987-09-21 | 1991-07-03 | Depiopharm S A | Water insoluble polypeptides |
| FR2647677B1 (fr) * | 1989-05-31 | 1991-09-27 | Roussel Uclaf | Nouvelles micro-proteines, procede de preparation et application a titre de medicaments de ces nouvelles micro-proteines |
| CH679207A5 (zh) * | 1989-07-28 | 1992-01-15 | Debiopharm Sa | |
| CH683149A5 (fr) * | 1991-07-22 | 1994-01-31 | Debio Rech Pharma Sa | Procédé pour la préparation de microsphères en matériau polymère biodégradable. |
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- 1994-11-25 NZ NZ277239A patent/NZ277239A/en not_active IP Right Cessation
- 1994-12-07 EG EG77194A patent/EG20787A/xx active
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1996
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- 1996-06-06 FI FI962354A patent/FI116121B/fi not_active IP Right Cessation
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102665401A (zh) * | 2009-11-16 | 2012-09-12 | 益普生制药股份有限公司 | 黑皮质素受体配体的药物组合物 |
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