CN1480217A - 药物制剂及其制备方法与应用 - Google Patents
药物制剂及其制备方法与应用 Download PDFInfo
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- CN1480217A CN1480217A CNA031486223A CN03148622A CN1480217A CN 1480217 A CN1480217 A CN 1480217A CN A031486223 A CNA031486223 A CN A031486223A CN 03148622 A CN03148622 A CN 03148622A CN 1480217 A CN1480217 A CN 1480217A
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- agent
- phosphate
- antibiotic
- salt
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Abstract
本发明涉及微溶于水的抗生素－抗炎药－盐和抗生素－抗炎药的药物制剂及其应用。对微溶于水的抗生素－抗炎药－盐进行了描述。阳离子部分的抗生素选自：庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素或吡甲四环素；阴离子部分的抗炎药选自：布洛芬、萘普生、消炎痛、地塞米松－21－磷酸盐、地塞米松－21－硫酸盐、曲安奈德－21－磷酸盐和曲安奈德－21－硫酸盐。药物制剂中的抗生素－抗炎药－盐用作抗生素－/抗生素长效制剂。对抗生素－抗炎药制剂进行了说明，固态的混合物由至少一种易溶于水的庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素或吡甲四环素等盐，和至少一种易溶于水的布洛芬、萘普生、消炎痛、地塞米松－21－磷酸盐、地塞米松－21－硫酸盐、曲安奈德－21－磷酸盐和曲安奈德－21－硫酸盐等盐，及至少一种无机和/或有机药物助剂形成，并以此制成片剂或模压制剂，用作永久或暂时的植入体。
Description
技术领域
本发明涉及一种药物制剂及其制备方法以及作为人类医学上和兽类医学上治疗和预防细菌局部感染的用途。
背景技术
在人类医学和兽类医学中，在治疗受微生物局部感染的软组织和硬组织时，需要在感染部位局部使用高浓度的抗生素。长期以来，人们都知道抗生素的系统应用存在着许多问题。为了使感染部位获得有效浓度的抗生素，在系统应用时，常常需要使用高剂量的抗生素。尤其在使用氨基甙类抗菌素时会由于抗菌素所致肾中毒和耳中毒而发生严重机体损伤。因此，人们很快就想到采用局部可使用的抗生素缓释体系，或者说，采用适宜的长效药物制剂。众所周知，微生物的局部感染过程是与感染组织的发炎过程密切相关的，这会使有机体的感染导致更多的损伤。因此，在采取制止微生物病原体的局部感染的同时，对发炎过程进行治疗，是十分有益的。
具有抗菌活性的用于治疗局部感染的上述缓释剂是许多专利和出版物的主题。除了吸收作用和扩散过程的物理延缓体系外，可采用一种微溶性的抗生素盐和抗生素复合物的缓释体系。迄今为止，人们对于用氨基糖苷-抗生素、四环素-抗生素和林可胺类-抗生素的难溶盐生产长效制剂不太重视。而制备四环素类抗生素的难溶性盐或复合物在数十年前就已普遍知晓。例如，四环素-氨基磺酸盐(磺胺四环素)早被推广用于抗生素疗法。(A.Jurando Soler，J.M.Puigmarti Codina：Antibiotic tetracycline sulfamate and itsderivatioes(抗菌四环素-氨基磺酸盐及其衍生物)，27.10.1970，US3,536,759；Anonym：Antibiotic tetracycline alkylsulfamates(抗菌四环素-烷基氨基磺酸盐)，16.10.1969，ES 354 173；C.Ciuro，A.Jurado：Stability of atetracycline derivative(四环素衍生物的稳定性)。Afindad 28(292)1971，1333-5)。还有氨基糖苷抗生素的一系列难溶性盐的报道。在制备庆大霉素难溶性盐时，基本上都采用高级脂肪酸、芳烷基羧酸、烷基硫酸盐和烷基磺酸盐(G.M.Luedemann，M.J.Weinstein：Gentamycin and method ofproduction(庆大霉素和生产方法)，16，07，1962，US 3,091,572)。用于制备庆大霉素盐的酸有月桂酸、硬脂酸、棕榈酸、油酸、苯基丁酸、萘-1-羧酸、月桂酰硫酸和十二烷基苯磺酸等。经多次证明这些盐是不利于使用的，因为它们是亲脂性、疏水性的物质，不宜按配方制备药剂。庆大霉素和宜他霉素(Etamycin)的脂肪酸盐是由庆大霉素和宜他霉素的盐与游离碱，在水中50-80℃下合成的。(H.Voege，P.Stadler，H.J.Zeiler，S，Samaan，K.G.Metzger：Sapringly-soluble salts of aminoglycosides and formationscontaining them with inhibited substance-release(易溶性氨基糖苷盐及含有这些盐的缓释物质的形成)28.12.1982，DE 32 48 328)。这些抗生素脂肪酸盐应该适用于作针剂。庆大霉素-十二烷基磺酸盐的制备及其作为药膏和乳剂中的应用也有阐述。(A.Jurado Soler，J.Puigmarti Codina，J.A.OrtizHernandez：Neue Gentamicinderivate，Verfahren zur Herstellung derselben unddiese enthaltende pharmazeutische Mittel(新型庆大霉素衍生物，其制备方法及含有这些衍生物的药物)，21，04，1975，DE 25 17 600)。同样的，还有由林可胺类-抗生素制成的难溶性盐，例如克林霉素棕榈酸盐(M.Cimbollek，B.Nies，R.Wenz，J.Kreuter：Antibiotic-impregnated heart valvescwing rings for treatment and prophlaxis of bacterial endocarditis(注入心脏阀缝合环的抗生素，用于细菌性心内膜炎的预防和感染)，Antimicrob.AgentsChemother.40(6)(1996)1432-1437)。一种新型难溶氨基糖苷-类黄酮-磷酸盐的制备方法也得到了发展，(H.Wahlig，E.Dingeldein，R.Kirchlechner，D.Orth，W.Rogalski：Flavonoid phosphate salts ofaminoglycoside antibiotics(氨基糖苷-类黄酮-磷酸抗生素盐)13，10，1986，US 4,617,293)。它们是氨基糖苷的羟基黄烷、羟基黄烯、羟基黄烷酮、羟基黄酮和羟基黄盐的衍生物的磷酸半酯盐，特别优选的是黄烷酮和黄酮的衍生物。这些难溶性盐应该用于制备长效制剂，例如，使它们进入胶原纤维网。(H.Wahlig，E.Dingeldein，D.Braun：Medicinally useful，shaped mass ofcollagen resorbable in the body(人体可吸收的药用胶原定型物质)22，09，1981，US 4,291,013)。
迄今为止，尚未见到有关微溶于水的抗生素-抗炎药的盐类药物制剂的报道。所述药物制剂是由甾类化合物的抗炎药和非甾类化合物的芳烷基羧酸与至少一种选自庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和吡甲四环素的抗生素制备而成的盐。
发明内容
本发明的任务是提供一种具有延缓释放生物活性物质作用的抗生素-抗炎药复合物，作为人类医学和兽类医学的长效药物制剂，以治疗微生物对骨骼和软组织的局部感染。
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，各从属权利要求给出了优选的实施方案。
庆大霉素(Gentamicin)、克林霉素(C1indamycin)、新霉素(Neomycin)、链霉素(Streoptomycin)、四环素(Tetracyclin)、多西环素(Doxicyclin)、氧四环素(Oxytetracyclin)和吡甲四环素(Rolitetracyclin)是常用的阳离子抗生素，它们的氨基经质子化形成盐，与常见的阴离子，例如，硫酸根离子、氯离子，形成易溶于水的盐。抗炎药布洛芬(Ibuprofen)、萘普生(Naproxen)、消炎痛(Indomethacin)、地塞米松-21-磷酸盐(Dexamethason-21-phosphat)、地塞米松-21-硫酸盐(Dexamethason-21-sulfat)、曲安奈德(Triamcinolon)-21-磷酸盐和曲安奈德-21-硫酸盐所组成的碱式盐都是易溶于水的盐。
上述抗生素与抗炎药形成的复合物能在水环境中控制释放抗生素和抗炎药，使它们在数天内缓慢释放。这种缓释作用的机理基本上与载体物质无关，也与载体物质表面的吸附作用无关。这些抗生素-抗炎药复合物可借助、也可不借助不同结构的吸附助剂加工成植入体。这种高效复合物的特性与复合方法不仅适用于某种特殊抗生素，还可应用于相似结构类型的系列抗生素。
本发明意外地发现，这些复合物的盐都是微溶于水的，它们的代表性抗生素选自：庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和吡甲四环素；抗炎药选自：布洛芬、萘普生、消炎痛、地塞米松-21-磷酸盐、地塞米松-21-硫酸盐、曲安奈德-21-磷酸盐和曲安奈德-21-硫酸盐。
上述复合物的盐由易溶于水的庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和吡甲四环素抗生素盐与易溶于水的抗炎药布洛芬、萘普生、消炎痛、地塞米松-21-磷酸盐、地塞米松-21-硫酸盐、曲安奈德-21-磷酸盐和曲安奈德-21-硫酸盐的碱式盐，通过相互的盐交换而获得的。将溶于水的抗生素盐与溶于水的抗炎药的盐混合，水中就有微溶于水的固态或油状的抗生素-抗炎药-盐沉淀下来。
庆大霉素-布洛芬、庆大霉素-萘普生、庆大霉素-消炎痛、庆大霉素-地塞米松-21-磷酸盐、庆大霉素-曲安奈德-21-磷酸盐、四环素-消炎痛、氧四环素-消炎痛、新霉素-消炎痛、克林霉素-消炎痛、链霉素-萘普生、四环素-萘普生、克林霉素-萘普生、链霉素-布洛芬等盐的应用是非常有益的。
此外，抗生素-抗炎药-盐的模压制剂(Formkrper)、片剂、粉剂、颗粒剂、丝线状剂、针织品状剂、绳状剂和纤维网状剂是十分实用的。本发明适用于作为永久的或暂时的植入体而使用。这就是说这些制成模压制剂、片剂、粉剂、颗粒剂、丝线状剂、针织品状剂、绳状剂和纤维网状剂的抗生素-抗炎药-盐，可以被用作高效活性的组合药物。
这些复合物的盐是形成在模压制剂、粉剂、颗粒剂、丝线状剂、针织品状剂、绳状剂和纤维网状剂上的覆层，并可用作永久的或暂时的植入体。该覆层可由抗生素-抗炎药-盐本身组成，也可由复合物的盐与聚合的覆层形成剂化合而成。
本发明是基于意外发现的结果，即在混合物中出现了固体聚集物。至少一种易溶于水的庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和/或吡甲四环素的盐，和至少一种易溶于水的布洛芬、萘普生、消炎痛、地塞米松-21-磷酸盐、地塞米松-21-硫酸盐、曲安奈德-21-磷酸盐和曲安奈德-21-硫酸盐等的盐，与至少一种无机和/或有机药物助剂形成抗生素复合物的长效制剂。这些复合物可以制成片剂或模压制剂。意外地发现这些片剂和模压制剂在水环境中延缓了药物的释放。这些发现表明，在水环境中片剂、模压制剂通过水的作用形成了微溶于水的抗炎的盐。这就意味着，抗生素-抗炎药-盐的这种有价值的合成方法可以应用于本发明的混合物，用至少一种易溶于水的庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和吡甲四环素的盐，和至少一种易溶于水的布洛芬、萘普生、消炎痛、地塞米松-21-磷酸盐、地塞米松-21-硫酸盐、曲安奈德-21-磷酸盐和曲安奈德-21-硫酸盐的盐，与至少一种无机和/或有机药物助剂形成片剂和模压制剂。这些意外的发现主要是用于制备成本很低的片剂和模压制剂。
具体实施方式
本发明的主题借助下面的非限定性实施例1-5作详细说明。
实施例1
庆大霉素-地塞米松磷酸盐的制备
将150mg庆大霉素硫酸盐(Ak 628)溶于1ml蒸馏水中。另将120mg地塞米松-21-磷酸钠(Fluka)溶于2ml蒸馏水中。随后，将地塞米松-21-磷酸盐溶液滴入到搅拌下的庆大霉素硫酸盐溶液中。此时，可见微粘性的絮状沉淀物沉淀出来。继续滴加地塞米松-21-磷酸盐-钠盐溶液，直至不再有沉淀出现为止。此沉淀固体用蒸馏水洗涤多次并干燥至恒重。
产量：163mg；FP-235℃(分解)；IR(cm-1)：3600-3000(OH)；2943(CH)；2871(CH)；1716(CO)；1664(芳香(Aromat))；1620，1466；1394；1302；1245；1100；983；890；851；529。
实施例2
将1000.0mg硫酸钙·二水合物(Fluka)、250.0mg聚-L-丙交酯(M-10000g/mo1)、49.7mg庆大霉素硫酸盐(Ak-628)和24.9mg地塞米松-21-磷酸钠(Fluka)组成的混合物进行研磨。每次对200mg混合物加5吨压力2分钟，使形成直径13mm的圆形模压制剂。
实施例3
将1000.0mg硫酸钙·二水合物(Fluka)、250.0mg聚-L-丙交酯(M-10000g/mol)、49.7mg庆大霉素硫酸盐(Ak-628)和86.8mg萘普生钠盐(经奈普生(Fluka)中和制备)组成的混合物进行研磨。每次对200mg混合物加5吨压力2分钟，使形成直径13mm的圆形模压制剂。
实施例4
将1000.0mg硫酸钙·二水合物(Fluka)、250.0mg聚-L-丙交酯(M-10000g/mol)、49.7mg庆大霉素硫酸盐(Ak-628)和78.5mg布洛芬-钠盐(经布洛芬(Fluka)中和制备)组成的混合物进行研磨。每次对200mg混合物加5吨压力2分钟，使形成直径13mm的圆形模压制剂。
实施例5
将1000.0mg硫酸钙·二水合物(Fluka)、250.0mg聚-L-丙交酯(M-10000g/mol)、49.7mg庆大霉素硫酸盐(Ak-628)和130.7mg消炎痛钠盐(经中和制备(Fluka))组成的混合物进行研磨。每次对200mg混合物加5吨压力2分钟，使形成直径13mm的圆形模压制剂。
抗生素-缓释试验
将实施例2-5中所制模压制剂放入pH7.4的泽伦森氏缓冲液(Srensen-Puffer)中，在37℃下放置两周。每天取样，更换释放介质。抗生素的释放用琼脂扩散试验进行，应用枯草芽胞杆菌ATCC 6633作试验菌。
表：实施例2-5中所制得的庆大霉素在泽伦森氏缓冲液中，37℃下随放置时间的累计释放(作为庆大霉素碱)
| 实施例 | 庆大霉素的累计释放(作为庆大霉素碱) [mg] | |||||||
| 放置时间[天] | ||||||||
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |
| 2 | 2.80 | 3.22 | 3.46 | 3.60 | 3.74 | 3.83 | 3.90 | 3.95 |
| 3 | 2.08 | 3.05 | 3.61 | 3.86 | 3.90 | 3.92 | 3.93 | 3.93 |
| 4 | 1.64 | 2.03 | 2.36 | 2.71 | 3.20 | 3.40 | 3.59 | 3.82 |
| 5 | 2.83 | 3.22 | 3.31 | 3.34 | 3.34 | 3.45 | 3.45 | 3.45 |
Claims (8)
1.一种药物制剂，其特征是含有一种盐，其代表性阳离子部分选自抗生素：庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和吡甲四环素中的至少一种，其代表性阴离子部分选自抗炎药：布洛芬、萘普生、消炎痛、地塞米松-21-磷酸盐、地塞米松-21-硫酸盐、曲安奈德-21-磷酸盐和曲安奈德-21-硫酸盐中的至少一种。
2.按照权利要求1所述的药物制剂，其特征是含庆大霉素-布洛芬、庆大霉素-萘普生、庆大霉素-消炎痛、庆大霉素-地塞米松-21-磷酸盐、庆大霉素-曲安奈德-21-磷酸盐、四环素-消炎痛、氧四环素-消炎痛、新霉素-消炎痛、克林霉素-消炎痛、链霉素-萘普生、四环素-萘普生、克林霉素-萘普生、链霉素-布洛芬组成的盐。
3.按照权利要求1或2所述的药物制剂，其特征是，所述制剂的剂型为模压制剂、片剂、粉剂、颗粒剂、丝线状剂、针织品状剂、绳状剂和纤维网状剂。
4.按照权利要求1或2所述的药物制剂，其特征是，这些盐是形成在模压制剂、粉剂、粒剂、丝线状剂、针织品状剂、绳状剂和纤维网状剂上的覆层。
5.一种药物制剂，其特征是，这些混合物呈固体状态，含有至少一种易溶于水的庆大霉素、克林霉素、新霉素、链霉素、四环素、多西环素、氧四环素和/或吡甲四环素的盐和至少一种易溶于水的布洛芬、萘普生、消炎痛、地塞米松-21-磷酸盐、地塞米松-21-硫酸盐、曲安奈德-21-磷酸盐和/或曲安奈德-21-硫酸盐以及采用至少一种无机或有机药物助剂并制成片剂和/或模压制剂。
6.权利要求3或5所述的药物制剂的制备方法，其特征是，通过水或含水环境对片剂和/或模压制剂的作用，形成微溶于水的抗炎-抗生素-盐的片剂和/或模压制剂、抗炎药-/抗生素-抗炎药-/抗生素-长效制剂。
7.权利要求1所述药物制剂的用途，用作抗生素-长效制剂。
8.权利要求3至5之任一项所述药物制剂的用途，该制剂被作为永久的或暂时的植入体使用。
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| FR2272680B1 (zh) | 1974-05-29 | 1978-07-21 | Hosbon Sa Lab | |
| DE2843963A1 (de) | 1978-10-09 | 1980-04-24 | Merck Patent Gmbh | Im koerper resorbierbare geformte masse auf basis von kollagen und ihre verwendung in der medizin |
| DE3206725A1 (de) | 1981-05-13 | 1982-12-02 | Merck Patent Gmbh, 6100 Darmstadt | Schwer loesliche salze von aminoglykosidantibiotika |
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| CA2432009C (en) | 2010-09-14 |
| ZA200304797B (en) | 2003-09-18 |
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| US7345024B2 (en) | 2008-03-18 |
| EP1374872A1 (de) | 2004-01-02 |
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| JP2004043464A (ja) | 2004-02-12 |
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| CA2432009A1 (en) | 2003-12-21 |
| EP1374872B1 (de) | 2005-09-28 |
| BR0301707A (pt) | 2004-08-24 |
| DE50301244D1 (de) | 2006-02-09 |
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