CN1264514C - 加替沙星的儿科制剂 - Google Patents
加替沙星的儿科制剂 Download PDFInfo
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- CN1264514C CN1264514C CNB02812409XA CN02812409A CN1264514C CN 1264514 C CN1264514 C CN 1264514C CN B02812409X A CNB02812409X A CN B02812409XA CN 02812409 A CN02812409 A CN 02812409A CN 1264514 C CN1264514 C CN 1264514C
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Life Sciences & Earth Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
本发明提供充分味道掩蔽使其能够应用于儿科制剂的喹诺酮抗菌药加替沙星,已经发现加替沙星与硬脂酸和棕榈酸之一或两者以窄重量比的结晶共沉淀可以有效掩蔽加替沙星的苦味。加替沙星在口腔内和含水混悬剂在整个给药周期、特别是14天内的味道被有效掩蔽。发现所结晶共沉淀中的加替沙星在胃内很容易被吸收利用。
Description
参考的相关申请
本申请请求享受2001年6月20日提交的美国临时专利申请系列号60/299,625的权益。
技术领域
本发明涉及适当味道掩蔽的加替沙星(gatifloxacin),使它可以以口服制剂使用,特别是儿科制剂。
背景技术
加替沙星,化学上称作1-环丙基-6-氟-1,4-二氢-8-甲氧基-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉甲酸,用下面结构表示:
加替沙星是一种广谱喹诺酮抗菌药,它公开并授权于美国专利No.4,980,470。美国专利No.5,043,450公开了分离为半水合物的加替沙星。美国专利No.5,880,283公开了加替沙星的倍半水合物结晶形式,它在制药中优于半水合物。无论加替沙星的具体形式,作为典型的喹诺酮类化合物,它具有非常苦的味道。
现已认识到喹诺酮类抗菌药,例如加替沙星,在儿童感染的治疗中具有重要的用途。那些带有苦味的抗菌药非常不利于儿科使用,因为许多儿科制剂是易于给药的液体形式。这样的治疗剂仅可以以液体形式给药,包括由干粉或颗粒组成的那些,如果由它们制备的制剂对儿童患者具有至少一种可按受的味道的话。通常,此类液体制剂是以粉末或颗粒的形式获得,它们由药师在分配时与水混合形成在矫味载体中的混悬液。活性成分此类制剂中的细微粒或颗粒或者必须保持悬浮在液体载体中,或者通过简单振摇容器很容易地重新分散在其中。
上述儿科混悬剂的一个缺点在于,微粒易于悬浮在水载体中,治疗剂的微粒/颗粒非常细小。微粒的细度将非常大的表面积暴露于含水载体。因此,可能出现治疗剂的沥滤,特别是随者时间。无论掩蔽治疗剂味道的结合的机制如何窦可能出现这种现象,例如微囊。除了有效掩蔽治疗剂的味道,所用的结合或包衣方式必须保持颗粒或微粒在口腔中的完整性,因为治疗剂在唾液作用下的任何可感知溶解或沥滤将可能否定该制剂的可接受味感。此外,虽然掩蔽治疗剂味道的方式必须在治疗的正常过程中和在口腔内保持其在载体中的完整性,它必须容易在胃内释放吸收该治疗剂以便达到其功效。
所属领域中已知有许多技术来掩蔽苦味治疗剂的味道。例如,Romanian专利No.88836(公开于1986年3月31日)公开了已知掩蔽缓慢丁酸苦味的方法,该方法暴露与硬脂酸以1∶10的比例、用丙酮作为常规溶剂在不超过40℃的温度下共沉淀。由该产物制备的片剂可咀嚼或悬浮在液体、通常是水中用于给药。许多其他代表性技术集中在可以与苦味活性药物混合、包衣在其上或与其结合的特定味道掩蔽物质。此类物质的实例包括:酸性磷脂或溶血磷脂,EP 0 631 787 B1;生育酚聚乙二醇琥珀酸酯,USP 5,891,469;某些离子交换树脂,WO01/05431 A1;和朴酸,其盐或衍生物,USP 5,808,076,USP 5,622,978公开了二氢吡啶类化合物和聚合物例如聚乙烯吡咯烷酮的无定形共沉淀,其通过分散在水中给药。据称该共沉淀通过使结晶度最小的技术而形成,因为结晶度对生物利用度产生负面作用。
还有许多教导是用蜡质物质包衣苦味药物并由此形成粉末,通常通过喷雾干燥、加入除去助溶剂等。USP 5,405,617公开了一种掩蔽苦味药物的方法,它通过将它与熔融态的硬脂酸硬脂基酯混合且喷雾冻凝形成粉末。欧洲专利申请EP 0 855 183 A2公开了相似的方法,其中可能衍生物预览脂肪酸在30℃-140℃之间混合形成掺混物并且混合直至形成掩蔽其苦味的颗粒为止。在某些情况中,例如加拿大专利中请2,227,314,冷却熔融的混合物固化且随后制粒。在WO98/35656中,苦味药物、脂质和超过填充剂的溶液填充为适当形式,此后通过冷冻干燥或其他方式除去溶剂且由模具中取出所得固体物得到离散的剂量单位。USP 4,865,851公开了通过液体或液体混合物的完整包衣得到的头孢呋乌酯的味道掩蔽制剂。
不考虑所属领域中众多掩蔽苦味药物味道的技术和药物辅料,对于特定药物仍然需要发现有效技术、辅料或其联合。这对于加替沙星来说是这种情形,特别是有关适合儿科给药的制剂。按照本发明提供了这样的制剂。应理解,虽然按照本发明生成的味道掩蔽的加替沙星的实用性重点在于儿科药物,但也适合于制备适合所有由于机体刺激或性能偏爱液体制剂的患者。本发明的味道掩蔽的加替沙星进一步的优点在于,由其制备的液体制剂在正常治疗给药日程中,特别是14天内稳定。
发明概述
按照本发明,提供一种足以掩蔽其天然极苦味道的加替沙星的剂型,使它可以有效地杂儿科制剂中使用。加替沙星与硬脂酸和棕榈酸中的至少一种以严格重量比形成共沉淀。蜡质组分的重量比对于含有它的制剂的味道掩蔽的优越性和稳定性非常重要。本发明进一步涉及一种制备味道掩蔽的加替沙星的方法、含有它的药物制剂及其在多种感染的治疗中的用途。
发明详述
按照本发明,提供了一种广谱抗菌药加替沙星,1-环丙基-6-氟-1,4-二氢-8-甲氧基-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉甲酸,的味道掩蔽形式。
已经证实加替沙星用作广谱抗菌治疗剂。业已证明加替沙星在肝损伤个体的感染治疗中安全且有效。还证明有效抗广谱微生物,包括肺炎链球菌的耐抗生素菌株,并且具有优异的总耐受性。
按照本发明,发现通过加替沙星与硬脂酸和棕榈酸的至少一种以特定重量比结晶共沉淀的形成来有效掩蔽可以加替沙星的特有的极苦味道。文献中报导的加替沙星的结晶形式,即半水合物和倍半水合物,在特性和晶体结构上不同。虽然加替沙星的另一种晶形可以用来制备所述的共沉淀,但优选形式是倍半水合物。本发明的优选共沉淀剂是硬脂酸。已经发现本发明中形成的结晶共沉淀优于加替沙星与硬脂酸、棕榈酸或其混合物结合的其他已知机理,也就是物理特性,包括稳定性,和特别是味道掩蔽性。所述的其他机理包括形成物理混合物,湿法或熔融制粒和加替沙星的微粒用脂肪酸包衣。
除形成加替沙星的味道掩蔽形式的特定机理优于所属领域已知的形成此类组合物的其他方法以外,已经发现硬脂酸和棕榈酸的至少一种在制备味道掩蔽剂型中的使用优于所属领域已知的其他脂肪物质,所属领域技术人员常常考虑这些其他脂肪物质证实在功能上是等同的。此外,本发明发现,与改变一种相对于另一或其他组分的百分比的比例相比,加替沙星与硬脂酸的特别窄重量比才产生最佳作用。虽然已知硬脂酸和棕榈酸用于形成其他治疗剂的味道掩蔽剂型,意外的是本发明形成的加替沙星剂型与利于其他脂肪物质制成的类似形式、通过其他机理或者其中这两种组分以不同重量比存在时对比具有明显的优越性。
按照本发明,加替沙星与选自硬脂酸、棕榈酸及其混合物的脂肪酸形成共沉淀。当该共沉淀由硬脂酸和棕榈酸的混合物形成时,它们是以约1∶5-5∶1的重量比,优选以等重量比使用。优选利于一种脂肪酸,最优选硬脂酸,来形成所述的共沉淀。微粒性能最佳,所述的脂肪酸组分与加替沙星用于形成本发明的共沉淀的重量比在相对窄的范围内变化。通常,在所述的共沉淀中加替沙星与脂肪酸的重量比是约1∶1.8-1∶2.3,首先约1∶2.1。仅就味道的标准考虑,由加替沙星和硬脂酸以1∶0.7-1∶1.4重量比的共沉淀制备的制剂具有由苦至无味的味道,而在1∶2.8和1∶3的重量比制成的那些具有增高的肥皂味。然而,如下所述,虽然味道是所述共沉淀的一个非常重要的特性,但它不是唯一考虑的因素。
所述共沉淀具有意外优秀的性质的事实可以由XRD和NMR研究的论据来解释,上述研究证明由加替沙星和脂肪酸以1∶2.1的重量比形成的共沉淀具有不同于由1∶1.4和1∶2.8的重量比形成的共沉淀的结构。虽然对此的解释不很确凿,但可以由观察结果推断,当加替沙星与脂肪酸的重量比由1∶0.7至1∶2.1时,所得共沉淀的溶解度明显降低。该共沉淀的溶解度对于其掩蔽加替沙星味道的能力非常重要,因为尽管制剂中甜味剂和矫味剂的存在,口腔内任何可感知的溶解作用都可能产生苦味。掩蔽加替沙星在口腔内的苦味的能力对于在儿科药物中的应用特别关键。
本发明的共沉淀优点在于,如上所述,它们事实上不受口腔内的可引起它们溶解、由此产生苦味的因素影响,例如pH和酶。这非常关键,因为加替沙星非常苦。然而,已经发现利于常规矫味和甜味剂可以有效掩蔽本发明的共沉淀溶解下释放到口腔内的加替沙星。本发明的结晶共沉淀的显著和意外的优点在于,由此形成的水混悬剂在正常条件下保存整个给药周期,通常至多为14天,不会溶解达到任何实质程度。这是一个显著的优越性,因为医生通常推荐其患者完成抗菌药的整个治疗周期以防止感染复发的可能性。如果产品在放置时随时间解离达到矫味/甜味剂不再能够掩蔽苦味治疗剂如加替沙星的固有苦味的程度时,所得的不适味道可能使患者无法完成医嘱的给药周期,特别是如果患者为儿童时。
如上所述,为了有效,掩蔽指定治疗剂的苦味的方法不但必须有效掩蔽味道且保持其在口腔内和整个典型给药周期内的完整性,而且必须容易使该治疗剂释放在胃中以便于吸收。利用所述口服混悬剂的加替沙星干燥制剂进行的溶解研究,在0.1N盐酸中为40mg/mL,pH1.2,显示出在10分钟内加替沙星100%释放。此外,利用所述口服混悬剂的加替沙星干燥制剂进行的对比临床口服生物利用度研究在40mg/mL下证实该混悬剂的加替沙星的生物利用度是400mg片剂的99%。
本发明的加替沙星和脂肪酸的共沉淀的制备首先是将主要成分溶解在适当溶剂中,并且加热来实现完全溶解。得到溶液的优选溶剂是低分子量醇,首选乙醇。通常,加替沙星和脂肪酸组分分散在溶剂中且将所得分散体加热至回流温度,一般约80℃,脂质所有固体全部溶解。实现溶解加入的溶剂的量通常足以形成浓度在约5%-10%(重量)之间的溶液,优选在约6.5%-8%(重量)。虽然较大量的溶剂可以用来形成溶液,但优选这些相对高浓度的加替沙星,这不但出于经济上的显见原因,而且使晶体生长最大化且在后续操纵中易于处理,如下所述。
一旦获得所述共沉淀的成分的溶液,保持加热在回流温度,即约80℃且轻轻搅动,即搅拌,2-3小时,优选约2-2.5小时。随后在控制的温和搅动下使该溶液缓慢冷却至约18℃达到结晶出共沉淀。所谓“缓慢冷却”是指在约2.5-4小时的时间内达到冷却。这种表示平均冷却速度大约每分钟0.25℃-0.4℃作为克服大规模处理设备典型特征的惯性的选择性方法,该溶液可以较快速地冷却至不低于45℃的温度,并且随后缓慢冷却,如上所述。
在上述冷却步骤中,结晶的启动通常特征在于在恢复冷却之前约4-8分钟的时间内出现若干度的温和放热。对于预期结晶共沉淀的所得浆液的最佳晶体生长和后续处理来说重要的是,该溶液的搅动(即搅拌)速度足够温和,使这些获得,即结晶的启动和温和放热,是在约32℃-35℃的温度下发生。以高速搅动将使结晶的启动和温和放热在高达42℃下引发,导致该浆液非常难以处理且具有不良的味道特性。在所属领域普通技术人员的职权范围内应考虑溶剂用量、冷却速率和搅拌的速度的多个参数的操纵是高于完成结晶启动和方式的最佳温度的约束内。
由上面的讨论可以理解,回流和缓慢冷却步骤在获得所述晶体共沉淀的预期味道掩蔽性质上非常重要。在冷却步骤中形成的所述晶体共沉淀的浆液保持在约15℃-20℃内同时继续温和搅拌2-18小时,优选2-4小时,并且真空过滤除去共沉淀。滤器上残留的湿滤饼在真空下于不超过30℃烘干。
在另一方法中,一旦所述共沉淀的成分的溶液形成并按照上述方法加热回流,所得溶液可以直接处理以除去溶剂,由此引发结晶。这种干燥处理可以在烘箱、超过锅或旋转蒸发器或其他类似装置内进行。烘箱中除去溶剂所有的温度通常在约40℃-50℃之间,而在常规旋转蒸发器中的温度可以略高,例如50-60℃。出于经济的显见原因和避免溶剂处理问题,过滤和干燥装置优选安装有最大可能回收溶剂的装置,使溶剂可以在加工中重新利用。
此后干燥的共沉淀被粉碎为适合使微粒悬浮且定期再分散在含水载体中的粒度范围。通常,考虑0.5-2.0mm的平均粒度范围,同时优选0.75-1.0的粒度范围。分散可以在任何安装有适当筛来控制所得微粒大小的常规设备。根据本发明优选该结晶共沉淀首先被粉碎为上述适当大小且随后在它们与赋形剂混合之后第二次粉碎。
含有加替沙星和脂肪酸的结晶共沉淀的制剂通过加热常规药用矫味和甜味剂来制备存在于含水裁体中的混悬剂。此外,所述的制剂可以含有药学可接受防腐剂、稳定剂、着色剂、湿润剂等。此类试剂的实例包括:作为防腐剂,对羟基苯甲酸甲酯,对羟基苯甲酸丙酯等;作为湿润剂,聚乙二醇200硬脂酸酯,十二烷基硫酸钠,聚山梨酯80等;作为助悬/稳定剂,黄原胶,微晶纤维素,羧甲基纤维素钠,羟丙基纤维素等;作为甜味剂,糖精钠,天冬甜素,木糖醇,蔗糖等;和作为矫味剂,香草,焦糖甜味加强剂(caramel sweet tone),巴西可可等。此类制剂在所述组合物中一般以制造商推荐的常规量使用。考虑所述的矫味、甜味和赋形剂将占最终干燥制剂的约75-90,优选约75-85%(重量)。
含有所述共沉淀和矫味、甜味和赋形剂的制剂充分混合在一起,并且如上所述,优选再次经粉碎装置以确保最终制剂的均匀粒度。随后将它们包装在适当容器中。容器可以是大尺寸的以容纳适量的水来形成共沉淀的混悬剂且可以进一步用含有必要量的纯水的第二容器来包装。所述颗粒的制剂和包装使由此形成的混悬剂通过加入推荐体积的水将提供每5mL汤匙200mg的加替沙星的剂量。该剂量可以改变,例如,用于形成混悬剂,其通过滴管分配以在指定数的液滴或1mL的部分中校准提供预定量的加替沙星。
应理解,在本发明的实施中许多其他实施方式和改变方案对于所属领域的普通技术人员来说在不脱离上述本发明的范围和实质下是显而易见的,并且容易进行。所以,所附权利要求书的范围不应局限在上述具体描述中,而是权利要求书由包括所有代表本发明可专利新颖性的特征构成,包括相关领域技术人员视作等同的所有特征和实施方式。本发明进一步参考下列试验工作说明。
实施例1
加替沙星-硬脂酸结晶共沉淀(1∶2.1重量)的制备
安装有机械搅拌器(57mm特氟龙桨式叶轮)的机械搅拌器、冷凝器、加热套和冷却浴的3颈500mL反应器中加热12.776g的加替沙星倍半水合物(31.85mM,1当量)和27.225的硬脂酸(95.71mM,3.0当量),向其中加热240.0mL的乙醇,95%USP。将该混合物加热并搅动达到完全回流(~80℃)以溶解固体。将所得溶液加热回流并搅拌2.0小时。使该溶液以0.25℃/分钟的冷却浴速度并轻轻搅动(80rpm)缓慢冷却至18℃。全部结晶需要约4小时且当溶液达到32.5℃时固体变得清晰可见。在结晶启动时,在约5分钟的时间内浴温由32.5℃上升至35℃。温和放热后,结晶过程的典型,冷却恢复到所需温度。将该浆液继续在18℃下混合2小时,此后搅动速度增加至约300rpm达约1分钟以最大达到批次均一性和稠度。真空下在带有Whatman#4滤纸的7cm布氏漏斗上过滤该浆液。反应器仅用回收母液漂洗以除去其中的固体。通过真空抽吸很好除去湿滤饼且随后用30-in Hg真空在30℃(最大)下烘干直至KF的含水量达到等于或小于1.5%的值。收率为37.15(36.59g修正,29.78mM,93.4%)的硬脂酸-加替沙星结晶共沉淀,KF含水量为1.5%w/w。
实施例2
用于口服混悬剂的加替沙星干燥制剂的配制
用于口服混悬剂的加替沙星干燥制剂,66.1mg/g。
组分 | 量/kg |
加替沙星-硬脂酸共沉淀(1∶2.1重量比) | 216.7gA |
木糖醇 | 165.2g |
天冬甜素 | 99.1g |
喷干人造巴西可可矫味剂 | 1.9g |
矫味剂,含有5%的二氧化硅的Creamde Vanilla Powder(天然和人造) | 6.9g |
微晶纤维素和羧甲基纤维素钠(Avicel RC-591) | 2.8g |
对羟基苯甲酸甲酯 | 2.3ag |
对羟基苯甲酸丙酯 | 0.3g |
二氧化钛 | 5.4g |
蔗糖 | 499.4g |
A216.7g的加替沙星-硬脂酸共沉淀等同于66.1g的加替沙星,基于100%纯度计。
将所有组分很好并以约25RPM掺混约10分钟以形成预混物,随后其通过安装有0.61mm筛的Fitzmill.将碾磨的物质转移回混合器并再次在约25RPM下混合约10分钟。将计算量的最终混合物填充到适当大小的高密度聚丙烯(HDPE)瓶中。例如,将63.7g的干燥制剂填充到200mLHDPE瓶中,当用46mL水构建时得到含有40mg的加替沙星/mL的105mL混悬剂。在14天的时间内测试该混悬剂的味道,该时间代表抗菌制剂的典型给药周期。结果证明该混悬剂的味道特性保持不变并令人满意,表明该混悬剂在保存期内稳定。
Claims (20)
1.加替沙星与选自硬脂酸、棕榈酸及其混合物的脂肪酸的一种结晶共沉淀,其中加替沙星与所述脂肪酸的重量比为1∶1.8-1∶2.3。
2.权利要求1的结晶沉淀,其中加替沙星与所述脂肪酸的重量比是1∶2.1。
3.权利要求1的结晶共沉淀,其中所述的脂肪酸是硬脂酸。
4.权利要求2的结晶共沉淀,其中所述的脂肪酸是硬脂酸。
5.权利要求1的结晶共沉淀,其中所述的脂肪酸是棕榈酸。
6.权利要求2的结晶共沉淀,其中所述的脂肪酸是棕榈酸。
7.权利要求1的结晶共沉淀,其中所述的脂肪酸是硬脂酸和棕榈酸以1∶5-5∶1重量比的混合物。
8.权利要求7的结晶共沉淀,其中该脂肪酸是硬脂酸和棕榈酸等同重量份的混合物。
9.一种用于存在于水中的混悬剂的口服给药的药物组合物,其中含有权利要求1的结晶共沉淀和药学可接受赋形剂。
10.权利要求9的药物组合物,其中该药学可接受赋形剂包括至少一种选自水溶性矫味剂和甜味剂的成员。
11.权利要求9的药物组合物,其中该结晶共沉淀中的脂肪酸是硬脂酸。
12.权利要求9的药物组合物,其中该结晶共沉淀中的脂肪酸是棕榈酸。
13.权利要求9的药物组合物,其中该结晶共沉淀中的脂肪酸是硬脂酸和棕榈酸以1∶5-5∶1重量比的混合物。
14.权利要求9的药物组合物在制备治疗感染的药物中的应用。
15.权利要求10的药物组合物在制备治疗感染的药物中的应用。
16.权利要求11的药物组合物在制备治疗感染的药物中的应用。
17.权利要求14的应用,其中该含水混悬剂含有足够量的所述结晶沉淀来提供其中每5mL含200mg的加替沙星的剂量。
18.一种形成加替沙星与选自硬脂酸、棕榈酸及其混合物的脂肪酸的结晶共沉淀的方法,该方法包括:
a)将加替沙星和所述脂肪酸以1∶1.8-1∶2.3的重量比溶解在醇溶剂中同时加热至回流温度以得到其溶液;
b)回流2-3小时该溶液同时搅拌;
c)在2.5-4小时期间缓慢冷却该溶液至18℃并搅拌以沉淀出加替沙星与所述脂肪酸的结晶共沉淀;
d)继续在2-4小时内保持该结晶共沉淀的所得浆液在15℃-20℃;和
e)回收并干燥该结晶共沉淀。
19.权利要求18的方法,其中该溶液在步骤a)中形成,并且含有加替沙星倍半水合物。
20.权利要求18的方法,其中该脂肪酸是硬脂酸。
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EP (1) | EP1406572A4 (zh) |
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EP2258349B1 (en) | 2004-05-11 | 2014-07-16 | Egalet Ltd. | Swellable dosage form comprising gellan gum |
US7838532B2 (en) * | 2005-05-18 | 2010-11-23 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US8524734B2 (en) * | 2005-05-18 | 2013-09-03 | Mpex Pharmaceuticals, Inc. | Aerosolized fluoroquinolones and uses thereof |
US20070051418A1 (en) * | 2005-09-02 | 2007-03-08 | Rowles Brian A | Multilayer tubes |
TW201010708A (en) * | 2008-06-02 | 2010-03-16 | Intervet Int Bv | Composition comprising an antibiotic and a corticosteroid |
LT2344129T (lt) | 2008-10-07 | 2018-05-10 | Horizon Orphan Llc | Aerozolinės fluorchinolono kompozicijos, skirtos farmakokinetikų pagerinimui |
ES2809177T3 (es) | 2008-10-07 | 2021-03-03 | Horizon Orphan Llc | Inhalación de levofloxacino para reducir la inflamación pulmonar |
RU2563809C2 (ru) | 2009-09-04 | 2015-09-20 | Мпекс Фармасьютикалс, Инк. | Применение левофлоксацина в форме аэрозоля для лечения муковисцидоза |
CN102397552B (zh) * | 2010-09-10 | 2016-06-08 | 广州自远生物科技有限公司 | 一种含喹诺酮类的药物复合制剂及其制备方法和应用 |
CN102397546A (zh) * | 2010-09-10 | 2012-04-04 | 广州自远生物科技有限公司 | 一种用于嗅觉或味觉敏感型动物的药物给药方法 |
BR112015023044A8 (pt) | 2013-03-15 | 2021-09-28 | Melinta Subsidiary Corp | Métodos para tratar infecções em pacientes acima do peso e obesos com o uso de antibióticos |
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US5405617A (en) | 1991-11-07 | 1995-04-11 | Mcneil-Ppc, Inc. | Aliphatic or fatty acid esters as a solventless carrier for pharmaceuticals |
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