CN111447924A - 二氮杂二环辛烷衍生物的药物形式及其制备方法 - Google Patents
二氮杂二环辛烷衍生物的药物形式及其制备方法 Download PDFInfo
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- CN111447924A CN111447924A CN201880068967.XA CN201880068967A CN111447924A CN 111447924 A CN111447924 A CN 111447924A CN 201880068967 A CN201880068967 A CN 201880068967A CN 111447924 A CN111447924 A CN 111447924A
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Abstract
Description
背景技术
青霉素和头孢菌素是临床广泛且常用的β-内酰胺类抗生素。然而,各种病原体获得的对β-内酰胺类抗生素的抗性对维持细菌感染的有效治疗具有破坏作用。与获得细菌耐药性相关的最重要的已知机制是在活性中心具有丝氨酸残基的A类、C类和D类β-内酰胺酶的产生。这些酶分解β-内酰胺类抗生素,导致抗菌活性丧失。A类β-内酰胺酶优先水解青霉素,而C类β-内酰胺酶具有有助于头孢菌素水解的底物特征。
市售的β-内酰胺酶抑制剂(例如,克拉维酸、舒巴坦和他唑巴坦)是已知的,且这些抑制剂主要对抑制产生A类β-内酰胺酶的细菌有效,并与青霉素抗生素一起作为混合物使用。然而,到目前为止,报道了250种或更多的β-内酰胺酶,包括产生甚至可分解碳青霉烯的A类KPC-2型β-内酰胺酶的耐药菌。
近年来,由上述耐药菌作为病原菌引起的传染病不仅在重大传染病中有发现,在社区获得性传染病中也偶尔有发现。目前可用的β-内酰胺酶抑制剂不足以抑制不断增加的β-内酰胺酶,需要新型β-内酰胺酶抑制剂用于耐药菌引起的难以治疗的细菌性传染病。由于商业可用抑制剂变得越来越无效,亟需抗菌剂以及β-内酰胺酶抑制剂的研发。
其中一种抗菌剂,由化合物(I)表示的(2S,5R)-N-(2-氨基乙氧基)-7-氧代-6-(磺氧基)-l,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺是一种可用于耐抗生素的革兰氏阴性细菌的“有效、广谱、非β-内酰胺β-内酰胺酶抑制剂”(Li,H.;Estabrook,M.;Jacoby,G.A.;Nichols,W.W.;Testa,R.T.;Bush,K.Antimicrob Agents Chemother2015,59,1789-1793.)。先前,(2S,5R)-N-(2-氨基乙氧基)-7-氧代-6-(磺氧基)-l,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺已有四种晶型已进行了表征并被本领域公知(见,例如国际公开号为WO2015/053297的专利申请)。
尽管先前已经表征了其他晶型,但是尚未实现提供良好的可再现性、高稳定性和高产率的大规模制造工艺。当开发用于商业工艺的技术时,当将小规模的实验室工艺转化为适合临床应用的大型生产工艺时,需要考虑若干因素和性质。
在某些方面(如易于制备、稳定性等)是至关重要的情况下,特定的药物组合物可以是优选的。在其它情况下,为了更大的溶解度和/或优异的药代动力学,不同的药物组合物可能是优选的。
发明内容
本申请涉及一种药物组合物和针对表示为(2S,5R)-N-(2-氨基乙氧基)-7-氧代-6-(磺氧基)-l,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(也被称为“化合物(I)”)的二氮杂二环辛烷衍生物的用于静脉输液的冻干物、及其生产方法。还描述了通过给予所述药物组合物治疗细菌感染的方法:
一方面,本申请提供了一种药物组合物,其包括由化合物(I)表示的化合物的冻干物和填充剂,其中,化合物(I)和所述填充剂的比例为0.1:1~10:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为5:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为3:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为2:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为1:1(mg/mL)。
在一实施例中,所述药物组合物包括填充剂,其中,所述填充剂为糖。在一实施例中,所述药物组合物包括填充剂,其中,所述填充剂为蔗糖。在另一实施例中,所述药物组合物包括填充剂,其中,所述填充剂为二水海藻糖。在一实施例中,所述药物组合物包括填充剂,其中,所述填充剂为甘露醇。在一实施例中,所述药物组合物包括冻干物,所述冻干物为无定形冻干物。在另一实施例中,所述药物组合物包括适于重建冻干物且适于肠外给药的无菌溶剂。
在本发明的另一方面,本申请提供了一种制备药物组合物的方法,所述药物组合物包括化合物(I)的冻干物和填充剂,其中,化合物(I)和所述填充剂的比例为0.1:1~10:1(mg/mL),该方法包括冻干含有填充剂的化合物(I)的水溶液,其中,冻干步骤包括:(a)冷冻该溶液;(b)通过降低真空压力和升高经冷冻的溶液的温度来干燥所述冷冻的溶液,以形成产品;然后,通过升高所述产品的温度来对所述产品进行第二次干燥。
在一实施例中,化合物(I)和所述填充剂的比例为5:1(mg/mL)。在一实施中,化合物(I)和所述填充剂的比例为3:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为2:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为1:1(mg/mL)。
在制备所述药物组合物的方法的一实施例中,所述冷冻步骤在至少-30℃±5℃或更低的温度下进行。在另一实施例中,所述冷冻步骤在-40℃±5℃下进行。在制备所述药物组合物的方法的另一实施例中,所述冷冻步骤在至少-30℃±5℃的温度下保持至少3h。在制备所述药物组合物的方法的一实施例中,在所述冷冻步骤之后将压力降至30mTorr。在制备所述药物组合物的方法的一实施例中,将第一次干燥步骤升高到至少-25℃±5℃或更高的温度。在制备所述药物组合物的方法的另一实施例中,将所述第二次干燥步骤升高到至少10℃±5℃或更高的温度。在一实施例中,所述第二次干燥步骤的温度在30mTorr下保持至少8h。
在一实施例中,所述方法包括化合物(I)的冻干物和填充剂,其中,所述填充剂为蔗糖。在一实施例中,所述方法包括化合物(I)的冻干物和填充剂,其中,所述填充剂为二水海藻糖。在一实施例中,所述方法包括化合物(I)的冻干物和填充剂,其中,所述填充剂为甘露醇。
在本发明的一方面,本申请提供了一种治疗需要进行治疗的对象的细菌感染的方法,其包括给予所述对象治疗有效量的化合物(I)的药物组合物,所述药物组合物包括化合物(I)的冻干物和填充剂,其中,化合物(I)和所述填充剂的比例为0.1:1~10:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为1:1~5:1(mg/mL)。在一实施例中,化合物(I)和所述填充剂的比例为2:1(mg/mL)。
在一实施例中,所述治疗细菌感染的方法包括向所述对象给予足以抑制细菌β-内酰胺酶的量的所述药物组合物。在另一实施例中,所述治疗细菌感染的方法中,所述β-内酰胺类抗生素包括青霉素、头孢菌素或单胺菌素。在一实施例中,所述治疗细菌感染的方法中,所述对象为人。
在一实施例中,所述β-内酰胺类抗生素为青霉素。在另一实施例中,所述β-内酰胺类抗生素为头孢菌素。在一实施例中,所述β-内酰胺类抗生素为单胺菌素。在一实施例中,所述需要进行治疗的对象为人。
在另一实施例中,所述β-内酰胺为β-内酰胺类抗生素,并且包括选自青霉烷(penam)、碳青霉烷(carbapenam)、氧青霉烷(oxapenam)、青霉烯(penem)、碳青霉烯(carbapenem)、单胺菌素、头孢烯(cephem)、碳头孢烯(carbacephem)和氧头孢烯(oxacephem)的核。
在另一实施例中,所述β-内酰胺类抗生素选自氨苄西林、阿莫西林、阿度西林、阿洛西林、氨曲南、比阿培南、卡比西林(carbeniccilin)、卡非西林、卡茚西林、卡卢莫南、头孢吡肟、头孢噻肟、头孢舒米、头孢洛林、头孢洛扎(ceftolozane)、头孢曲松、头孢他啶、头孢烯、多尼培南、艾他培南、氟氧头孢、美罗培南、哌拉西林、他唑巴坦、替卡西林和替吉莫南(tigermonam),或其药学上可接受的盐或酯。
在另一实施例中,所述β-内酰胺类抗生素为美罗培南或其药学上可接受的盐或酯。
所述化合物可单独或与β-内酰胺类抗生素和/或与其它非β-内酰胺类抗生素联合用于治疗人或动物的细菌感染。
参考以下详细描述,本发明的这些和其它方面将是明显的。为此,本文阐述了各种参考文献,其更详细地描述了某些背景信息、工艺、化合物和/或组合物,并且各自以引用的方式并入本文中。
附图说明
结合附图可以更好地理解以下详细说明,以下详细说明通过示例的方式给出,并不旨在将本发明仅限于所描述的特定实施例。
图1示出了二水海藻糖制剂于各种温度下在13周内的稳定性研究的结果;
图2示出了甘露醇制剂于各种温度下在13周内的稳定性研究的结果。
具体实施方式
在以下描述中,阐述了某些特定细节,以便充分理解本发明的各实施例。然而,本领域技术人员将理解,在没有这些细节的情况下也可以实施本发明。除非上下文另外要求,否则,在整个说明书和权利要求书中,“包括”一词及其变形应被解释为开放式的、包容式的含义(即,“包括但不限于”)。
整个说明书中对“一个实施例”或“一实施例”的提及是指结合实施例描述的特定特征、结构或特性包括在本发明的至少一个实施例中。因此,在整个说明书中的各个地方出现的短语“在一个实施例中”或“在一实施例中”不一定全部指相同的实施例。此外,所述特定特征、结构或特性可以以任何合适的方式组合在一个或多个实施例中。
定义
如本文中所使用的,除非有相反的说明,否则以下术语和短语具有以下指出的含义。
化合物(I)的冻干物可以以各种异构形式存在,也可以以一种或多种互变异构形式存在,所述互变异构形式包括单一互变异构体和多个互变异构体的混合物。术语“异构体”旨在涵盖本发明化合物的所有异构形式,包括该化合物的互变异构形式。术语“互变异构体”是指从分子的一个原子到同一分子的另一个原子的质子转移。
本发明的化合物或其药学上可接受的盐可含有一个或多个不对称中心,因此可以产生对映异构体、非对映异构体和可以根据绝对立体化学定义为(R)-或(S)-或对氨基酸定义为(D)-或(L)-的其它立体异构形式。本发明意在包括所有这样的可能的异构体,以及它们的外消旋和光学纯形式。光学活性(+)和(-)、(R)-和(S)-或(D)-和(L)-异构体可使用手性合成子(chiral synthons)或手性试剂来制备,或使用常规的技术(例如,色谱法和分级结晶)拆分。用于制备/分离单个对映异构体的常规技术包括由合适的光学纯前体手性合成或使用例如手性高压液相色谱法(HPLC)拆分外消旋体(或盐或衍生物的外消旋体)。当本文所述的化合物包含烯属双键或其它几何不对称中心时,除非另有说明,否则所述化合物包括E型和Z型几何异构体。同样地,所有互变异构形式也意图包括在内。
本文所述的一些化合物可具有非对称中心,因此以不同的对映异构和非对映异构形式存在。本发明的化合物可以是光学异构体或非对映异构体的形式。因此,本发明涵盖光学异构体、非对映异构体及其混合物(包括外消旋混合物)形式的本发明的化合物及其如本文所述的用途。本发明化合物的光学异构体可通过已知技术如不对称合成、手性色谱法或通过使用光学活性拆分剂对立体异构体进行化学分离获得。
除非另有说明,否则“立体异构体”是指化合物的一种立体异构体,其基本上不含该化合物的其它立体异构体。因此,具有一个手性中心的立体异构纯(stereomericallypure)化合物基本上不含该化合物的相反的对映异构体。具有两个手性中心的立体异构纯化合物基本上不含该化合物的其它非对映异构体。典型的立体异构纯化合物包含大于约80重量%的该化合物的一种立体异构体和小于约20重量%的该化合物的其它立体异构体,例如大于约90重量%的该化合物的一种立体异构体和小于约10重量%的该化合物的其他立体异构体,或大于约95重量%的该化合物的一种立体异构体和小于约5重量%的该化合物的其它立体异构体,或大于约97重量%的该化合物的一种立体异构体和少于约3重量%的该化合物的其它立体异构体。本发明考虑了各种立体异构体及其混合物,并且包括“对映异构体”,所述“对映异构体”是指分子不可重叠的互为镜像的两种立体异构体。
如果所示出的结构与给定的该结构的名称之间存在差异,则以所示出的结构为准。在整个本申请中,化合物(I)与(2S,5R)-N-(2-氨基乙氧基)-7-氧代-6-(磺氧基)-l,6-二氮杂二环[3.2.1]辛烷-2-甲酰胺可互换使用。另外,如果未使用例如粗线或虚线指示结构或结构的一部分的立体化学,则所述结构或所述结构的一部分将被解释为涵盖其所有立体异构体。然而,在存在多个手性中心的情况下,结构和名称可以表示为单一对映异构体,以辅助描述相对立体化学。有机合成领域的技术人员由制备其的方法将知道所述化合物是否制备为单一对映异构体。
在本说明书中,“药学上可接受的盐”是本发明化合物的药学上可接受的有机或无机酸或碱的盐。代表性的药学上可接受的盐包括例如碱金属盐、碱土金属盐、铵盐、水溶性盐和水不溶性盐,例如,乙酸盐、amsonate(4,4-二氨基二苯乙烯-2,2-二磺酸盐)、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、丁酸盐、钙(calcium)、依地酸钙(calcium edetate)、右旋樟脑磺酸盐(camsylate)、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐、二盐酸盐(dihydrochloride)、乙二胺四乙酸盐(edetate)、乙二磺酸盐(edisylate)、丙酸酯十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酰对氨基苯胂酸盐(glycollylarsanilate)、六氟磷酸盐、4-己基间苯二酚盐(hexylresorcinate)、海巴明(hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、异硫代硫酸盐(isothionate)、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物(methylbromide)、甲基硝酸盐(methylnitrate)、甲基硫酸盐(methylsulfate)、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐(N-methylglucamineammonium salt)、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(pamoate)(1,1-亚甲基-双-2-羟基-3-萘甲酸盐(1,1-methene-bis-2-hydroxy-3-naphthoate),einbonate)、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、聚半乳糖醛酸盐、丙酸盐、对甲苯磺酸盐、水杨酸盐、硬脂酸盐、碱式醋酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐(sulfosaliculate)、苏拉明盐(suramate)、单宁酸盐、酒石酸盐、茶氯酸盐(teoclate)、甲苯磺酸盐、三乙基碘化物(triethiodide)和戊酸盐。药学上可接受的盐在结构上可具有多于一个的带电原子。在这种情况下,药学上可接受的盐可以具有多个反离子。因此,药学上可接受的盐可以具有一个或多个带电原子和/或一个或多个反离子。
术语“治疗”是指改善或根除与传染病相关的疾病或症状。在某些实施例中,这样的术语是指因向患有这种传染病的患者给予一种或多种预防或治疗剂而使传染病的扩散或恶化最小化。
术语“有效量”是指足以在传染病的治疗或预防中提供治疗或预防益处或足以延迟或最小化与传染病相关的症状的本发明化合物或其它活性成分的量。此外,关于本发明的化合物的治疗有效量是指单独使用或与其它疗法组合使用在传染病的治疗或预防中提供治疗益处的治疗剂的量。与本发明化合物结合使用时,该术语可以包括改善整体治疗、减少或避免疾病的症状或病因、或增强与另一种治疗剂的治疗功效或协同作用的量。构成“治疗有效量”的本发明化合物的量将根据化合物、病症及其严重性、给药方式以及待治疗的哺乳动物的年龄而变化,但是可以由本领域普通技术人员根据自己的知识和本发明内容采用常规方法确定。
“患者”或“对象”包括动物,例如,人、牛、马、绵羊、羔羊、猪、家鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠。所述动物可以是哺乳动物,例如,非灵长类和灵长类(例如,猴和人)。在一个实施例中,患者为人,例如,婴儿、儿童、青少年或成人。
术语“前药”是指药物前体,其为一种当施用给患者后在成为活性药理剂(activepharmacological agent)之前须通过代谢过程进行化学转化的化合物。根据化合物(I)的化合物的示例性前药为酯、乙酰胺和酰胺。
化合物(I)的冻干物可以通过将一个或多个原子替换为具有不同原子质量或质量数的原子进行同位素标记。可掺入化合物(I)的同位素的示例包括氢、碳、氮、氧、磷、氟、氯或碘的同位素。此类同位素的说明分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。这些放射性同位素标记的化合物可用于测定生物分布、组织浓度和来自生物组织的运输和排泄动力学,所述生物组织包括给予所述标记化合物的对象。标记的化合物也用于确定疗效、作用位点或作用方式、以及候选治疗剂与药理学上重要靶标的结合亲和力。因此,化合物(I)的某些放射性同位素标记的冻干物可用于药物和/或组织分布研究。鉴于放射性同位素氚(即3H)和碳-14(即14C)易于掺入且其检测手段是现成的,他们尤其可用于这一目的。
较重同位素如氘(即2H)的取代可提供某些治疗优点,该些治疗优点由更大的代谢稳定性(例如,延长含氘化合物的体内半衰期)引起。用氘取代氢可以减少治疗效果所需的剂量,因此在发现或临床应用中可能是优选的。
用正电子发射同位素(如11C、18F、15O和13N)取代可提供本发明化合物的标记类似物,可用于正电子发射断层扫描(PET)研究,例如,用于检查底物受体占用。同位素标记的化合物通常可通过本领域技术人员已知的常规技术或通过类似于下文制备和示例部分所述的方法使用合适的同位素标记反应物制备。
本文公开的本发明的实施例也意在包括化合物(I)的体内代谢产物。这样的产物可以由例如在给予所述组合物后主要由酶活性引起的氧化、还原、水解、酰胺化、酯化、二聚和类似过程产生。因此,本发明包括在向哺乳动物给予这样的组合物足以产生代谢产物的一段时间后,作为作用于化合物(I)的组合物的酶或非酶活性的副产物产生的化合物。代谢产物,特别是药学活性的代谢产物通常通过向对象(如大鼠、小鼠、豚鼠、猴子或人)给予可检测剂量的该组合物的放射性同位素标记的化合物以足以使代谢发生的时间段、然后将代谢产物从从接收所述放射性同位素标记的化合物的对象身上获得的尿、血液或其他生物样品中分离出来来进行鉴定。
本发明还提供了化合物(I)的冻干物的药物组合物的药学上可接受的盐形式。通过将药学上合适的酸或药学上合适的碱与本发明化合物接触而形成的酸和碱加成盐均在本发明的范围内。
为此,“药学上可接受的酸加成盐”是指那些保持了游离碱(其不是生物学上或其它方面所不期望的)的生物学有效性和性质且由无机酸和有机酸形成的盐,其中,所述无机酸例如是但不限于:盐酸、氢溴酸、硫酸、硝酸、磷酸等;所述有机酸例如是但不限于:乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
类似地,“药学上可接受的碱加成盐”是指那些保持了游离酸(其不是生物学上或其它方面所不期望的)的生物学有效性和性质的盐。这些盐是通过将无机碱或有机碱加入到游离酸中而制备的。从无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。优选的无机盐为铵、钠、钾、钙和镁盐。从有机碱衍生的盐包括但不限于伯、仲和叔胺的盐;包括天然存在的取代胺、环状胺和碱性离子交换树脂的取代胺,例如,氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、地阿诺(deanol)、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、苯乙苄胺、苄星(benzathine)、乙二胺、葡糖胺、葡甲胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、多胺树脂等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
通常,结晶会产生所述组合物的化合物的溶剂化物。如本文所用,术语“溶剂化物”是指包括本发明化合物的一个或多个分子与一个或多个溶剂分子的聚集体。所述溶剂可以为水,在这种情况下溶剂化物可以为水合物。或者,所述溶剂可以为有机溶剂。因此,本发明的化合物可以作为包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等的水合物及相应的溶剂化形式存在。所述组合物的化合物可以是真正的溶剂化物,而在其他情况下,所述组合物的化合物可以仅保留不定水或者是水加上一些不定溶剂的混合物。
根据本发明的一系列制备方法,可以良好的重现性和高的产率生产由前述化合物(I)表示的化合物(特别是冻干物)的药物组合物。
在一方面,提供了本发明的基本上纯的多晶型形式。例如,本发明包括本申请中所述的非晶形式,所述非晶形式的纯度为约≥95%。例如,所述形式的纯度可以为约≥95%、≥96%、≥97%、≥98%或≥99%。
在一些实施例中,化合物(I)的冻干物以基本上纯的形式分离。本文所述的API的纯度大于约90重量%、约91重量%、约92重量%、约93重量%、约94重量%、约95重量%、约96重量%、约97重量%、约98重量%或约99重量%。在另一实施例中,所述API的纯度大于约95重量%。例如,所述API的纯度可以为≥95%、≥96%、≥97%、≥98%或≥99%。
药物制剂
在一个实施例中,将经冻干的化合物(I)配制成药学上可接受的组合物,其含有有效量的非晶形式,以在将所述药物组合物给予哺乳动物后治疗所关注的特定疾病或病症。根据本发明的药物组合物可包括经冻干的化合物(I)以及药学上可接受的载体、稀释剂或赋形剂。
在这点上,“药学上可接受的载体、稀释剂或赋形剂”包括但不限于已被美国食品和药物管理局批准可用于人或家畜的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂或乳化剂。
此外,“哺乳动物”包括人、家养动物(例如,实验室动物和家庭宠物(例如,猫、狗、猪、牛、绵羊、山羊、马、兔))和非家养动物(例如,野生动物等)。
本发明的药物组合物可以通过将本发明的化合物与适当的药学上可接受的载体、稀释剂或赋形剂组合而制备得到,并且可以配制成固体、半固体、液体或气态形式的制剂,例如,片剂、胶囊、粉剂、颗粒剂、软膏剂、溶液、栓剂、注射剂、吸入剂、凝胶剂、微球剂和气雾剂。此类药物组合物的典型给药方式包括但不限于口服、局部施用、经皮、吸入、肠外、舌下、口含、直肠、阴道和鼻内。本文所用的术语“肠外”包括皮下注射、静脉内、肌肉内、胸骨内注射或输液技术。本发明的药物组合物配制成使其在给患者给予该组合物后其中所含的活性成分是生物可利用的。将给予对象或患者的组合物采取一个或多个剂量单位的形式,其中例如片剂可以是单个剂量单位,并且,气雾剂形式的本发明化合物的容器可以容纳多个剂量单位。制备这些剂型的实际方法是已知的,或者对于本领域技术人员而言将是明显的;例如,见Remington:The Science andPractice ofPharmacy,第20版(Philadelphia CollegeofPharmacy and Science,2000)。在任何情况下,将要给药的组合物包含治疗有效量的本发明的化合物或其药物学上可接受的盐,以根据本发明的教导治疗所关注的疾病或病症。
本发明的药物组合物可以是液体形式的。所述载体可以为液体,其中,所述组合物例如是可注射液体或气雾剂,所述可注射液体或气雾剂可用于例如吸入给药。
另外,可以存在以下物质中的一种或多种:粘合剂,如羧甲基纤维素、乙基纤维素、微晶纤维素、西黄蓍胶或明胶;赋形剂,如淀粉、乳糖或糊精;崩解剂,如海藻酸、海藻酸钠、羟基乙酸淀粉钠(Primogel)、玉米淀粉等;润滑剂,如硬脂酸镁或Sterotex;助流剂,如胶态二氧化硅;甜味剂,如蔗糖或糖精;增味剂,如薄荷、水杨酸甲酯或桔子香精;以及着色剂。
当所述药物组合物为胶囊形式时,例如,明胶胶囊,除了上述类型的材料外,还可以含有液体载体,例如,聚乙二醇或油。
所述药物组合物可以是液体形式,例如,酏剂、糖浆、溶液、乳剂或悬浮剂。所述液体可以通过注射来递送。在旨在通过注射给药的组合物中,可以包括表面活性剂、防腐剂、润湿剂、分散剂、悬浮剂、缓冲剂、稳定剂和等渗剂中的一种或多种。
无论本发明的液体药物组合物是溶液剂、悬浮剂或其它类似形式,其均可包括以下佐剂中的一种或多种:无菌稀释剂,如注射用水、盐溶液(优选生理盐水)、林格氏溶液、等渗氯化钠、固定油(如可用作溶剂或悬浮介质的合成甘油单酯或甘油二酯)、聚乙二醇、甘油、丙二醇或其它溶剂;抗菌剂,如苯甲醇或尼泊金甲酯;抗氧化剂,如抗坏血酸或亚硫酸氢钠;螯合剂,如乙二胺四乙酸;缓冲剂,如乙酸盐、柠檬酸盐或磷酸盐;以及张力调节剂,如氯化钠或右旋糖。所述肠外制剂可封闭在安瓿瓶、一次性注射器或由玻璃或塑料制成的多剂量小瓶中。生理盐水为优选的佐剂。可注射的药物组合物优选为无菌的。
本发明的用于肠外给药的液体药物组合物应包含一定量的本发明的化合物,使得将获得合适的剂量。
如上所述,肠外制剂包括化合物(I)和赋形剂。可选地,所述药物组合物中包括至少两种赋形剂(例如,两种、三种或更多种赋形剂)。所述药物组合物中使用的赋形剂包括但不限于糖、盐、氨基酸、二价阳离子和表面活性剂。这些赋形剂有助于所述制剂的稳定性。在一些示例中,这些赋形剂在药物组合物中的使用,因此在肠外制剂中的使用,允许药物组合物长期储存(例如,储存十二个月或更长)而不损失化合物(I)活性。
本文所述的药物组合物使用的合适的糖包括例如单糖和二糖。在一些示例中,所述药物组合物包括甘露醇、山梨醇、蔗糖、二水海藻糖或其组合。合适的糖的进一步示例包括乳糖、右旋糖、左旋糖、葡萄糖和麦芽糖。
所述药物组合物和/或冻干制剂中使用的糖可包括一种糖或两种或多种糖的组合。例如,所述药物组合物可以包括作为所述制剂中存在的糖的蔗糖,或者可以包括作为制剂中存在的糖的甘露醇和山梨醇的组合。在冻干制剂中存在的包括糖的赋形剂的浓度在本文中可表示为基于液体药物组合物(即冻干之前包括液体载体的药物组合物)的重量的重量百分比。基于所述药物组合物的重量,存在于所述药物组合物中的糖的总浓度可为10重量%或更小。例如,基于液体药物组合物的重量,糖的总浓度可以为小于7.5重量%(例如,基于液体药物组合物的重量,小于7.4重量%、小于7.3重量%、小于7.2重量%、小于7.1重量%、小于7重量%、小于6重量%、小于5重量%、小于4重量%、小于3重量%、小于2重量%或小于1重量%)。例如,所述药物组合物中存在的蔗糖的浓度可以为所述液体药物组合物的重量的0.1重量%~5重量%、1重量%~4.5重量%、或2重量%~4重量%(例如3重量%)。
可使用本领域已知的技术和设备进行冻干。所述冻干过程可以例如使用冻干机来进行。冻干可包括冷冻和随后干燥所述液体药物制剂。可选地,所述冻干包括产品装载阶段、冷冻阶段和初次干燥和二次干燥阶段。将所述产品装载到冻干机中,将搁架设置到目标温度设定点达预定时间段。所述冷冻阶段包括将搁架以受控的速率(℃/h)冷却至目标设定点。将所述产品在所述冷冻阶段保持预定的时间量。在所述冷冻步骤中,所述液体药物制剂可以在适当的时间段内冷却至低于0℃的温度,以形成冷冻产品。可选地,所述液体药物制剂可被冷却至-50℃或更低的温度。
在一些示例中,所述液体药物制剂可被冷却10h或更短时间。例如,所述药物制剂可冷却9h或更短、8h或更短、7h或更短、6h或更短、5h或更短、4h或更短、3h或更短、2h或更短、1h或更短、或30min或更短。
可选地,所述冻干过程可包括退火步骤,在该退火步骤中,将冷冻的药物制剂加热至环境温度或低于环境温度,然后再次冷却以形成冷冻产品。在一些示例中,不进行所述退火步骤。
然后,所述冷冻产品可以在减压(例如,通过施加真空)条件下干燥以形成冻干的药物制剂。可选地,可对冷冻的药物制剂施加30~80μm Hg(例如,50μm Hg)的真空压力。
所述干燥步骤可以在环境温度、低于环境温度或高于环境温度的温度下进行。例如,所述干燥步骤可在40℃或更低、30℃或更低、20℃或更低、10℃或更低、或0℃或更低的温度下进行。可选地,所述冻干的药物制剂可以在一个或多个额外的干燥步骤中于环境温度、低于环境温度或高于环境温度的温度下进行进一步的干燥,以去除残留的水。例如,可在-10℃~50℃(例如,0℃~40℃,10℃~30℃,或20℃~25℃)的温度下进行所述额外的干燥步骤。此外,所述冻干药物制剂可以在惰性气体(例如,氮气)或惰性气体的组合的存在下进行干燥。例如,冻干容器和/或药物储存容器可以用惰性气体吹扫并封盖,以避免所述药物制剂暴露于空气中。在一个或多个干燥步骤之后,所述冻干药物制剂的含水量可为例如小于20%。在一些示例中,所述冻干药物制剂的含水量小于15%、小于10%、小于5%、小于4%、小于3%、小于2%、小于1%、小于0.5%或小于0.1%。
所述冻干的药物制剂可在例如约环境温度下稳定一段时间(例如,至少一天)。在一些示例中,所述药物制剂在约4℃或更低的温度下稳定至少3个月(例如,至少四个月、至少5个月、至少6个月、至少7个月、至少8个月、至少9个月、至少10个月、至少11个月、至少12个月、至少13个月、至少14个月、至少15个月、至少16个月、至少17个月、至少18个月或大于3个月的任何时间)。本文还描述了本文所述的药物制剂的制备方法,然后冻干所述制剂以制备冻干药物制剂。根据这些方法制备的药物制剂包括低水平的颗粒,因此适于通过肠外输液或注射给药。在一些示例中,使用根据USP<788>(其全部内容并于本文中)的光阻法(light obscuration particle count test)和/或显微镜法(microscopic particlecount test)来确定所述方法中颗粒的水平。
本发明的药物组合物可包括改变固体或液体剂量单位的物理形式的各种材料。
本发明的液体形式的药物组合物可以包括与本发明化合物结合的试剂,从而辅助所述化合物的递送。可以这种能力发挥作用的合适试剂包括单克隆或多克隆抗体、蛋白质或脂质体。
本发明的药物组合物可由可作为气雾剂给药的剂量单位组成。术语“气雾剂”用于表示从胶体性质的系统到由加压包装组成的系统的各种系统。可通过液化或压缩气体或通过分配活性成分的合适的泵系统进行递送。为了递送活性成分,本发明化合物的气雾剂可以在单相、双相或三相系统中递送。气雾剂的递送包括必要的容器、活化剂、阀、子容器等,它们一起可形成试剂盒。本领域的技术人员无需过多实验即可确定优选的气雾剂。
本发明的药物组合物可通过制药领域公知的任何方法制备。例如,可通过将本发明的化合物与无菌蒸馏水组合形成溶液来制备旨在通过注射给药的药物组合物。可以加入表面活性剂以促进均匀溶液或悬浮液的形成。表面活性剂是与本发明化合物非共价相互作用以促进化合物在水性递送系统中的溶解或均匀悬浮的化合物。
治疗用途
所述组合物的化合物或其药学上可接受的盐或酯以治疗有效量给药,所述治疗有效量将根据多种因素而变化,所述因素包括:所采用的特定化合物的活性;所述化合物的代谢稳定性和作用长度;所述患者的年龄、体重、健康状况、性别和饮食;给药的方式和时间;排泄率;联合用药;具体病情或病症的严重程度;以及接受治疗的所述对象。
所述组合物的化合物或其药学上可接受的盐或酯也可以与一种或多种其它治疗剂同时、之前或之后给药。这种组合疗法包括给予包含本发明化合物和一种或多种另外的活性剂的单一药物剂量制剂,以及在其自身单独的药物制剂中给予本发明化合物和每种活性剂。在使用单独的剂量制剂的情况下,所述组合物的化合物和一种或多种另外的活性剂可以在基本上相同的时间(即同时),或在分开的时间(即顺序地)给药;组合疗法应理解为包括所有这些方案。
冻干化合物(I)或冻干化合物(I)的药物组合物的治疗有效剂量通常为约1~2500mg/d、约10~约1500mg/d、约10~约1000mg/d、约10~约500mg/d、约10~约250mg/d、约10~约100mg/d或约10~约50mg/d。所述治疗有效剂量可以以一种或多种剂量给药。然而,应当理解的是,对任何特定患者,本发明化合物的具体剂量将取决于各种因素,例如,年龄、性别、体重、一般健康状况、饮食、待治疗患者的个人反应、给药时间、待治疗疾病的严重程度、给予的特定化合物的活性、剂型、给药方式和合并用药。在给定的情况下的治疗有效量将容易确定,并且在普通临床医生或医师的技能和判断内。在任何情况下,所述化合物或组合物将以一定剂量且根据患者的独特状况递送治疗有效量的方式给药。
术语“β-内酰胺类抗生素”是指含有β-内酰胺官能团的具有抗生素性质的化合物。可与由化合物(I)表示的本发明化合物组合使用的β-内酰胺类抗生素的示例为市售青霉素、头孢菌素、青霉烯、碳青霉烯和单胺菌素。
可以与由化合物(I)表示的本发明化合物组合使用的β-内酰胺类抗生素的示例为常用的青霉素(例如,阿莫西林、氨苄西林、阿洛西林、美洛西林、阿帕西林、海他西林、巴卡西林、羧苄西林、里拉西林、替卡西林、哌拉西林、甲氧西林、环己西林、酞氨西林、苯唑西林、氯唑西林、双氯西林)和常用的头孢菌素(例如,头孢噻吩、头孢噻啶、头孢克洛、头孢羟氨苄、头孢孟多、头孢唑啉、头孢氨苄、头孢拉定、头孢吡硫、头孢呋辛、头孢西丁、头孢乙腈、头孢替安、头孢噻肟、头孢曲嗪(cefatriazine)、头孢磺啶、头孢哌酮、头孢唑肟、头孢甲肟、头孢美唑、头孢来星、头孢尼西、头孢地嗪、头孢匹罗、头孢吡肟、头孢他啶、头孢匹胺、头孢曲松、头孢拉宗、头孢丙烯、头孢克肟、头孢托罗(ceftobiprole)、头孢洛林(ceftaroline)、头孢络宁(cefalonium)、头孢米诺、头孢雷特、头孢唑喃、头孢西丁、头孢替坦、氯碳头孢(loracarbef)、头孢地尼、头孢托仑、头孢他美(cefetamet)、头孢卡品、头孢达肟、头孢布烯、头孢沙定、拉氧头孢和CXA-101)。可以使用碳青霉烯类的β-内酰胺类抗生素,例如,亚胺培南、美罗培南、帕尼培南、比阿培南、多尼培南、厄他培南等。诸如氨曲南、卡芦莫南、替吉莫南等的单胺菌素类的β-内酰胺类抗生素,可以用作抗生素的组合搭档。
示例
本申请涉及适于肠外给药的化合物(I)的药物组合物。标题化合物,化合物(I)在水溶液中会分解和二聚,因此研发了冻干制剂。申请人发现了包括糖和化合物(I)的冻干制剂,以提供适合静脉给药的无定形冻干物。
在一方面,本申请提供了一种无定形冻干制剂及其制备方法,所述无定形冻干制剂包括化合物(I)和糖,例如,二水海藻糖、蔗糖和甘露醇。测试了几种作为无定形冻干产品的赋形剂的填充剂。在本申请中,蔗糖、二水海藻糖和甘露醇的测试浓度为50mg/mL,而API的浓度固定在100mg/mL(见表1)。研制了冻干制剂以提供相对高于-30℃的玻璃化转变温度(Tg')、优异的配合料均匀度和良好的稳定性。使用差示扫描量热法(DSC)分析了这三种制剂的Tg',并使用冷冻干燥显微镜(Freeze-drying Microscope)分析了崩塌温度(Tcollapse)。所有这三种制剂的Tg'均高于-30℃(见表2)。另外,发现所有批次冻干饼外观均是均一的。
表1.含海藻糖制剂的冻干方法示例
表2.含糖制剂的Tg'和Tcollapse
化合物(I)中潜在的有机杂质通常与制备相关,可以是起始材料、前体、中间体、母体化合物的降解产物或反应物的副产物。在所述API的研发过程中,稳定性研究表明存在三种主要杂质,其特征在于并被称为“RS1”,其代表一种降解产物,{[6-[(2-氨基乙氧基)氨基甲酰基]哌啶-3-基)氨基]氧基}磺酸({[(6-[(2-aminoethoxy)carbamoyl]piperdin-3-yl)amino]oxy}sulfonic acid);“RS2”,其表示化合物(I)的加合物,((l-(6-((2-氨基乙氧基)氨基甲酰基)哌啶-3-基)-3-(2-((7-氧代-6-(磺氧基)-1,6-二氮杂二环[3.2.1]辛烷-2-羧酰氨基)氧基)乙基)脲基)氧基)硫酸(((1-(6-((2-aminoethoxy)carbamoyl)piperidin-3-yl)-3-(2-((7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)ureido)oxy)sulfonic acid);以及“RS3”,其代表另一副产物,2-((2-(叔丁基氨基)乙氧基)氨基甲酰基)-7-氧代-l,6-二氮杂二环[3.2.1]辛烷-6-基硫酸氢盐(2-((2-(tert-butylamino)ethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen sulfate)。为了增加水溶液的稳定性,并因此将存在的杂质最小化,开发了本制剂。申请人发现API与糖的摩尔比对Tcollapse和Tg'有影响,以提供具有优异稳定性的制剂。较高的Tg'和Tcollapse可使制造过程中的冷冻温度更高,降低冻干饼崩塌的风险,确保配合料均匀度并易于制造。
将所述冻干制剂进行稳定性研究,结果示于表3、表4、图1和图2中。表3示出了1个月期间的数据。表4示出另一技术批次在1年期间的数据,而图1和图2示出了分别针对二水海藻糖制剂和甘露醇制剂在各种温度下在13周期间的稳定性研究。
表3. 1个月后药品稳定性技术批次的数据
表4.1年期间药品稳定性技术批次的数据
以上所述的各种实施例可以被组合以提供另外的实施例。如果需要采用各种专利、申请和出版物的概念以提供其他实施例,则可以修改实施例的各方面。根据以上详细描述,可以对实施例进行这些和其他改变。一般地,在以下权利要求中,所使用的术语不应被解释为将权利要求限制于说明书和权利要求中所公开的具体实施例,而应被解释为包括所有可能的实施例以及权利要求所述的等同物的全部范围。因此,权利要求不受本公开的限制。
Claims (20)
2.根据权利要求1所述的药物组合物,其特征在于,化合物(I)和所述填充剂的比例为3:1(mg/mL)。
3.根据权利要求1所述的药物组合物,其特征在于,化合物(I)和所述填充剂的比例为2:1(mg/mL)。
4.根据权利要求1所述的药物组合物,其特征在于,化合物(I)和所述填充剂的比例为1:1(mg/mL)。
5.根据权利要求1所述的药物组合物,其特征在于,所述填充剂为蔗糖、海藻糖、脱水物或甘露醇。
7.根据权利要求6所述的方法,其特征在于,化合物(I)和所述填充剂的比例为3:1(mg/mL)。
8.根据权利要求6所述的方法,其特征在于,化合物(I)和所述填充剂的比例为2:1(mg/mL)。
9.根据权利要求6所述的方法,其特征在于,化合物(I)和所述填充剂的比例为1:1(mg/mL)。
10.根据权利要求6所述的方法,其特征在于,所述冷冻步骤在至少-30℃±5℃或更低的温度下进行。
11.根据权利要求7所述的方法,其特征在于,所述冷冻步骤在-40℃±5℃下进行。
12.根据权利要求6所述的方法,其特征在于,在所述冷冻步骤之后,将压力降低到30mTorr。
13.根据权利要求6所述的方法,其特征在于,将第一次干燥步骤升高到至少25℃±5℃或更高的温度。
14.根据权利要求6所述的方法,其特征在于,将所述第二次干燥步骤升高到至少10℃±5℃或更高的温度。
15.根据权利要求6所述的方法,其特征在于,所述填充剂为蔗糖、海藻糖脱水物或甘露醇。
17.根据权利要求17所述的方法,其特征在于,化合物(I)和所述填充剂的比例为1:1~3:1(mg/mL)。
18.根据权利要求17所述的方法,其特征在于,化合物(I)和所述填充剂的比例为2:1(mg/mL)。
19.根据权利要求16所述的治疗需要进行治疗的对象的细菌感染的方法,其特征在于,包括向所述对象给予足以抑制细菌β-内酰胺酶的量的所述药物组合物。
20.根据权利要求16所述的方法,其特征在于,β-内酰胺类抗生素包括青霉素、头孢菌素或单胺菌素。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102834395A (zh) * | 2009-10-09 | 2012-12-19 | 诺维塞尔公司 | 药物化合物的多晶型形式和假多晶型形式 |
WO2013180197A1 (ja) * | 2012-05-30 | 2013-12-05 | Meiji Seikaファルマ株式会社 | 新規β-ラクタマーゼ阻害剤とその製造法 |
CN105612159A (zh) * | 2013-10-08 | 2016-05-25 | 明治制果药业株式会社 | 二氮杂二环辛烷衍生物的结晶及其制备方法 |
CN106715429A (zh) * | 2014-01-21 | 2017-05-24 | 沃克哈特有限公司 | 7‑氧代‑二氮杂二环[3.2.1]辛烷衍生物及其作为抗菌剂的用途 |
CN107001366A (zh) * | 2014-12-05 | 2017-08-01 | 明治制果药业株式会社 | 二氮杂二环辛烷衍生物的结晶以及稳定的冻干制剂的制备方法 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03193735A (ja) * | 1989-12-22 | 1991-08-23 | Shionogi & Co Ltd | グリコペプチド系抗生物質の安定化組成物 |
US7378408B2 (en) | 2001-11-30 | 2008-05-27 | Pfizer Inc. | Methods of treatment and formulations of cephalosporin |
CN101264088B (zh) * | 2008-04-25 | 2011-11-23 | 黄芝芳 | 一种含量稳定、溶解快速的抗菌素组合物 |
US8796257B2 (en) * | 2011-12-02 | 2014-08-05 | Naeja Pharmaceutical Inc. | Bicyclic compounds and their use as antibacterial agents and β-lactamase inhibitors |
BR112015003592B1 (pt) * | 2012-08-25 | 2020-04-14 | Wockhardt Ltd | derivados de 1,6-diazabiciclo[3,2,1]octan-7-ona e seu uso no tratamento de infecções bacterianas |
TWI644908B (zh) | 2013-09-24 | 2018-12-21 | 明治製菓藥業股份有限公司 | 二氮雜二環辛烷衍生物之製法及其中間體 |
US20180243286A1 (en) | 2015-01-24 | 2018-08-30 | Wockhardt Limited | Antibacterial compositions of a beta-lactamase inhibitor with a cephalosporin |
WO2016120752A1 (en) | 2015-01-28 | 2016-08-04 | Wockhardt Limited | A process for preparation of (2s, 5r)-n-(2-amino ethoxy)-6-(sulfooxy)-7-oxo-1,6- diazabicyclo [3.2.1] octane-2-carboxamide |
WO2016151543A1 (en) | 2015-03-25 | 2016-09-29 | Wockhardt Limited | Pharmaceutical compositions comprising antibacterial agents |
-
2018
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- 2018-09-25 WO PCT/IB2018/001185 patent/WO2019064065A1/en unknown
-
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- 2020-03-24 IL IL273539A patent/IL273539A/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102834395A (zh) * | 2009-10-09 | 2012-12-19 | 诺维塞尔公司 | 药物化合物的多晶型形式和假多晶型形式 |
WO2013180197A1 (ja) * | 2012-05-30 | 2013-12-05 | Meiji Seikaファルマ株式会社 | 新規β-ラクタマーゼ阻害剤とその製造法 |
CN105612159A (zh) * | 2013-10-08 | 2016-05-25 | 明治制果药业株式会社 | 二氮杂二环辛烷衍生物的结晶及其制备方法 |
CN106715429A (zh) * | 2014-01-21 | 2017-05-24 | 沃克哈特有限公司 | 7‑氧代‑二氮杂二环[3.2.1]辛烷衍生物及其作为抗菌剂的用途 |
CN107001366A (zh) * | 2014-12-05 | 2017-08-01 | 明治制果药业株式会社 | 二氮杂二环辛烷衍生物的结晶以及稳定的冻干制剂的制备方法 |
Non-Patent Citations (2)
Title |
---|
姚日生等主编: "《制药工程原理与设备》", 31 March 2007, 北京:高等教育出版社 * |
胡英等主编: "《药物制剂 第2版》", 28 February 2013, 北京:中国医药科技出版社 * |
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