CN1703201A - 用于医药用途的固体粒子抗真菌组合物 - Google Patents
用于医药用途的固体粒子抗真菌组合物 Download PDFInfo
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- CN1703201A CN1703201A CNA2003801012260A CN200380101226A CN1703201A CN 1703201 A CN1703201 A CN 1703201A CN A2003801012260 A CNA2003801012260 A CN A2003801012260A CN 200380101226 A CN200380101226 A CN 200380101226A CN 1703201 A CN1703201 A CN 1703201A
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- itraconazole
- antifungal
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Abstract
本发明涉及亚微米到微米尺寸的抗真菌剂粒子组合物。更具体地,本发明涉及用于医药用途的抗真菌剂水悬浮液。
Description
相关申请的交叉参考:
本申请是提交于2002年9月17日的美国专利申请序列号10/246,802(它是提交于2001年10月19日的美国专利申请序列号10/035,821的部分继续申请)的部分继续申请,和提交于2001年12月12日的美国专利申请序列号10/021,692的部分连续申请,这两个申请都是提交于2001年9月17日的美国专利申请序列号09/953,979的部分继续申请,后者是提交于2001年6月5日的美国专利申请序列号09/874,637的部分继续申请,专利申请09/874,637要求在2000年12月22日提交的临时申请序列号60/258,160的优先权,所有这些申请都被引入本文以供参考,并成为本文的一部分。
联邦赞助的研究或开发:
不适用。
发明背景:
技术领域
本发明涉及抗真菌剂组合物。更具体地,本发明涉及用于医药用途的抗真菌剂的水悬浮液。
发明背景
一般认为,相对其它抗菌剂而言,极其缺乏用于治疗系统性真菌疾病的有效抗真菌药物。在美国只批准了十种抗真菌药物用于治疗系统性真菌感染。使用最普遍的五种抗真菌药物是两性霉素B、氟胞嘧啶、酮康唑、伊曲康唑、和氟康唑。后三种化合物被归入三唑类,有关的分子结构通式如图1所示。
三唑类抗真菌剂的一个例子是伊曲康唑(图2)。伊曲康唑能有效治疗系统性霉菌病,尤其是曲霉病和念珠菌病。为了克服溶解度缺陷引起的生物利用度问题,已经制备了伊曲康唑的新的口服和静脉制剂。例如,当伊曲康唑在羟丙基-β-环糊精中配制时,所述环糊精是一种能与药物形成包合配合物的载体低聚糖,伊曲康唑的生物利用度得到提高,从而提高了水溶性。已知其市售制剂的商品名为SPORANOX注射剂,由JANSSEN PHARMACEUTICA PRODUCTS,L.P发明。目前该药由Abbott Labs生产,由Ortho Biotech,Inc配销。
静脉用伊曲康唑可用于选定的临床环境中。例子是如下两类病人的胃酸缺乏:一类是AIDS病人,由于与其它药物的协同治疗导致其不能有效吸收口服药物,或者另一类是不能口服药物的病危病人。目前的商品,SPORANOX注射剂,装在含250mg伊曲康唑和10g羟丙基-β-环糊精(称为”HPBCD”)的25mL玻璃瓶中。这些小瓶在使用前用50mL 0.9%盐水稀释。得到的环糊精浓度在再生的产品中超过10%(w/v)。尽管传统认为HPBCD对于注射来说是安全的,但是,已经有报道说如10%这样的高浓度在动物模型中会诱导内皮组织产生重大的改变(Duncker G;Reichelt J.;Effects of the pharmaceutical cosolventhydroxypropyl-beta-cyclodextrin on porcine cornal endothelium.Graefe′sArchive for Clinical and Experimental Ophthalmology(Germany)1998,236/5,380-389)。
其它赋形剂经常被用于配制水溶性差的静脉注射药物。例如,紫杉醇(Taxol,由Bristol-Myers Squibb生产)包含52.7%(w/v)的Cremophor EL(聚氧乙基化蓖麻油)和49.7%(v/v)无水乙醇,USP。CremophorEL的给药会导致不期望的超敏反应(Volcheck,G.W.,VanDellen,R.G.Anaphylaxis to intravenous cyclosporine and tolerance to oralcyclosporine:case report and review.Annals of Allergy,Asthma,andImmunology,1998,80,159-163;Singla A.K.;Garg A.;Aggarwal D.,Paclitaxel and its formulations.International Journal of Pharmaceutcs.2002,235/1-2,179-192)。
由于与增溶剂有关的潜在毒性问题,在配制中有必要使增溶剂的水平最小化,其中不用完全依赖可能导致不良反应的添加剂就能达到更高的药物负荷。
在水中为难溶或不溶的药物的递送是一个挑战。当这些药物制剂被配制成一种亚微米到微米尺寸的粒子的稳定悬浮液时,它们可具有重要的有益效果。精确控制粒尺寸对这些制剂的安全和有效的使用是必要的。制药用途的适用性包括小粒子尺寸(<50μm)、低毒(例如从毒性配方组分或剩余溶剂)、和给药后药物粒子的生物利用度。
美国专利No.2,745,785公开了一种递送不溶性药物的方法。该专利公开了一种制备适合于非肠道给药的青霉素G晶体的方法。该方法包括如下步骤:通过加水减少青霉素G的溶解度,从而使青霉素G在甲酰胺溶液中重结晶。‘785专利进一步指出,青霉素G粒子能用如下物质包衣:润湿剂如卵磷脂、或乳化剂、表面活性和消泡剂、或山梨聚糖的部分高级脂肪酸酯或其聚氧化烯衍生物、或芳烷基聚醚醇或其盐。‘785专利还公开了在压力下用空气喷净法微粉化青霉素G,以形成范围为约5至20微米的晶体。
另一种方法在美国专利No.5,118,528被公开,它公开了一种制备纳米粒子的方法。该方法包括如下步骤:(1)制备一种物质在一种溶剂或溶剂混合物中的液相,可以向其中加入一种或多种表面活性剂;(2)制备非溶剂或非溶剂混合物的第二液相,该非溶剂与物质的溶剂或溶剂混合物混溶;(3)搅拌下使(1)和(2)混合;(4)除去不需要的溶剂,得到纳米粒子的胶态悬浮液。‘528专利公开了,它不需要能量的供给就能得到小于500nm的物质粒子。尤其是,‘528专利声明,没有必要使用高能量装置如超声波仪和均化器。
美国专利No.4,826,689公开了一种从水不溶性药物或其它有机化合物制备均一尺寸粒子的方法。首先,将一种合适的固体有机化合物溶解于有机溶剂中,该溶液能用非溶剂稀释。然后,注入含水沉淀液体,沉淀具有基本均一的平均直径的未聚集粒子。然后将粒子从有机溶剂中分离出来。依照该发明,根据有机化合物和所需的粒子尺寸,温度、非溶剂和有机溶剂的比率、注入速率、搅拌速率和体积等参数可以变化。‘689专利公开了形成亚稳态药物的方法,该药物是热力学不稳定的并最终转变为更稳定的晶态。‘689专利公开了捕捉该亚稳态药物,此时的自由能在起始药物溶液自由能和稳定晶形自由能之间。‘689专利公开了,使用结晶抑制剂(例如聚乙烯吡咯烷酮)和表面活性剂(例如聚(氧乙烯)-共-(氧丙烯))来使沉淀物足够稳定,从而用离心过滤、薄膜过滤或反渗透等方法得到分离。
美国专利5,091,188;5,091,187和4,725,442公开了:(a)用天然或合成磷脂包裹药物小粒子,或(b)将药物溶解在合适的亲脂性载体中,并且形成被天然或半合成的磷脂稳定的乳状液。
另一种提供用于医药用途的不溶性药物的方法被公开于美国专利No.5,145,684。该‘684专利公开了在表面改性剂存在的情况下,不溶性药物通过湿磨法产生有效平均粒子尺寸小于400nm的药物粒子。‘684专利强调在该方法中有望不用任何溶剂。‘684专利公开了表面改性剂以足够的量被吸附在药物粒子表面,以阻止凝聚成更大粒子。
但是,另一种提供用于医药用途的不溶性药物的试验被公开于美国专利No.5,922,355。该‘355专利公开了用如下方法得到不溶性药物的亚微米尺寸的粒子:使用表面改性剂和磷脂的混合物,紧接着使用超声处理、均化、研磨、微流态化、沉淀或重结晶等技术使粒子尺寸变小。
美国专利No.5,780,062公开了一种制备不溶性药物小粒子的方法,包括如下步骤:(1)将药物溶解在与水混溶的第一溶剂中;(2)制备聚合物和两亲物在第二水溶剂中的第二溶液,其中药物基本不溶解,由此形成聚合物/两亲物复合体;(3)混合第一步和第二步的溶液,以沉淀药物和聚合物/两亲物复合体的聚集体。
美国专利No.5,858,410公开了一种适于医药用途的药物纳米悬浮液。该‘410专利公开了,将至少一种治疗上活性的固体化合物分散在溶剂中,使其在活塞-间隙均化器中进行高压均化,得到平均直径为10nm到1000nm的粒子,该尺寸由光子关联能谱法(PCS)测定,总群体中大于5μm的粒子比例小于0.1%(数量分布由库乐尔特颗粒计数器测定),不用预先转化为熔化物,其中活性化合物在室温下是固体,不溶解,只有在水、水介质和/或有机溶剂中微溶或中等溶解。在‘410专利中的实施例公开了在均化前进行喷射研磨。
美国专利No.4,997,454公开了一种从固体化合物制备均一尺寸粒子的方法。该‘454专利的方法包括如下步骤:将固体化合物溶于合适的溶剂中,然后注入沉淀液体,从而使具有基本均一的平均直径的非聚集粒子沉淀下来。然后将粒子从溶剂中分离。‘454专利不赞同形成晶态粒子,因为在沉淀过程中晶体会溶解并重结晶,因此使粒子尺寸分布范围变宽。‘454专利赞同在沉淀过程中,在粒子亚稳态捕获粒子。
美国专利No.5,605,785公开了制备照相用化合物的无定形分散体的方法。形成无定形分散体的方法包括任何已知的乳化方法,其产生了含有无定形粒子的分散相。
美国专利No.6,245,349公开了抗真菌剂的浓缩药物递送组合物,它是由如下组分配制而成:磷脂组分、选自丙二醇或某种聚乙二醇化合物中的组分、具有高的亲水-亲油平衡值(HLB)的表面活性剂、和药物组分,以及任选的水和/或油组分。浓缩药物递送组合物可以用含水流体稀释,以形成水包油型微乳状液组合物。
发明概述:
本发明涉及用一种或多种表面活性剂包衣的亚微米到微米大小的抗真菌剂粒子的水悬浮液组合物。由光散射法(HORIBA)或微观测量法测定,抗真菌剂粒子的容重(volume-weighted)平均粒子直径应该小于约50μm。更优选地,粒子尺寸应该小于约7μm,甚至更优选小于约2μm,甚至更优选小于约400nm,最优选小于约100nm,或任意范围或其中范围的组合。
在本发明的一个实施方案中,抗真菌剂为三唑类抗真菌剂。在本发明的另一个实施方案中,该三唑类抗真菌剂选自:伊曲康唑、酮康唑、咪康唑、氟康唑、瑞扶康唑、伏立康唑、沙康唑、艾伯康唑、genaconazole、和泊沙康唑。在本发明的优选实施方案中,抗真菌剂是伊曲康唑。
在优选的实施方案中,该组合物适合用于制药。
本发明中用于包裹粒子的合适的表面活性剂可选自:离子型表面活性剂、非离子型表面活性剂、生物学来源的表面活性剂、或氨基酸和它们的衍生物。
优选的离子型表面活性剂是胆汁盐,优选的胆汁盐是脱氧胆酸盐。优选的非离子型表面活性剂是聚烷氧醚,优选的聚烷氧醚是Poloxamer188。另一种优选的非离子型表面活性剂是Solutol HS 15(聚乙烯-660-羟基硬脂酸酯)。还有另一种优选的非离子型表面活性剂是羟乙基淀粉。优选的生物学来源的表面活性剂是清蛋白。
在一个优选的实施方案中,本发明的粒子悬浮在还有pH调节剂的水介质中。合适的pH调节剂包括但不限于:三羟甲基氨基甲烷缓冲液、磷酸盐、醋酸盐、乳酸盐、THAM(三(羟甲基)氨基甲烷)、葡甲胺(N-甲基葡萄糖胺)、柠檬酸盐、氢氧化钠、盐酸、和氨基酸如甘氨酸、精氨酸、赖氨酸、丙氨酸和亮氨酸。水介质也可以包含渗透压调节剂,例如但不限于甘油、单糖如葡萄糖、和糖醇如甘露醇和山梨糖醇。
在本发明的另一个实施方案中,抗真菌剂的含量按重量体积比(w/v)计优选为约0.01%至约50%,更优选约0.05%至约30%,最优选约0.1%至约20%。
在还一个实施方案中,表面活性剂的含量优选为约0.001%至约5%w/v,更优选从约0.005%至约5%w/v,最优选从约0.01%至约5%w/v。
在本发明的一个实施方案中,除去组合物中的水介质以形成干粒子,然后该粒子可以被重新配制,得到一种可接受的药物剂型。
在另一个实施方案中,水悬浮液组合物被冷冻。
在本发明的一个优选实施方案中,组合物包括由亚微米到微米大小的伊曲康唑粒子的水悬浮液,其含量为0.01-50%w/v,这些粒子被如下物质所包裹:0.001-5%w/v的胆汁盐(例如脱氧胆酸盐)、0.001-5%w/v的聚烷氧乙醚(例如泊洛沙姆188)和被加入以调节配制渗透压的甘油。
在本发明的另一个优选实施方案中,组合物包括伊曲康唑的水悬浮液,其含量为约0.01-50%w/v,这些粒子被如下物质所包裹:约0.001-5%w/v的胆汁盐(例如脱氧胆酸盐)、0.001-5%w/v的聚乙烯-660-羟基硬脂酸酯(w/v)和被加入以调节配制渗透压的甘油。
在本发明的另一个优选实施方案中,组合物包括伊曲康唑的水悬浮液,其含量为约0.01-50%w/v,这些粒子被如下物质所包裹:约0.001-5%聚乙烯-660-羟基硬脂酸酯(w/v)和被加入以调节配制渗透压的甘油。
在本发明的还一个优选实施方案中,组合物包括伊曲康唑的水悬浮液,其含量为0.01-50%w/v,这些粒子被约0.001-5%(w/v)的清蛋白所包裹。
在又一个优选实施方案中,本发明的组合物通过微量沉淀方法制得,该方法包括如下步骤:(i)在与水混溶的第一溶剂中溶解抗真菌剂得到一种溶液;(ii)把上述溶液和第二水性溶剂混合,得到预悬浮液;(iii)向预悬浮液中加入能量,形成如下粒子,其平均有效粒子尺寸小于50μm;更优选小于约7μm,甚至更优选小于约2μm,甚至更优选小于约400nm,最优选小于约100nm或任意范围或其中各范围的组合,其中抗菌剂在第一溶剂中的溶解度比在第二溶剂中大,第一溶剂或第二溶剂包括一种或多种表面活性剂,这些表面活性剂选自:非离子型表面活性剂、离子型表面活性剂、生物学来源的表面活性剂、和氨基酸以及它们的衍生物。
参考附图和伴随的说明,本发明的这些和其他方面和特征将会被讨论。
附图简述:
图1是三唑类抗真菌剂的分子结构通式;
图2是伊曲康唑的分子结构式;
图3是用于本发明的微量沉淀过程的方法A的示意图,以制备悬浮液;
图4是用于本发明的微量沉淀过程的方法B的示意图,以制备悬浮液;
图5是一个曲线图,该图比较了SPORANOX和本发明的伊曲康唑的制剂1悬浮液的药物代谢动力学,其中ITC=在制剂1(80mg/kg)推注后测量的伊曲康唑的血浆浓度;ITC-OH=在制剂1(80mg/kg)推注后测量的初级代谢产物羟基伊曲康唑的血浆浓度;总计=在制剂1(80mg/kg)推注后测量的伊曲康唑和羟基伊曲康唑(ITC+ITC-OH)的联合浓度;Sporanox-ITC=在20mg/kg的Sporanox IV推注后测量的伊曲康唑的血浆浓度;Sporanox-ITC-OH=在20mg/kg的Sporanox IV推注后测量的初级代谢产物羟基伊曲康唑的血浆浓度;Sporanox-总计=在20mg/kg的Sporanox IV推注后测量的伊曲康唑和羟基伊曲康唑(ITC+ITC-OH)的联合浓度;
图6是一个曲线图,该图比较了用SPORANOX(顶面板)和制剂1(底面板)治疗的平均体重和白色念珠菌菌落计数数据;
图7是一个曲线图,该图显示了在各种剂量的伊曲康唑悬浮液制剂(制剂1)给药后,伊曲康唑(1-ITC)和它的代谢物羟基-伊曲康唑(1-ITC-OH)在肾中的分布(在每个数据点旁边的数字表示在肾中发现的真菌菌落计数,这与由该数据点表示的悬浮液剂量有关);
图8是一个曲线图,该图显示了肾中的真菌计数,它随着肾中伊曲康唑含量的升高而下降。(注:S=SPORANOX,N=制剂1的纳米悬浮液)。
优选实施方案详述
尽管本发明容许的实施方案存在许多形式,但如图所示,将在本文中详细描述其具体实施方案,应理解:所公开内容被认为是本发明原理的例证,不是用于将本发明限于所述的具体实施方案。
本发明涉及一种抗真菌组合物,它包括用一种或多种表面活性剂包衣的亚微米到微米大小的抗真菌剂粒子的水悬浮液。由光散射法(HORIBA)或微观测量法测定,抗真菌剂粒子直径的容重粒子大小应小于约50μm。更优选地,粒子尺寸应该小于约7μm,更优选小于约2μm,甚至更优选小于约400nm,甚至更优选小于约200nm,最优选小于约100nm、或任意范围或其中范围的组合。
抗真菌剂优选是水溶性差的有机化合物。“水溶性差”是指化合物的水溶性小于10mg/ml,优选小于1mg/ml。抗真菌剂的优选种类是三唑类抗真菌剂,它的分子结构通式如图1所示。三唑类抗真菌剂的例子包括但不限于:伊曲康唑、酮康唑、咪康唑、氟康唑、瑞扶康唑、伏立康唑、沙康唑、艾伯康唑、genaconazole、和泊沙康唑。本发明优选的抗真菌剂是伊曲康唑。伊曲康唑的分子结构如图2所示。
本发明适于医药用途。这些组合物能通过各种途径进行给药。优选的给药途径是肠道外和口服。肠道外给药的方式包括静脉内注射、动脉内注射、鞘内注射、腹膜内注射、眼内注射、关节内注射、肌肉注射、皮下注射等。本发明也可以通过其它途径给药,包括口服、面颊、牙周、直肠、鼻、肺、经皮或局部。在本发明的一个实施方案中,组合物的水介质被除去形成干粒子。除去水介质的方法可以是本领域所知的任一种方法。一个例子是蒸发。另一个例子是冷冻干燥或冻干法。然后将干粒子制成任意令人满意的物理形式,其包括但不限于:溶液、片剂、胶囊、悬浮液、乳膏、洗剂、乳剂、气雾剂、粉剂、包含到用于持续释放的贮存器或基质装置中(例如植入物或透皮贴剂)等。这些药物形式的给药途径包括但不限于:肠道外、口服、面颊、牙周、直肠、鼻、肺、经皮和局部等。此外,活性药物试剂可以通过受控的或持续的释放剂型递送,包含到递药装置如可植入装置和透皮贴剂中。药物可以被配制用于系统递送或用于组织和/或受体特异性寻靶。
本发明的水悬浮液也可以被冷冻以提高贮藏稳定性。冷冻水悬浮液来提高稳定性在普通转让和共同未决的美国专利申请序列号No.60/347,548中被公开,该专利引入本文以供参考,并成为本文的一部分。
在本发明的一个实施方案中,抗真菌剂的含量按重量体积比(w/v)计优选为约0.01%至约50%,更优选约0.05%至约30%w/v,最优选约0.1%至约20%w/v。
本发明中用于包裹粒子的合适的表面活性剂可选自:离子型表面活性剂、非离子型表面活性剂、生物学来源的表面活性剂、或氨基酸和它们的衍生物。离子型表面活性剂可以是阴离子型表面活性剂或阳离子型表面活性剂。
合适的阴离子型表面活性剂包括但不限于:月桂酸钾、月桂基硫酸钠、十二烷基硫酸钠、烷基聚氧乙烯硫酸酯、藻酸钠、琥珀酸二辛酯磺酸钠、丙三酯、羧甲基纤维素钠、胆酸和其它胆汁酸(例如,胆酸、脱氧胆酸、甘氨胆酸、牛磺胆酸、甘脱氧胆酸(glycodeoxycholic acid))及其盐(例如脱氧胆酸钠等)。
合适的阳离子型表面活性剂包括但不限于:季铵化合物,例如苯扎氯铵、十六烷基三甲基溴化铵、月桂基二甲基苄基氯化铵、酰基肉碱盐酸盐、或烷基卤化吡啶鎓。
合适的非离子型表面活性剂包括:聚氧乙烯脂肪醇醚(Macrogol和Brij)、聚氧乙烯山梨聚糖脂肪酸酯(Polysorbates)、聚氧乙烯脂肪酸酯(Myrj)、山梨聚糖酯(Span)、甘油单硬脂酸酯、聚乙二醇、聚丙二醇、十六醇、十六醇十八醇混合物、十八醇、芳烷基聚醚醇、聚氧乙烯-聚氧丙烯共聚物(poloxomers)、polaxamines、甲基纤维素、羟基纤维素、羟丙基纤维素、羟丙基甲基纤维素、非结晶纤维素、多糖,包括淀粉和淀粉衍生物,比如羟乙基淀粉(HES)、聚乙烯醇、和聚乙烯吡咯烷酮。在本发明的一个优选形式中,非离子型表面活性剂是聚氧乙烯-聚氧丙烯共聚物,优选丙二醇和乙二醇的嵌段共聚物。这些聚合物以商品名POLOXAMER出售,有时也称为PLURONIC,并由包括Spectrum Chemical和Ruger的几个供应商销售。聚氧乙烯脂肪酸酯中包括具有短烷基链的那些物质。这种表面活性剂的一个例子是BASFAktiengesellschaft生产的SOLUTOL HS 15,聚乙烯-660-羟基硬脂酸酯。
合适的生物学来源的表面活性剂包括如下分子如清蛋白、酪蛋白、肝素、水蛭素、或其它合适的蛋白质或多糖等。其它合适的表面活性剂包括任意氨基酸,比如亮氨酸、丙氨酸、缬氨酸、异亮氨酸、赖氨酸、天冬氨酸、谷氨酸、甲硫氨酸、苯丙氨酸、或这些氨基酸的其它衍生物,比如酰胺或酯衍生物以及由这些氨基酸形成的多肽。
优选的离子型表面活性剂是胆汁盐,优选的胆汁盐是脱氧胆酸盐。优选的非离子型表面活性剂是聚烷氧基醚,优选的聚烷氧基醚是Poloxamer 188。另一种优选的非离子型表面活性剂是Solutol HS 15(聚乙烯-660-羟基硬脂酸酯)。还一种优选的非离子表面活性剂是羟乙基淀粉。优选的生物学来源的表面活性剂是清蛋白。
在本发明的另一个实施方案中,表面活性剂的含量优选为约0.001%至5%w/v,更优选从约0.005%至约5%w/v,最优选约0.01%至5%w/v。
在本发明的优选实施方案中,粒子悬浮于还包含pH调节剂的水介质中。合适的pH调节剂包括但不限于:三羟甲基氨基甲烷缓冲液、磷酸盐、醋酸盐、乳酸盐、THAM(三(羟甲基)氨基甲烷)、葡甲胺(N-甲基葡萄糖胺)、柠檬酸盐、氢氧化钠、盐酸、和氨基酸例如甘氨酸、精氨酸、赖氨酸、丙氨酸和亮氨酸。水介质可以另外包含渗透压调节剂,例如但不限于甘氨酸、单糖如葡萄糖,和糖醇如甘露醇和山梨糖醇。
在本发明的优选实施方案中,组合物包括伊曲康唑粒子的水悬浮液,其含量为0.01-50%w/v,这些粒子被如下物质所包裹:0.001-5%w/v的胆汁盐(例如脱氧胆酸盐),0.001-5%w/v的聚烷氧醚(例如Poloxamer 188)、和被加入以调节配制渗透压的甘油。
在本发明的另一个优选实施方案中,组合物包括伊曲康唑的水悬浮液,其含量为约0.01-50%w/v,这些粒子被如下物质所包裹:约0.001-5%w/v的胆汁盐(例如脱氧胆酸盐),0.001-5%w/v的聚乙烯-660-羟基硬脂酸酯、和被加入以调节配制渗透压的甘油。
在本发明的另一个优选实施方案中,组合物包括伊曲康唑的水悬浮液,其含量为约0.01-50%w/v,这些粒子被如下物质所包裹:约0.001-5%w/v的聚乙烯-660-羟基硬脂酸酯、和被加入以调节配制渗透压的甘油。
在本发明的还一个优选实施方案中,组合物包括伊曲康唑的水悬浮液,其含量为0.01-50%w/v,这些粒子被约0.001-5%w/v的清蛋白所包裹。
在本发明中,制备这种悬浮液的方法在普通转让和共同未决的美国专利申请序列号09/874,499;09/874,799;09/874,637;和10/021/692中被公开;这些专利引入本文以供参考,并成为本文的一部分。制备这种悬浮液以用于实施本发明的一般方法如下所述。
这些方法通常被分为三个一般类别。每一类都具有如下步骤:(1)在与水混溶的第一有机溶剂中溶解抗真菌剂,得到第一溶液;(2)第一溶液与第二水溶剂混合,使抗真菌剂沉淀,得到预悬浮液;(3)以高剪切力混合或加热的形式向预悬浮液中加入能量,产生具有上述期望尺寸范围的抗真菌剂的稳定形式。
根据抗真菌剂的物理性质区别这三类方法,这些性质通过X-光衍射研究、差示扫描量热法(DSC)研究、或其它合适的研究确定,所述研究在加入能量步骤之前和之后进行。在第一类方法中,在加入能量步骤之前处于预悬浮液的抗真菌剂为无定形、半结晶形、或过冷液体形式,并具有平均有效的粒子大小。在加入能量步骤之后,抗真菌剂处于结晶形,其平均有效的粒子大小基本上与预悬浮液相同(也就是小于约50μm)。
在第二类方法中,在加入能量步骤之前抗真菌剂处于结晶形,具有平均有效的粒子大小。在加入能量步骤之后,抗真菌剂处于结晶形,其平均有效的粒子大小基本上与加入能量步骤之前的相同,但是在加入能量步骤之后的晶体不太可能聚集。
通过激光动态光散射法和光学显微术可观察有机化合物的较低聚集趋势。
在第三类方法中,在增加能量步骤之前抗真菌剂处于结晶形,其易碎且具有平均有效的粒子大小。“易碎”是指粒子易碎,更容易碎裂成更小的粒子。在加入能量步骤之后,有机化合物处于结晶形,其平均有效粒子大小比预悬浮液的晶体小。与不易碎的结晶形态的有机化合物相比,通过采取必要的步骤来放置易碎的结晶形的有机化合物,能更快和更有效地进行后续的加入能量步骤。
加入能量步骤能以任何方式进行,其中预悬浮液被暴露于空化、剪切或冲击力。在本发明的一个优选形式中,加入能量步骤是退火步骤。退火在本发明中是指:通过单一或重复施加能量(直接加热或机械应力),紧接着热弛豫,把热力学不稳定的物质转变成更稳定的形式。这种能量的降低可以通过把固体形式从不太规则的形式转变为比较规则的晶格结构来实现。或者,这种稳定化可以通过表面活性剂分子在固-液界面的重排来实现。
这三种方法将会在下面分别讨论。但是应理解,在下面要讨论的任一类方法中,要考虑待处理的任何药物,来选择工艺条件,如表面活性剂或其组合的选择、表面活性剂的用量、反应温度、溶液的混合速度、沉淀速度等。
第一类方法以及第二和第三类方法可进一步被划分为两个子类:方法A和B,它们分别以图解形式显示于图3和图4中。
本发明的第一溶剂为一种溶剂或多种溶剂的混合,其中相关的抗真菌剂是相对可溶的,而且可以与第二溶剂混溶。这些溶剂的例子包括但不限于:聚乙烯吡咯烷酮、N-甲基-2-吡咯烷酮(也称为N-甲基-2-吡咯烷酮)、2-吡咯烷酮、二甲亚砜、二甲基乙酰胺、乳酸、甲醇、乙醇、异丙醇、3-戊醇、正丙醇、甘油、丁二醇(丁二醇)、乙二醇、丙二醇、单酰化和二酰化的单酸甘油酯(比如甘油辛酸酯)、二甲基异山梨醇、丙酮、二甲基甲酰胺、1、4-二恶烷、聚乙二醇(比如PEG-4、PEG-8、PEG-9、PEG-12、PEG-14、PEG-16、PEG-120、PEG-75、PEG-150)、聚乙二醇酯(其例子如PEG-4二月桂酸酯、PEG-20二月桂酸酯、PEG-6异硬脂酸酯、PEG-8棕榈酸硬脂酸酯、PEG-150棕榈酸硬脂酸酯)、聚乙二醇山梨聚糖(比如PEG-20山梨聚糖异硬脂酸酯)、聚乙二醇单烷基醚(其例子如PEG-3二甲基醚、PEG-4二甲基醚)、聚丙二醇(PPG)、聚藻酸亚丙酯、PPG-10丁二醇、PPG-10甲基葡萄糖醚、PPG-20甲基葡萄糖醚、PPG-15硬脂醚、丙二醇二辛酸酯/二癸酸酯、丙二醇月桂酸酯。
方法A
在方法A中(见图3),抗真菌剂首先溶解于第一溶剂中得到第一溶液。根据抗真菌剂在第一溶剂中的溶解性,抗真菌剂的加入量为约0.01%(w/v)至约50%(w/v)。必须将浓缩物从约30℃加热到约100℃,以确保抗真菌剂在第一溶剂中完全溶解。
提供第二水溶液,向其中加入一种或多种表面活性剂。该表面活性剂选自如上所述的离子型表面活性剂、非离子型表面活性剂、或生物学来源表面活性剂。
还希望向第二溶液中加入pH调节剂,比如氢氧化钠、盐酸、三羟甲氨基甲烷缓冲液或柠檬酸盐、醋酸盐、乳酸盐、葡甲胺或类似物。第二溶液的pH范围应该在约3到约11之间。
在本发明的一种优选形式中,制备亚微米大小的抗真菌剂粒子的方法包括将第一溶液加入到第二溶液的步骤。加入速度取决于抗真菌剂的批量大小和沉淀动力学。典型地,对于小规模实验室方法(制备1升),加入速度为约0.05cc/分钟至约10cc/分钟。在加入过程中,溶液应该处于持续搅拌状态。利用光学显微镜法已经观察到,形成了无定形粒子、半结晶固体或过冷液体以得到预悬浮液。该方法另外包括如下步骤:使预悬浮液进行退火步骤,以使无定形粒子、过冷液体或半结晶固体转变为更稳定的固态结晶。所得粒子具有平均有效粒子尺寸,这由动态光散射法(例如在上述范围中的光相关性光谱学、激光衍射、小角激光散射(LALLS)、中角激光散射(MALLS)、遮光法(例如Coulter法)、流变学或显微镜方法(光学或电子))测量得到。
能量加入步骤包括通过超声处理、均化、逆流均化(例如,MiniDeBEE2000均化器,得自BEE Incorporated,NC,在该装置中,流体射流沿着第一通道被导引,在第一通道中放入一个结构,使流体以受控流动途径沿着新的通道被改变方向,从而乳化或混合该流体)、微流态化、或其它能提供撞击、剪切或空化力的方法加入能量。在这个阶段样品可以被冷却或加热。在本发明的一种优选形式中,通过均化实施退火步骤。在本发明的另一种优选形式中,退火可以通过乳化装置的使用来实现,其记述于美国专利5,720,551中,该专利被引入本文以供参考,并在此处成为本文的一部分。
根据退火速度,希望将加工样品的温度调节到约-30℃至30℃的范围。或者,为了在加工的固体中达到一个理想的相变,也有必要在退火步骤阶段将预悬浮液加热到约30℃至约100℃的温度范围。
方法B
方法B与方法A在下列方面有区别。第一个区别是将一种表面活性剂或几种表面活性剂的组合加入到第一溶液中。该表面活性剂可以选自如上所述的离子型表面活性剂、非离子型表面活性剂、或生物学来源表面活性剂。
假如在制剂中使用了注射用水,并且采用了用于溶液灭菌的恰当方式,那么应用本发明所述方法得到的药物悬浮液就可以作为一种可注射的溶液直接给药。可以通过药物浓缩液(药物、溶剂和任选的表面活性剂)和稀释介质(水、任意的缓冲系和表面活性剂)在混合得到预悬浮液之前的单独灭菌来完成灭菌。灭菌方法包括首先通过3.0微米的滤器进行预过滤,之后通过0.45微米粒子滤器过滤,之后用蒸汽或加热灭菌、或用两次重复的0.2微米膜滤器进行灭菌过滤。
任选地,无溶剂悬浮液可以通过沉淀后除去溶剂来制备。这能通过离心过滤、透析、渗滤、力场分馏、高压过滤、或本领域众所周知的其它分离技术来完成。典型地,通过一到三次连续的离心过滤可以彻底除去N-甲基-2-吡咯烷酮;在每次离心过滤之后,上清液被轻轻倒出并抛弃。没有有机溶剂的新鲜量取的悬浮液媒介物被加到剩下的固体中,通过均化来分散该混合物。本领域的其他技术人员将认识到,其它高剪切混合技术可以应用在这个再生步骤中。
此外,可以通过利用上述段落中描述的分离方法,将任何不理想的赋形剂如表面活性剂等替代成一种更理想的赋形剂。在离心过滤或过滤之后,溶剂和第一媒介物可以随上清液一起抛弃。然后,可以加入一种没有溶剂和没有第一赋形剂的新鲜量取的悬浮液赋形剂。或者,可以加入新的表面活性剂。例如,在离心过滤和除去上清液后,由药物、N-甲基-2-吡咯烷酮(溶剂)、Poloxamer 188(第一赋形剂)、脱氧胆酸钠、丙三醇和水组成的悬浮液可以被磷脂(新表面活性剂)、丙三醇和水来代替。
I.第一类方法
第一类方法一般包括如下步骤:在水混溶的第一溶剂中溶解抗真菌剂,之后将该溶液和一种水溶液混合以得到预悬浮液,其中抗真菌剂处于无定形形式、半结晶形式、或过冷液体形式,这通过X射线衍射研究、DSC、光学显微镜法或其它分析技术测量,并具有平均有效粒子尺寸,其范围在上述的一个有效粒子尺寸范围中。混合步骤之后是能量加入步骤,本发明中的优选形式是退火步骤。
II.第二类方法
第二类方法包括基本上与第一类方法中的步骤相同的步骤,但是在下列方面有不同。对于预悬浮液的X射线衍射、DSC和其它合适的分析技术显示,抗真菌剂处于结晶形式,并具有平均有效粒子尺寸。在能量加入步骤之后,抗真菌剂具有与在能量增加步骤之前基本上相同的平均有效粒子尺寸,但是当与预悬浮液粒子相比时,该抗真菌剂聚集成更大粒子的趋势较小。不受理论的约束,据信粒子稳定性的区别可能归因于表面活性剂分子在固液界面的重有序化。
III.第三类方法
第三类方法修改了第一类和第二类方法中的前两个步骤,以确保在预悬浮液中的抗真菌剂处于易碎形式且具有平均有效粒子尺寸(例如细长针和薄板)。通过选择合适的溶剂、表面活性剂或表面活性剂的组合、单独溶液的温度、混合速度和沉淀速度等,可以形成易碎粒子。通过在第一溶液和水溶液混合的步骤中引入晶格缺陷(例如晶体的裂开面)也可以增强易碎性。这通过例如在沉淀步骤中提供的快速结晶而产生。在能量加入步骤中,这些易碎晶体被转变成晶体,该晶体在动力学上被稳定,并且其平均有效粒子尺寸比预悬浮液的要小。“在动力学上被稳定”是指,与在动力学上未被稳定的粒子相比,在动力学上被稳定的粒子聚集的趋势下降。在这种情况下,能量加入步骤导致易碎粒子的碎裂。与没有采取步骤使有机化合物处于易碎形式的加工相比,通过确保预悬浮液粒子处于易碎状态,有机化合物能更容易更快地被制成在所需尺寸范围的粒子。
实施例1:1%伊曲康唑悬浮液的制备
每100mL悬浮液包含:
伊曲康唑 1.0g(1.0%w/v)
脱氧胆酸钠盐一水合物 0.1g(0.1%w/v)
Poloxamer 188,NF 0.1g(0.1%w/v)
丙三醇,USP 2.2g(2.2%w/v)
氢氧化钠,NF(0.1N或1.0N) 用于pH调节
盐酸,NF(0.1N或1.0N) 用于pH调节
注射用无菌水,USP QS
目标pH(范围) 8.0(6到9)
制备微量沉淀用的表面活性剂溶液(2升)
将注射用无菌水注入适当清洁的池中并搅拌。加入所需量的丙三醇,搅拌直至溶解。加入所需量的脱氧胆酸钠盐一水合物,搅拌直至溶解。如果必要,用最小量的氢氧化钠和/或盐酸将表面活性剂溶液的pH调节到8.0。用0.2μm滤器过滤该表面活性剂溶液。定量地将表面活性剂溶液转移到为均化器提供的容器中。在加料漏斗中边混合边冷却该表面活性剂溶液。
制备替换溶液
制备4升替换溶液。将WFI注入适当清洁的池中并搅拌。将称重的Poloxamer 188(Spectrum Chemical)加到量过体积的水中。开始混合Poloxamer 188/水的混合物,直到Poloxamer 188完全溶解。加入所需量的丙三醇,搅拌直至溶解。一旦丙三醇已经完全溶解,就加入所需量的脱氧胆酸钠盐一水合物,并搅拌直至溶解。如果必要,用最小量的氢氧化钠和/或盐酸将洗液的pH调节到8.0。用0.2μm膜滤器过滤该替换溶液。
制备药物浓缩物
对于2L的批料,将120.0mL的N-甲基-2-吡咯烷酮加到250mL烧杯中。称量2.0g Poloxamer188。称量20.0g伊曲康唑(Wyckoff)。将称重的Poloxamer 188和N-甲基-2-吡咯烷酮转移到250mL烧杯中。搅拌直至溶解,然后加入伊曲康唑。加热搅拌直至溶解。将该药物浓缩物冷却至室温,用0.2微米的滤器过滤。
微量沉淀
将足够的WFI加到表面活性剂溶液中,该表面活性剂已经在供应均化器的容器中,从而获得想要的目标浓缩物。当该表面活性剂溶液被冷却后,连续混合下开始将药物浓缩物加入到该表面活性剂溶液中。
均化
慢慢地增加均化器的压力,直到操作压力达到10,000psi。边混合边循环均化该悬浮液。对于在50Hz下的2,000mL的悬浮液,通过一次应需要约54秒。均化后,采集20mL样品用于粒子尺寸分析。冷却该悬浮液。
洗涤替换
然后将该悬浮液分装到500mL离心瓶。离心,直到发现洁净的沉淀分离物。测量上清液的体积,并用更早以前制备的新鲜的替换溶液来替换。定量地将每个离心瓶中的沉淀物转移到适当清洁的带标签的容器中,用于再悬浮(合并样品)。合并样品的再悬浮在高剪切混合机中进行,直到看不见明显的块状物。采集20mL样品用于粒子尺寸分析。
然后将该悬浮液分装到500mL离心瓶。离心,直到发现洁净的沉淀分离物。测量上清液的体积,并用更早以前制备的新鲜的替换溶液来替换。定量地将每个离心瓶中的沉淀物转移到适当清洁的带标签的容器中,用于再悬浮(合并样品)。合并样品的再悬浮在高剪切混合机中进行,直到看不见明显的块状物。采集20mL样品用于粒子尺寸分析。
第二次均化
将上述悬浮液转移到均化器的加料漏斗中,在混合下冷却该悬浮液。慢慢地增加均化器的压力,直到操作压力达到10,000psi。边监控溶液的温度边进行均化。均化后,冷却悬浮液并采集三份30mL样品用于粒子分析。将剩余的悬浮液收集到2升的瓶子中。
填充
基于可接受的粒子尺寸确定测试(指50nm到2微米的容重直径),将30mL样品采集到带橡皮塞的50mL玻璃小瓶中。
实施例2:伊曲康唑悬浮液的其它制剂
伊曲康唑悬浮液与不同组合的表面活性剂的其它制剂也能用实施例1中描述的方法来制备。表1总结了各种伊曲康唑悬浮液的表面活性剂的组成。
表1:各种1%伊曲康唑悬浮液组成的总结
制剂编号 | 制剂中的表面活性剂 | 量* |
1 | Poloxamer 188脱氧胆酸丙三醇 | 0.1%0.1%2.2% |
2 | Poloxamer 188脱氧胆酸丙三醇 | 0.1%0.5%2.2% |
3 | Poloxamer 188脱氧胆酸丙三醇 | 2.2%0.1%2.2% |
4 | Poloxamer 188脱氧胆酸丙三醇 | 2.2%0.5%2.2% |
9 | Solutol脱氧胆酸丙三醇 | 0.3%0.5%2.2% |
14331-1 | Solutol丙三醇 | 1.5%2.2% |
14443-1 | 清蛋白 | 5% |
*%按最终体积悬浮液的重量计算(w/v)
实施例3:市售伊曲康唑制剂(SPORANOX)和本发明悬浮液组合物之间的急性毒性比较。
市售伊曲康唑制剂(SPORANOX)的急性毒性与本发明的各种1%伊曲康唑制剂的急性毒性相比较,结果列于表1中。SPORANOX来自Janssen Pharmaceutical Products,LP.。它以被羟丙基-β-环糊精溶解的1%静脉内(I.V.)溶液的形式使用。结果列于表2中,对每种制剂指出了最大容受剂量(MTD)。
表2:各种伊曲康唑制剂的急性毒性比较
制剂编号 | 结果与结论 |
SPORANOXI.V. | LD10=30mg/kgMTD=20mg/kg(轻微共济失调) |
1 | MTD=320mg/kg;NOEL=80mg/kg脾obsb:320mg/kg红耳/足:≥160mg/kg |
2 | MTD=320mg/kg脾obsb:320mg/kg轻微嗜睡:320mg/kg血尿:≥80mg/kg尾obsc:≥40mg/kg |
3 | MTD=160mg/kg;NOEL=80mg/kg脾obsb:320mg/kg红耳/足:≥160mg/kg |
4 | MTD=160mg/kgLD20=320mg/kg脾obsb:320mg/kg轻微嗜眠:320mg/kg血尿:≥40mg/kg尾obsc:≥40mg/kg |
9 | LD60=320mg/kg;MTD=160mg/kg脾obsb:320mg/kg尾obs:320mg/kg红耳/足:≥160mg/kg血尿:≥40mg/kg |
14331-1 | MTD=40mg/kg;NOEL=40mg/kgLD40=80mg/kg |
14443-1 | LD40=80mg/kg;NOEL=40mg/kg |
a环糊精=羟丙基-β-环糊精
b脾obs=增大和/或苍白
c尾obs=灰色到黑色和/或坏死
LD50=导致50%死亡率的致死量
NOEL=无影响浓度
MTD=最大耐受剂量
实施例4:SPORANOX与伊曲康唑悬浮液制剂的药物代谢动力学的比较
年轻成年雄性Sprague Dawley大鼠被静脉(IV)处理,用20mg/kg的SPORANOX注射剂或制剂1通过尾部静脉以1ml/min的速度单独注射。给药后,动物被麻醉并且在不同的时间点(n=3)采集回流血液。时间点如下:0.03、0.25、0.5、1、2、4、6、8、24、48、96、144、192、288和360小时(SPORANOX注射剂只到192小时)。血液和EDTA一起被收集到试管中,并以3200rpm的速度离心分离15分钟,以分离血浆。在分析以前血浆在-70℃冷冻储藏。母体伊曲康唑和代谢物羟基-伊曲康唑的浓度用高效液相色谱仪(HPLC)测定。伊曲康唑(ITC)和羟基-伊曲康唑(OH-ITC)的药物代谢动力学(PK)参数用WinNonlinProfessional Version3.1(Pharsight Corp.,Mountain View,CA)的非分割方法获得。
表3提供了由每个伊曲康唑制剂确定的血浆药物代谢动力学参数的比较。不再在48小时对20mg/kg的SPORANOX注射剂和在96小时对制剂1的血浆伊曲康唑进行检测。最初在0.25小时对20mg/kg的SPORANOX注射剂和制剂1的血浆羟基-伊曲康唑进行检测。不再在96小时对20mg/kg的SPORANOX注射剂和在144小时对制剂1的羟基-伊曲康唑进行检测。
表3:对Sporanox和悬浮液制剂在对大鼠IV给药后的血浆药物代谢动力学参数的比较
被分析物 | PK参数 | SPORANOXI.V. | 制剂1 |
伊曲康唑 | Cmax(μg/ml) | 13.2 | 30.41 |
Tmax(h) | 0.03 | 0.03 | |
AUC(0-∞)(μg.h/ml) | 28.25 | 16.70 | |
T1/2(h) | 5.36 | 14.36 | |
CL(μl/h) | 176.97 | 299.35 | |
MRT(h) | 4.48 | 13.29 | |
羟基-伊曲康唑 | Cmax(μg/ml) | 0.78 | 0.40 |
Tmax(h) | 4.0 | 24 | |
AUC(0-∞)(μg.h/ml) | 13.41 | 17.89 | |
T1/2(h) | 5.89 | 15.50 | |
MRT(h) | 12.17 | 30.99 |
图5比较了SPORANOX和伊曲康唑粒子悬浮液制剂1的药物代谢动力学(PK)。如上所示,因为该悬浮液制剂的毒性比SPORANOX要低,所以在这个同等毒性实验中它的给药量更高。SPORANOX以20mg/kg来给药,而制剂1以80mg/kg来给药。SPORANOX的血浆浓度在20小时内下降得较快。而本悬浮液制剂的伊曲康唑血浆浓度保持在高浓度约3-4倍长的时间。伊曲康唑的血浆浓度在30分钟时显示初始最小值。这与血浆浓度的最小值相符,该最小值是由脾和肝的巨噬细胞对药物纳米晶体的螯合作用所引起的,因此临时性地从循环中除去药物。但是,当巨噬细胞明显地释放药物进入循环,药物浓度就很快反弹。而且,如图5中羟基伊曲康唑代谢物的PK曲线所示,制剂1药物被有效地代谢。与SPORANOX制剂的代谢物PK曲线相比较,悬浮液制剂代谢物的出现速度被滞后。但是,对于悬浮液的母体分子来说,代谢物在循环中持续的时间比SPORANOX制剂的代谢物更长。当AUC(在血液浓度与时间曲线下面的面积)被剂量归一化之后,该悬浮液的生物利用度至少和SPORANOX一样。
实施例5:伊曲康唑的其它悬浮液制剂的药物代谢动力学研究
对不同的伊曲康唑制剂在各种不同剂量下也进行了药物代谢动力学的研究。其结果总结于表4中。
表4:各种伊曲康唑纳米悬浮液制剂在对大鼠IV给药后的血浆药物代谢动力学参数
被分析物 | PK参数 | 制剂1,40mg/kg | 制剂1,80mg/kg | 制剂3,80mg/kg |
伊曲康唑 | Cmax(μg/ml) | 119.16 | 446.33 | 365.09 |
Tmax(h) | 0.03 | 0.03 | 0.03 | |
AUC(0-∞)(μg.h/ml) | 42.67 | 143.7 | 108.87 | |
T1/2(h) | 23.95 | 25.89 | 38.46 | |
CL(μl/h) | 234.38 | 139.18 | 183.71 | |
MRT(h) | 24.37 | 27.45 | 31.21 | |
羟基-伊曲康唑 | Cmax(μg/ml) | 0.61 | 1.03 | 0.52 |
Tmax(h) | 24.0 | 24.0 | 24.0 | |
AUC(0-∞)(μg.h/ml) | 37.71 | 70.24 | 51.27 | |
T1/2(h) | 22.27 | 23.21 | 50.29 | |
MRT(h) | 43.06 | 46.80 | 60.81 |
实施例6:抗真菌功效研究
用9.5×106或3×106cfu C.albicans/ml盐水静脉一次接种的正常大鼠和免疫抑制(在接种前和接种当天每天施用泼尼松龙两次)大鼠,用SPORANOX注射剂每天1次静脉处理,连续处理10天,第一剂在接种后4到5小时施用。最初2天SPORANOX注射剂的剂量为5或20mg/kg,然后在余下8天为5或10mg/kg,这是由于以20mg/kg剂量给药2天后产生的毒性。类似地,用1×106.5cfu C.albicans/ml的盐水接种的免疫抑制大鼠,用制剂1每隔一天一次以20、40或80mg/kg静脉处理,共10天,在接种当天开始。在C.albicans接种后11天,杀死用SPORANOX注射剂和制剂1处理的大鼠,大鼠的肾被采集、称重和培养,用于C.albicans菌落数和伊曲康唑和羟基-伊曲康唑浓度的确定。当发现未处理的参照大鼠处于垂死状态或动物体重为20%时,采集其肾。另外,在每个研究过程中要定期测量体重。
用SPORANOX注射剂和制剂1处理的免疫抑制大鼠的比较结果列于表5和图6中。每天以10-20mg/kg的量注射SPORANOX看来比每天以5mg/kg的量注射SPORANOX的效果要略好。基于肾菌落数,每隔一天以20mg/kg的剂量施用制剂1看来与每天以20mg/kg的剂量施用SPORANOX注射剂的效果一样,可能比以5mg/kg(例如,推荐的临床剂量)的量施用SPORANOX注射剂更有效果,反之,基于肾菌落数(即C.albicans没有被检测)和升高的肾伊曲康唑浓度,较高剂量的制剂1看来更有效。
表5:平均C.albicans菌落数和伊曲康唑和羟基-伊曲康唑的肾中浓度
C.albicans效价 | 肾中浓度 | |||
处理 | 计数(cfu/g) | 发病率 | ITC(μg/g) | OH-ITC(μg/g) |
无处理(3×106cfu/ml) | 6.9×104 | 6/6 | -- | -- |
SPORANOX,5mg/kg,(3×106cfu/ml) | 96.5 | 6/6 | 1.2 | 1.5 |
SPORANOX,10-20mg/kg,(3×106cfu/ml) | 12.4 | 4/6 | 8.5 | 8.0 |
无处理(2.5×106cfu/ml) | 3.5×105 | 6/6 | -- | -- |
制剂1,20mg/kg,(2.5×106cfu/ml) | 5.3 | 4/6 | 6.1 | 5.7 |
制剂1,40mg/kg,(2.5×106cfu/ml) | 0 | 0/6 | 18.5 | 6.0 |
制剂1,80mg/kg,(2.5×106cfu/ml) | 0 | 0/6 | 41.2 | 6.2 |
图6是用SPORANOX(顶面板)与用制剂(底面板)1处理的平均体重和C.albicans菌落数的数据比较。
在上述实施例中,本发明中的抗真菌剂的粒子悬浮液制剂显示出比相同药物的常规完全溶解的制剂毒性更低。因此,可以施用更多的药物,而不会带来不良反应。因为在注射后药物粒子不会立即溶解,所以它们被捕获在肝和脾中的储藏库中。它们作为延长释放的避难所,允许不太频繁地给药。给药的剂量越大允许靶器官中出现的药物浓度就越高,在此处靶器官指肾(图7)。在该器官中药物浓度越高导致传染性有机体的杀死率越高(图8)。
实施例7:其它三唑类抗真菌剂的预示性实施例
本发明期望使用实施例1所述的方法制备亚微米或微米大小的三唑类抗真菌剂的1%悬浮液和实施例2所述的制剂,除了该抗真菌剂是除伊曲康唑以外的三唑类抗真菌剂。可用的三唑类抗真菌剂的例子包括但不陷于:酮康唑、咪康唑、氟康唑、瑞扶康唑、伏立康唑、沙康唑、艾伯康唑、genaconazole、和泊沙康唑。
实施例8:非三唑类抗真菌剂的预示性实施例
本发明期望使用实施例1所述的方法制备亚微米或微米大小的非三唑类抗真菌剂的1%悬浮液和实施例2所述的制剂,除了该抗真菌剂是除伊曲康唑以外的两性霉素B或氟胞嘧啶。
如上所述可以观察到,可以实施许多变化和修改而不背离本发明的精神和范围。应理解,对于本文说明的具体仪器没有任何限制,或应推断出对其没有任何限制。当然,旨在通过附加的权利要求书包括在该权利要求范围内的所有这些修改。
Claims (68)
1.一种包括亚微米到微米尺寸粒子的水悬浮液的组合物,所述粒子包含抗真菌剂,该抗真菌剂被至少一种选自如下类型的表面活性剂所包裹:离子型表面活性剂、非离子型表面活性剂、生物学来源表面活性剂、和氨基酸及它们的衍生物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于50μm。
2.如权利要求1所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于约7μm。
3.如权利要求1所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于约2μm。
4.如权利要求1所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于约400nm。
5.如权利要求1所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于100nm。
6.如权利要求1所述的组合物,其中抗真菌剂是三唑类抗真菌剂。
7.如权利要求6所述的组合物,其中三唑类抗真菌剂选自:伊曲康唑、酮康唑、咪康唑、氟康唑、瑞扶康唑、伏立康唑、沙康唑、艾伯康唑、genaconazole、和泊沙康唑。
8.如权利要求1所述的组合物,其中抗真菌剂是伊曲康唑。
9.如权利要求1所述的组合物,其中离子型表面活性剂选自:阴离子型表面活性剂和阳离子型表面活性剂。
10.如权利要求9所述的组合物,其中阴离子型表面活性剂选自:月桂酸钾、三乙醇胺硬脂酸脂、月桂基硫酸钠、十二烷基硫酸钠、烷基聚氧乙烯硫酸酯、藻酸钠、琥珀酸二辛酯磺酸钠、丙三酯、羧甲基纤维素钠、胆汁酸和它们的盐、和羧甲基纤维素钙。
11.如权利要求10所述的组合物,其中胆汁酸选自:胆酸、脱氧胆酸、甘氨胆酸、牛磺胆酸和甘脱氧胆酸。
12.如权利要求9所述的组合物,其中阳离子型表面活性剂选自:季铵化合物、苯扎氯铵、十六烷基三甲基溴化铵、壳聚糖和月桂基二甲基苄基氯化铵。
13.如权利要求1所述的组合物,其中非离子型表面活性剂选自:聚氧乙烯脂肪醇醚、山梨聚糖脂肪酸酯、聚氧乙烯脂肪酸酯、山梨聚糖酯、甘油单硬脂酸酯、聚乙二醇、十六醇、十六醇十八醇混合物、十八醇、poloxomers、poloxamines、甲基纤维素、羟基纤维素、羟丙基纤维素、羟丙基甲基纤维素、非结晶纤维素、聚乙烯醇和聚乙烯吡咯烷酮。
14.如权利要求1所述的组合物,其中生物学来源表面活性剂选自:清蛋白、肝素、酪蛋白和水蛭素。
15.如权利要求1所述的组合物,其中氨基酸选自:亮氨酸、丙氨酸、缬氨酸、异亮氨酸、赖氨酸、天冬氨酸、谷氨酸、甲硫氨酸、和苯丙氨酸。
16.如权利要求1所述的组合物,其中氨基酸衍生物是酰胺、酯、或多肽。
17.如权利要求1所述的组合物,其中表面活性剂是胆汁盐。
18.如权利要求17所述的组合物,其中胆汁盐是脱氧胆酸盐。
19.如权利要求1所述的组合物,其中表面活性剂是聚烷氧醚。
20.如权利要求19所述的组合物,其中聚烷氧醚是Poloxamer188。
21.如权利要求1所述的组合物,其中表面活性剂是羟乙基淀粉。
22.如权利要求1所述的组合物,其中表面活性剂是聚乙烯-660-羟基硬脂酸酯。
23.如权利要求1所述的组合物,其中表面活性剂是清蛋白。
24.如权利要求1所述的组合物,其中水介质还包括pH调节剂。
25.如权利要求24所述的组合物,其中pH调节剂选自:三羟甲基氨基甲烷缓冲液、磷酸盐、醋酸盐、乳酸盐、三(羟甲基)氨基甲烷、葡甲胺(N-甲基葡萄糖胺)、柠檬酸盐、氢氧化钠、盐酸和氨基酸。
26.如权利要求25所述的组合物,其中氨基酸选自:甘氨酸、精氨酸、赖氨酸、丙氨酸、和亮氨酸。
27.如权利要求1所述的组合物,还包括渗透压调节剂。
28.如权利要求27所述的组合物,其中渗透压调节剂选自:丙三醇、单糖和糖醇。
29.如权利要求28所述的组合物,其中单糖是右旋糖。
30.如权利要求28所述的组合物,其中糖醇是甘露醇或山梨糖醇。
31.如权利要求1所述的组合物,其中抗真菌剂的含量为从约0.01%至约50%w/v。
32.如权利要求1所述的组合物,其中抗真菌剂的含量为从约0.05%至约30%w/v。
33.如权利要求1所述的组合物,其中抗真菌剂的含量为从约0.1%至约20%w/v。
34.如权利要求1所述的组合物,其中表面活性剂的含量为从约0.001%至约5%w/v。
35.如权利要求1所述的组合物,其中表面活性剂的含量为从约0.005%至约5%w/v。
36.如权利要求1所述的组合物,其中表面活性剂的含量为从约0.01%至约5%w/v。
37.如权利要求1所述的组合物通过如下途径给药,该途径选自:肠道外、口服、面颊、牙周、直肠、鼻、肺和局部。
38.如权利要求1所述的组合物通过肠道外给药。
39.如权利要求38所述的组合物,其中肠道外给药选自:静脉内注射、动脉内注射、鞘内注射、腹膜内注射、眼内注射、关节内注射、肌肉注射和皮下注射。
40.如权利要求1所述的组合物,其中水介质被除去以得到干粒子。
41.如权利要求40所述的组合物,其中除去水介质的方法选自:蒸发和冷冻干燥。
42.如权利要求40所述的组合物,其中除去水介质的方法是冷冻干燥。
43.如权利要求40所述的组合物,其中干粒子被制成可接受的药剂形式。
44.如权利要求43所述的组合物,其中药剂形式选自:肠溶液、片剂、胶囊、悬浮液、乳膏、洗剂、乳剂、肺制剂、局部制剂、控制或持续释放制剂、和组织特异性靶向递送制剂。
45.如权利要求1所述的组合物,其中该组合物被冷冻。
46.一种包括亚微米到微米尺寸的伊曲康唑粒子的水悬浮液的组合物,该粒子被至少一种表面活性剂和一种渗透压调节剂所包裹,其中由激光衍射法测得纳米粒子的容重平均粒子尺寸小于50μm,且其中伊曲康唑的含量为约0.01%至约50%w/v,表面活性剂的含量为约0.001%至约5%。
47.如权利要求46所述的组合物,其中表面活性剂选自:胆汁盐、聚烷氧醚、羟乙基淀粉、聚乙烯-660-羟基硬脂酸酯、和清蛋白。
48.如权利要求47所述的组合物,其中胆汁盐是脱氧胆酸盐。
49.如权利要求47所述的组合物,其中聚烷氧醚是Poloxamer188。
50.如权利要求46所述的组合物,其中表面活性剂是羟乙基淀粉。
51.如权利要求46所述的组合物,其中表面活性剂是聚乙烯-660-羟基硬脂酸酯。
52.如权利要求46所述的组合物,其中表面活性剂是清蛋白。
53.如权利要求46所述的组合物,其中渗透压调节剂是丙三醇。
54.如权利要求46所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于7μm。
55.如权利要求46所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于2μm。
56.如权利要求46所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于400nm。
57.如权利要求46所述的组合物,其中由激光衍射法测得粒子的容重平均粒子尺寸小于100nm。
58.一种包含亚微米到微米尺寸伊曲康唑粒子的水悬浮液的组合物,该粒子被至少一种表面活性剂和一种渗透压调节剂所包裹,其中由激光衍射法测得粒子的容重平均粒子尺寸小于2μm,该表面活性剂选自:胆汁盐、聚烷氧醚、羟乙基淀粉、聚乙烯-660-羟基硬脂酸酯、和清蛋白,伊曲康唑的含量为约0.01%至约50%w/v,表面活性剂的含量为约0.001%至约5%。
59.如权利要求58所述的组合物,其中渗透压调节剂是丙三醇。
60.一种包含亚微米到微米尺寸伊曲康唑粒子的水悬浮液的组合物,该粒子被包括胆汁盐和聚烷氧醚的表面活性剂、和以丙三醇为渗透压调节剂的混合物所包裹,其中由激光衍射法测得粒子的容重平均粒子尺寸小于约2μm,且其中伊曲康唑的含量为约0.01%至约50%w/v,胆汁盐的含量为约0.001%至约5%w/v,聚烷氧醚的含量为约0.001%至约5%w/v,丙三醇的含量为约2.2%w/v。
61.如权利要求60所述的组合物,其中胆汁盐是脱氧胆酸盐。
62.如权利要求60所述的组合物,其中聚烷氧醚是Poloxamer188。
63.一种包含亚微米到微米尺寸伊曲康唑粒子的水悬浮液组合物,该粒子被包括胆汁盐和聚乙烯-660-羟基硬脂酸酯的表面活性剂、和以丙三醇为渗透压调节剂的混合物所包裹,其中由激光衍射测得粒子的容重平均尺寸小于2μm,且其中伊曲康唑的含量为约0.01%至约50%w/v,胆汁盐的含量为约0.001%至约5%w/v,聚乙烯-660-羟基硬脂酸酯的含量为约0.001%至约5%w/v,丙三醇的含量为约2.2%w/v。
64.一种制备抗真菌剂粒子的组合物的方法,包括如下步骤:
(i)在与水混溶的第一溶剂中溶解抗真菌剂得到一种溶液,该第一溶剂选自:N-甲基-2-吡咯烷酮、2-吡咯烷酮、二甲亚砜、二甲基乙酰胺、乳酸、醋酸和其它液体羧酸、甲醇、乙醇、异丙醇、3-戊醇、正丙醇、甘油、丁二醇、乙二醇、丙二醇、单酰化和二酰化的单酸甘油酯、二甲基异山梨醇、丙酮、二甲基甲酰胺、1,4-二恶烷、聚乙二醇、聚乙二醇酯、聚乙二醇山梨聚糖、聚乙二醇单烷基醚、聚丙二醇、聚藻酸亚丙酯、PPG-10丁二醇、PPG-10甲基葡萄糖醚、PPG-20甲基葡萄糖醚、PPG-15硬脂醚、丙二醇二辛酸酯、丙二醇二癸酸酯、丙二醇月桂酸酯;
(ii)把上述溶液和第二水性溶剂混合,得到预悬浮液;和
(iii)向预悬浮液中加入能量以形成如下粒子,其平均有效粒子尺寸小于50μm;
其中抗真菌剂在第一溶剂中的溶解度比在第二溶剂中的溶解度大,并且该第二溶剂包括一种或多种表面活性剂,其选自:非离子型表面活性剂、离子型表面活性剂、生物学来源表面活性剂、和氨基酸及它们的衍生物。
65.如权利要求64所述的组合物,其中平均有效粒子尺寸小于约7μm。
66.如权利要求64所述的组合物,其中平均有效粒子尺寸小于约2μm。
67.如权利要求64所述的组合物,其中平均有效粒子尺寸小于约400nm。
68.如权利要求64所述的组合物,其中平均有效粒子尺寸小于约100nm。
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- 2003-10-02 MX MXPA05003740A patent/MXPA05003740A/es unknown
- 2003-10-02 AU AU2003279785A patent/AU2003279785A1/en not_active Abandoned
- 2003-10-02 WO PCT/US2003/031411 patent/WO2004032902A1/en active Application Filing
- 2003-10-02 JP JP2004543135A patent/JP2006504733A/ja not_active Withdrawn
- 2003-10-02 CA CA002498488A patent/CA2498488A1/en not_active Abandoned
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102106832A (zh) * | 2011-02-12 | 2011-06-29 | 华中师范大学 | 酮康唑纳米混悬剂冻干粉及其制备方法 |
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BR0315215A (pt) | 2005-08-16 |
MXPA05003740A (es) | 2005-06-17 |
US20030072807A1 (en) | 2003-04-17 |
ZA200502740B (en) | 2005-10-13 |
AU2003279785A1 (en) | 2004-05-04 |
HK1079704A1 (zh) | 2006-04-13 |
KR20050055754A (ko) | 2005-06-13 |
CA2498488A1 (en) | 2004-04-22 |
JP2006504733A (ja) | 2006-02-09 |
NO20052285L (no) | 2005-05-10 |
NO20052285D0 (no) | 2005-05-10 |
WO2004032902A1 (en) | 2004-04-22 |
EP1565166A1 (en) | 2005-08-24 |
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