CN1121860C - 提高生物利用度的抗真菌组合物 - Google Patents
提高生物利用度的抗真菌组合物 Download PDFInfo
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- CN1121860C CN1121860C CN97196513A CN97196513A CN1121860C CN 1121860 C CN1121860 C CN 1121860C CN 97196513 A CN97196513 A CN 97196513A CN 97196513 A CN97196513 A CN 97196513A CN 1121860 C CN1121860 C CN 1121860C
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Abstract
含有下列物质的药用组合物：i)为(-)-(2R-顺式)-4-[4-[4-[4-[[5-(2，4-二氟代苯基)-四氢-5-(1H-1，2，4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基]-2，4-二氢-2-(S)-1-乙基-2-(S)-羟丙基]-3H-1，2，4-三唑-3-酮的抗真菌剂；ii)至少一种非-离子表面活性剂；和iii)稀释剂。该组合物使具有极低水溶性的抗真菌化合物在哺乳动物如人类中具有提高的生物利用度。
Description
技术领域
本发明涉及新的三唑抗真菌化合物的提高或改善了生物利用度的组合物。
背景技术
国际专利申请WO 95/17407号(1995年6月29日公开)介绍了一类新的四氢呋喃/三唑抗真菌化合物。发现其中的一个特殊的化合物(2R-顺式)-4-[4-[4-[4-[[5-(2，4-二氟代苯基)-四氢-5-(1H-1，2，4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基]-2，4-二氢-2-(S)-1-乙基-2-[(S)-羟丙基]-3H-1，2，4-三唑-3-酮在含水混悬剂中对偶发性的真菌例如曲霉属(Aspergillis)、假丝酵母属(Candida)、隐球酵母属(Cryptococcus)以及其它的偶发性真菌具有有效的抗真菌活性。然而，发现非水溶液组合物例如粉剂或颗粒剂的抗真菌活性和/或生物利用度降低，设想是由于该化合物极低的水溶性。因此需要提供抗真菌和/或生物利用度提高或改善的该抗真菌化合物的药用组合物。
发明内容
本发明涉及含有下列物质的药用组合物：
i)下式的抗真菌剂：
ii)至少一种非-离子表面活性剂；和
iii)稀释剂。
所述药用组合物也可以含有其它任选的本领域技术人员已知的赋形剂，例如iv)崩解剂，v)粘合剂，vi)润滑剂，助流剂(glident)和/或着色剂。该药用组合物也可以制成其它适当的剂型，例如胶囊剂(为固体填充的、半固体填充的或液体填充的)、片剂、复制粉剂或口服凝胶。
在另一个实施方案中，本发明涉及包含下列物质的药用组合物：
约18-50％(重量)的抗真菌剂；
约9-50％(重量)的至少一种非离子表面活性剂；
约12-60％(重量)的为微晶纤维素的稀释剂；
约4-10％(重量)的为交联羧甲基纤维素钠的崩解剂；
约3-6％(重量)的为聚乙烯吡咯烷酮的粘合剂；和
约0.3-1.5％(重量)的为硬脂酸镁的润滑剂；和
任选约3-8％(重量)的十二烷基硫酸钠。
我们令人吃惊和出乎意料地发现：在含有特别是抗真菌化合物的药用组合物中包含非离子表面活性剂，可以提高抗真菌化合物的生物利用度(否则具有极低的水溶性)。
也已经发现与水混悬剂相比，在含有特别是抗真菌化合物的药用组合物中包含非离子表面活性剂，可以提高抗真菌化合物的生物利用度。这些结果大大令人吃惊和出乎意料，因为已知的参考资料例如Peter G.Welling(Pharmacokinetics，Processes and Mathematics，AmericanChemical Society，Washington DC，ACS Monograph 185，1986，第57页)指出溶液和混悬剂产生的生物利用度一般比胶囊或片剂更令人满意。J.G.Nairn(Remington’s Pharmaceutical Sciences，第18版，1990，Mack Publishing Co.，第83章，第1519页)也指出因为药物是在溶解状态下被吸收，所以一般发现口服剂型的吸收率按下列顺序降低：水溶液＞水混悬剂＞胶囊或片剂。
本发明具有能够提供抗真菌化合物的药用组合物的优点，该组合物可以容易地制成具有有效抗真菌活性和/或生物利用度的非水溶液或“干燥”剂型，例如胶囊剂、片剂或粉剂。
WO 95/17407(1995年6月29日公开)公开了具有下式的抗真菌化合物和其酯以及醚或其药学上可接受的盐：
其中R1为被一个或两个羟基取代的直链或支链(C3-C8)烷基。在WO95/17407的实施例24和32中指出的上述类别的化合物中特别优选的化合物为抗真菌化合物：(-)-(2R-顺式)-4-[4-[4-[4-[[5-(2，4-二氟代苯基)-四氢-5-(1H-1，2，4-三唑-1-基甲基)呋喃-3-基]甲氧基]苯基]-1-哌嗪基]苯基]-2，4-二氢-2-[(S)-1-乙基-2-(S)-羟丙基]-3H-1，2，4-三唑-3-酮(此后指抗真菌化合物)；式：C37H42F2N8O4；分子量：700.8；m.p.164-165℃，[a]D 25-29℃±3(c＝1.0，CHCl3)，其结构用下式表示：
在抗真菌化合物生产的最后步骤或在常规的结晶步骤后，用常规的微粒化技术可以获得抗真菌化合物微粒化的颗粒。
在使用微粒化技术时，用常规的技术可以将抗真菌化合物微粒化至所需的粒度范围，例如使用球磨机、超声方法或优选使用流能磨碎机如trost流能磨(得自Plastomer Products，Newton，Pennsylvania18940)。当使用流能磨碎机时，所需的粒度可以通过改变向所述磨中加入抗真菌药的送料的速率获得。
约99％微粒化的抗真菌颗粒长度小于或等于100微米，其95％小于或等于90微米。优选约99％微粒化的颗粒长度小于或等于50微米，其95％小于或等于40微米。更优选约99％微粒化的颗粒长度小于或等于20微米，其95％小于或等于10微米。
所述组合物中该抗真菌化合物的用量为有效控制目的真菌。此量可以为该组合物重量的约2％-约85％，更优选5％-约80％，最优选约18％-约50％(重量)。在特定的剂型例如胶囊、片剂等中组合物的量可以为每一剂型含有约10-约500mg抗真菌化合物，优选约50-约200mg。例如在胶囊中可以含有约50或约100mg抗真菌剂。同样，在片剂中可以含有约50mg、约100mg或约200mg抗真菌化合物。
本发明的药用组合物可以制成任何适当的剂型，例如胶囊(为固体填充的、半固体填充的或液体填充的)、片剂、复制粉剂或口服凝胶。
用下列术语描述本发明的药用组合物、可以用于其制剂的成分以及评价其生物活性或生物利用度的方法。
剂型-指制成释放体系的含有抗真菌化合物以及无活性的成分的组合物，即片剂、胶囊剂、口服凝胶、复制粉剂或混悬剂。
胶囊-指由甲基纤维素、聚乙烯醇或变性明胶或淀粉制得的用于保存或容纳含有所述活性抗真菌化合物的组合物的特定的容器或外壳。硬壳胶囊一般由相对高胶凝强度的骨明胶和猪皮明胶的混合物制得。所述胶囊本身可以含有少量的染料、遮光剂、增塑剂和防腐剂。
片剂-指含有活性成分(抗真菌化合物)以及适当的稀释剂的压制或模塑的固体剂型。可以通过压制混合物或经湿法制粒、干法制粒或挤压获得的颗粒制备所述片剂。
口服胶凝剂-指分散或溶解于亲水半固体基质中的抗真菌药物。
复制粉剂指含有抗真菌药物和适当的稀释剂的粉末混合物，可以将其悬浮于水或糖浆中。
表面活性剂-指可以减少两个不相混溶的相间的界面张力的化合物，因为表面活性剂是含有两个局部的分子，一部分为亲水性的，另一部分为亲油性的。
非离子表面活性剂-指缺少静离子电荷并在含水介质中不会离解至明显程度的表面活性剂。非离子表面活性剂的性质主要取决于分子中亲水性和亲油性基团的比例。亲水性基团包括氧化乙烯基(-OCH2CH2-)和羟基。通过改变亲油性分子如脂肪酸中上述基团的数目，可获得从强亲油性和水不溶性化合物如单硬脂酸甘油酯到强亲水性和水溶性化合物如macrogol的物质。在这两种极端类型之间包括那些亲水性和亲油性基团的比例较均匀平衡的物质，如macrogol酯和醚以及脱水山梨醇衍生物。适当的非离子表面活性剂可发现于Martindale的The Extra Pharmacopoeia(第28版，1982，The Pharmaceutical Press，London，Great Britan，第370-379页)。这些非离子表面活性剂包括环氧乙烷和氧化丙烷的嵌段共聚物、脂肪酸的乙二醇和甘油酯及其衍生物、脂肪酸的聚氧乙烯酯(macrogol酯)、脂肪酸的聚氧乙烯醚及其衍生物(macrogol醚)、聚乙烯醇和脱水山梨醇酯。
优选的非离子表面活性剂为环氧乙烷和环氧丙烷的嵌段共聚物。
适当的环氧乙烷和环氧丙烷的嵌段共聚物一般称为“Poloxamers”，它包括下面化学结构所表示的那些物质：
其中a为从约10-约110的整数，优选约12-101，更优选约12-80；和
b为约20-约60的整数，更优选约20-约56；也优选约20-27。更优选，a为80，b为27，或者称为PluronicF68表面活性剂，BASFCorporation的商标名，Mount Olive，New Jersey，USA。PluronicF68表面活性剂也称为Poloxamer 188。该表面活性剂的平均分子量为8400，在20℃时为固体，77℃时粘度(Brookfield)为1000cps。其它适当的环氧乙烷和环氧丙烷的嵌段共聚物包括Pluronic F87，也称为Poloxamer 237，其中a为64，b为37；和Pluronic F127，也称为Poloxamer 407，其中a为101，b为56。
适当的脂肪酸的乙二醇酯和甘油酯以及它们的衍生物包括单油酸甘油酯和相似的水溶性衍生物。
适当的脂肪酸的聚氧乙烯酯(macrogol酯)包括聚氧乙烯蓖麻油和氢化蓖麻油衍生物；
适当的脂肪酸聚氧乙烯醚和它们的衍生物(macrogol醚)包括Cetomacrogel 1000、Lauromacrogols(一系列不同链长的macrogols的十二烷基醚)如Laureth 4、Laureth 9和Lauromacrogol 400。
适当的脱水山梨醇酯(脱水山梨醇中的一个或多个羟基与脂肪酸例如硬脂酸、棕榈酸、油酸或月桂酸形成的酯)包括，如Polysorbate 20、Polysorbate 40、Polysorbate 60、Polysorbate 65、Polysorbate 80、Polysorbate 85、脱水山梨醇单月桂酸酯、脱水山梨醇单油酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇单硬脂酸酯、脱水山梨醇倍半油酸酯、脱水山梨醇三油酸酯和脱水山梨醇三硬脂酸酯。
所述组合物中非离子表面活性剂的量为总组合物的约5-约50％(重量)，更优选为约5-约25％(重量)。
本发明的组合物也可任选含有阴离子表面活性剂，如十二烷基硫酸钠，其用量为总组合物的约1-约10％(重量)，更优选约3-约8％(重量)。
稀释剂-指通常用于补充所述组合物或剂型的主要部分的物质。适当的稀释剂包括糖，如乳糖、蔗糖、甘露醇或山梨醇；来自小麦、玉米和马铃薯的淀粉；纤维素如微晶纤维素。所述组合物中稀释剂的用量可为总组合物的约10-约90％(重量)，优选约25-约75％，更优选约30-约60％(重量)，甚至更优选约12-约60％。
崩解剂-指加入到所述组合物中以帮助其分解(崩解)和释放药物的物质。适当的崩解剂包括淀粉；“冷水可溶性”改良淀粉，例如羧甲基淀粉钠；天然和合成树胶，例如刺槐豆胶、刺梧桐树胶、瓜耳胶、黄蓍胶和琼脂；纤维素衍生物例如甲基纤维素和羧甲基纤维素钠；微晶纤维素和交联微晶纤维素例如交联羧甲基纤维素钠；藻酸盐例如藻酸和藻酸钠；粘土例如膨润土以及泡腾剂混合物。所述组合物中崩解剂的量可以为组合物的约2-约15％(重量)，更优选约4-约10％(重量)。
粘合剂-指将粉末粘合或“胶粘”在一起的物质并通过形成颗粒使它们粘结，因此在所述制剂中用作“粘结剂”。粘合剂可以增加所述稀释剂或填充剂的粘结力。适当的粘合剂包括糖，例如蔗糖；来自小麦、玉米和马铃薯的淀粉；天然树胶例如阿拉伯胶、明胶和黄蓍胶；海藻衍生物例如藻酸、藻酸钠和藻酸铵钙；纤维性物质例如甲基纤维素和羧甲基纤维素钠和羟丙基甲基纤维素；聚乙烯吡咯烷酮以及无机物例如硅酸镁铝。组合物中粘合剂的量可以为组合物的约2-约20％(重量)，更优选约3-约10％(重量)，甚至更优选约3-约6％(重量)。
润滑剂-指加入到剂型中以使片剂、颗粒剂等在压制后通过降低磨擦或磨损从塑模或冲模中脱模的物质。适当的润滑剂包括金属硬脂酸盐，例如硬脂酸镁、硬脂酸钙或硬脂酸钾；硬脂酸；高熔点蜡；和水溶性润滑剂例如氯化钠、苯甲酸钠、乙酸钠、油酸钠、聚乙二醇和d，1-亮氨酸。通常在压制前最后一个步骤加入润滑剂，因为它们必须存在于所述颗粒的表面上和存在于颗粒与压片机部件之间。所述组合物中润滑剂的量可以为组合物的约0.2-约5％(重量)，优选为0.5-约2％，更优选为约0.3-约1.5％(重量)。
助流剂-指预防结块并提高颗粒流动性的物质，以使流动平滑且均匀。适当的助流剂包括二氧化硅和滑石粉。组合物中助流剂的量可以为总组合物的约0.1-约5％(重量)，优选为0.5-约2％(重量)。
着色剂-指给所述组合物或所述剂型提供颜色的赋形剂。此类赋形剂可包括吸附在适当的吸附剂例如粘土或氧化铝上的食物级别的染料和食物级别颜料。着色剂的量为组合物的约0.1-约5％(重量)，优选约0.1-约1％。
生物利用度-指与标准或对照相比，所述活性药物成分或治疗部分由给药的剂型吸收进入系统循环的速率和程度。
Cmax值指测量的抗真菌化合物的最大血浆浓度(即“峰值”)。
AUC(0-72hr)值指在指定时间内抗真菌剂血浆/血清浓度-时间曲线下的面积。
制备片剂的常规方法是已知的。此类方法包括干法，例如直接压片和由挤压生产的颗粒压片或湿法或其它特定的方法。
可以通过将抗真菌化合物与含有表面活性剂以及所需量的稀释剂和任选的崩解剂、润滑剂、粘合剂、助流剂和/或着色剂的非离子聚环氧乙烷和环氧丙烷混合或制粒制备本发明的组合物。然后可以将上述组合物用于填充胶囊。或者可以将上述组合物压制成片剂。
下列实施例描述含有所述抗真菌化合物的本发明的组合物，但是不认为它们限制权利要求书的范围。
具体实施方式
实施例1.胶囊组合物组分 mg/胶囊 ％wt抗真菌化合物 100 19Pluronic F68表面活性剂 50 9.5微晶纤维素 300 56.9(a)交联羧甲基纤维素钠 25 4.7聚乙烯吡咯烷酮 25 4.7(b)交联羧甲基纤维素钠 25 4.7硬脂酸镁 2.5 0.5
527.5 100
实施例2.胶囊组合物组分 mg/胶囊 ％wt抗真菌化合物 100 25Pluronic F68表面活性剂 100 25微晶纤维素 136 34(a)交联羧甲基纤维素钠 20 5聚乙烯吡咯烷酮 20 5(b)交联羧甲基纤维素钠 20 5硬脂酸镁 4 1
400 100
实施例1-2、4-5、10-12和15中胶囊的制备
在适当的混合器中，根据实施例10-12的方法，将抗真菌化合物、Pluronic F68、微晶纤维素稀释剂、(a)交联羧甲基纤维素钠崩解剂和任选的十二烷基硫酸钠混合5-10分钟。将聚乙烯吡咯烷酮粘合剂溶于水中，用该聚乙烯吡咯烷酮溶液将上述混合物制粒。将已制粒的混合物置于烘箱中于45-50℃干燥过夜或流化床干燥至水分小于2％。将颗粒过20目筛并混合研磨的颗粒5分钟。取部分研磨的颗粒，与硬脂酸镁润滑剂混合，过筛，然后将该过筛的颗粒与上述研磨的颗粒的剩余部分一起混合。加入(b)交联羧甲基纤维素钠并混合5-10分钟。将颗粒填充进适当大小的胶囊中至所需的装量。
实施例3.在水混悬剂中的组合物
制备在4ml蒸馏水中的含有59.8mg Pluronic F68的混悬剂。向上述溶液中加入200mg抗真菌化合物，混合以得到均匀的混悬剂。
对照实施例.胶囊剂组分 mg/胶囊 ％wt抗真菌化合物 100.0 28.6十二烷基硫酸钠表面活性剂 22.5 6.4微晶纤维素 178.0 50.9羟乙酸淀粉钠 45.0 12.8硬脂酸镁 4.5 1.3
350 100
对照实施例中胶囊的制备
在混合器中将抗真菌化合物、十二烷基硫酸钠(表面活性剂)、微晶纤维素和羟乙酸淀粉钠混合10分钟。加入硬脂酸镁并混合5分钟。将颗粒填充进适当大小的胶囊中至所需的装量。
生物利用度实验
将在二个胶囊中的或在混悬剂中的200mg剂量的抗真菌化合物给狗喂药。于选定的时间收集血清样本并用装备有紫外检测器的高效液相色谱通过HPLC/UV检测程序进行分析。在下表中，Cmax和AUC(0-72hr)值为抗真菌化合物的生物利用度的指标。AUC值越大，血清中超过72小时期间所积累的抗真菌化合物的总量越大。
| 生物利用度指标 | 胶囊实施例1 | 胶囊实施例2 | 混悬剂实施例3 | 胶囊对照实施例 |
| Cmax | 2.3 | 1.8 | 1.5 | 0.95 |
| AUC(0-72hr)μg/hr/ml | 92.5 | 69.4 | 59.3 | 29.72 |
上述结果表明实施例1和2胶囊的生物利用度超过实施例3的水混悬剂的生物利用度，明显超过对照实施例胶囊的生物利用度。
实施例4.胶囊中的组合物组分 mg/胶囊 ％wt抗真菌化合物 50.00 19Pluronic F68表面活性剂 25.00 9.5微晶纤维素 150.00 56.9(a)交联羧甲基纤维素钠 12.50 4.7聚乙烯吡咯烷酮 12.50 4.7(b)交联羧甲基纤维素钠 12.50 4.7硬脂酸镁 1.25 0.5
263.75 100
实施例5.胶囊中的组合物组分 mg/胶囊 ％wt抗真菌化合物 100.00 22.2Pluronic F68表面活性剂 50.00 11.1微晶纤维素 245.25 54.5(a)交联羧甲基纤维素钠 15.00 3.3聚乙烯吡咯烷酮 22.50 5.0(b)交联羧甲基纤维素钠 15.00 3.3硬脂酸镁 2.25 0.5
450.00 100
实施例6.片剂中的组合物组分 mg/片 ％wt抗真菌化合物 100.00 22.2Pluronic F68表面活性剂 50.00 11.1微晶纤维素 245.25 54.5(a)交联羧甲基纤维素钠 15.00 3.3聚乙烯吡咯烷酮 22.50 5.0(b)交联羧甲基纤维素钠 15.00 3.3硬脂酸镁 2.25 0.5
450.00 100
实施例7.片剂中的组合物组分 mg/片 ％wt抗真菌化合物 100.0 19Pluronic F68表面活性剂 50.0 9.5微晶纤维素 300.0 56.9(a)交联羧甲基纤维素钠 25.0 4.7聚乙烯吡咯烷酮 25.0 4.7(b)交联羧甲基纤维素钠 25.0 4.7硬脂酸镁 2.5 0.5
527.5 100
实施例8.片剂中的组合物组分 mg/片 ％wt抗真菌化合物 200.0 19Pluronic F68表面活性剂 100.0 9.5微晶纤维素 600.0 56.9(a)交联羧甲基纤维素钠 50.0 4.7聚乙烯吡咯烷酮 50.0 4.7(b)交联羧甲基纤维素钠 50.0 4.7硬脂酸镁 5.0 0.5
1025.0 100
实施例9.片剂中的组合物组分 mg/片 ％wt抗真菌化合物 200.0 22.2Pluronic F68表面活性剂 100.0 11.1微晶纤维素 490.5 54.5(a)交联羧甲基纤维素钠 30.0 3.3聚乙烯吡咯烷酮 45.0 5.0(b)交联羧甲基纤维素钠 30.0 3.3硬脂酸镁 4.5 0.5
900.0 100
实施例6-9和13-14中片剂的制备
在适当的混合器中，根据实施例13-14的方法，将抗真菌化合物、Pluronic F68、微晶纤维素稀释剂、(a)交联羧甲基纤维素钠崩解剂和任选的十二烷基硫酸钠混合5-10分钟。将聚乙烯吡咯烷酮粘合剂溶于水中，用该聚乙烯吡咯烷酮溶液将上述混合物制粒。将已制粒的混合物置于烘箱中于45-50C干燥过夜或流化床干燥至水分小于2％。将颗粒过20目筛并混合研磨的颗粒5分钟。取部分研磨的颗粒，与硬脂酸镁润滑剂混合，过筛，然后将该过筛的颗粒与上述研磨的颗粒的剩余部分一起混合。加入(b)交联羧甲基纤维素钠并混合5-10分钟。将颗粒压制成所需重量的片剂。
实施例10.胶囊中的组合物组分 mg/胶囊 ％wt抗真菌化合物 200.00 44.44Pluronic F68表面活性剂 100.00 22.23十二烷基硫酸钠 30.00 6.67微晶纤维素 65.26 14.50(a)交联羧甲基纤维素钠 15.00 3.33聚乙烯吡咯烷酮 22.50 5.0(b)交联羧甲基纤维素钠 15.00 3.33硬脂酸镁 2.24 0.5
450.00 100
实施例11.胶囊中的组合物组分 mg/胶囊 ％wt抗真菌化合物 200.00 44.44Pluronic F68表面活性剂 50.00 22.23十二烷基硫酸钠 15.00 6.67微晶纤维素 32.63 14.50(a)交联羧甲基纤维素钠 7.50 3.33聚乙烯吡咯烷酮 11.25 5.0(b)交联羧甲基纤维素钠 7.50 3.33硬脂酸镁 1.12 0.5
225.00 100
实施例12.胶囊中的组合物组分 mg/胶囊 ％wt抗真菌化合物 100.00 26.67Pluronic F68表面活性剂 50.00 13.33十二烷基硫酸钠 15.00 4.00微晶纤维素 164.38 43.84(a)交联羧甲基纤维素钠 12.50 3.33聚乙烯吡咯烷酮 18.75 5.0(b)交联羧甲基纤维素钠 12.50 3.33硬脂酸镁 1.87 0.5
375.00 100
实施例13.片剂中的组合物组分 mg/片 ％wt抗真菌化合物 100.00 22.22Pluronic F68表面活性剂 50.00 11.11十二烷基硫酸钢 30.00 6.67微晶纤维素 215.25 47.84(a)交联羧甲基纤维素钠 15.00 3.33聚乙烯吡咯烷酮 22.50 5.00(b)交联羧甲基纤维素钠 15.00 3.33硬脂酸镁 2.25 0.50
450.0 100
实施例14.片剂中的组合物组分 mg/片 ％wt抗真菌化合物 200.00 22.22Pluronic F68表面活性剂 100.00 11.11十二烷基硫酸钠 30.00 6.67微晶纤维素 430.50 47.84(a)交联羧甲基纤维素钠 30.00 3.33聚乙烯吡咯烷酮 45.00 5.00(b)交联羧甲基纤维素钠 30.00 3.33硬脂酸镁 4.50 0.50
450.00 100
实施例15.胶囊中的组合物组分 mg/胶囊 ％wt抗真菌化合物 100.00 26.67Pluronic F68表面活性剂 50.00 13.33微晶纤维素 179.38 47.84(a)交联羧甲基纤维素钠 12.50 3.33聚乙烯吡咯烷酮 18.75 5.00(b)交联羧甲基纤维素钠 12.50 3.33硬脂酸镁 1.87 0.50
375.00 100
实施例16-23胶囊组合物。用基本与实施例1-2、4-5和10-12相同的方法，但是用Pluronic F87代替Pluronic F68。
实施例24-29片剂组合物。用基本与实施例6-9和13-14相同的方法，但是用Pluronic F127代替Pluronic F68。
Claims (8)
1.一种用于治疗真菌感染的药用组合物，该组合物包含
18-50％重量下式的抗真菌剂：
9-50％重量至少一种非离子表面活性剂，该表面活性剂为环氧乙烷和环氧丙烷的嵌段共聚物；
12-60％重量稀释剂，所述稀释剂为微晶纤维素；
4-10％重量崩解剂，所述崩解剂为交联羧甲基纤维素钠；
3-6％重量粘合剂，所述粘合剂为聚乙烯吡咯烷酮；
0.3-1.5％重量润滑剂，所述润滑剂为硬脂酸镁；
并包含或不包含3-8％重量十二烷基硫酸钠；其中所述组合物为胶囊、片剂或复制粉剂。
2.权利要求1的药用组合物，其中所述非离子表面活性剂为下列化学结构代表的环氧乙烷和环氧丙烷的嵌段共聚物：其中
a为10-110的整数，
b为20-60的整数。
3.权利要求2的药用组合物，其中对于所述非离子表面活性剂而言，
a为12-80的整数，
b为20-56的整数。
4.权利要求2的药用组合物，其中对于所述非离子表面活性剂而言，a为80，b为27。
5.权利要求1-4中任一项的药用组合物，其中所述非离子表面活性剂在组合物中的量为9.5-11％重量。
6.权利要求1-4中任一项的药用组合物，其中所述组合物中的非离子表面活性剂为普流罗尼克F68表面活性剂。
7.权利要求1的药用组合物，其中所述崩解剂的量为5.0％重量。
8.权利要求1的药用组合物，其中所述粘合剂的量为5.0％重量。
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| CA (1) | CA2255663C (zh) |
| CO (1) | CO4840511A1 (zh) |
| CZ (1) | CZ293586B6 (zh) |
| DE (1) | DE69710729T2 (zh) |
| ES (1) | ES2169440T3 (zh) |
| HK (1) | HK1017855A1 (zh) |
| HU (1) | HU221371B1 (zh) |
| ID (1) | ID16956A (zh) |
| IL (1) | IL126979A (zh) |
| MY (1) | MY118988A (zh) |
| NO (1) | NO316997B1 (zh) |
| NZ (1) | NZ332699A (zh) |
| PE (1) | PE68898A1 (zh) |
| PL (1) | PL188401B1 (zh) |
| RU (1) | RU2207119C2 (zh) |
| SK (1) | SK281818B6 (zh) |
| TR (1) | TR199802424T2 (zh) |
| TW (1) | TW504390B (zh) |
| WO (1) | WO1998007429A2 (zh) |
| ZA (1) | ZA974428B (zh) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2157731B1 (es) * | 1998-07-21 | 2002-05-01 | Liconsa Liberacion Controlada | Preparacion farmaceutica oral de un compuesto de actividad antifungica y procedimiento para su preparacion. |
| JP5767429B2 (ja) | 1999-11-12 | 2015-08-19 | アッヴィ・インコーポレイテッド | 固体分散剤中の結晶化阻害剤 |
| DE10026698A1 (de) | 2000-05-30 | 2001-12-06 | Basf Ag | Selbstemulgierende Wirkstoffformulierung und Verwendung dieser Formulierung |
| TWI337083B (en) * | 2001-01-26 | 2011-02-11 | Schering Corp | Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| AU2003230189A1 (en) * | 2003-01-29 | 2004-08-23 | Nitin Bhalachandra Dharmadhikari | Oral controlled release pharmaceutical composition containing metaxalone as active agent |
| US8025899B2 (en) | 2003-08-28 | 2011-09-27 | Abbott Laboratories | Solid pharmaceutical dosage form |
| CN103379917B (zh) | 2010-11-01 | 2016-10-12 | 梅琳塔治疗公司 | 药物组合物 |
| RU2450807C1 (ru) * | 2011-05-11 | 2012-05-20 | Общество с ограниченной ответственностью фирма "Вита" | Стабилизированный фармацевтический состав с противогрибковым действием |
| CN103845292A (zh) * | 2012-11-29 | 2014-06-11 | 正大天晴药业集团股份有限公司 | 泊沙康唑微丸及其制备方法 |
| US9763934B2 (en) * | 2014-03-05 | 2017-09-19 | Professional Compounding Centers Of America | Synergistic effect of poloxamer-based composition and itraconazole on fungus and yeast |
| TR201620462A2 (tr) | 2016-12-31 | 2018-07-23 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | POSAKONAZOL İÇEREN FARMASÖTİK BİLEŞİMLER ve ÜRETİM YÖNTEMİ |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4791111A (en) * | 1985-12-23 | 1988-12-13 | Janssen Pharmaceutica, N.V. | [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles having anti-microbial properties |
| US5039676A (en) * | 1990-05-11 | 1991-08-13 | Schering Corporation | Tri- and tetra-substituted-oxetanes and tetrahydrofurans and intermediates thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU681753B2 (en) * | 1993-12-21 | 1997-09-04 | Merck Sharp & Dohme Corp. | Tetrahydrofuran antifungals |
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1997
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- 1997-05-21 WO PCT/US1997/019388 patent/WO1998007429A2/en active IP Right Grant
- 1997-05-21 ES ES97949341T patent/ES2169440T3/es not_active Expired - Lifetime
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- 1997-05-21 DE DE69710729T patent/DE69710729T2/de not_active Expired - Lifetime
- 1997-05-21 CN CN97196513A patent/CN1121860C/zh not_active Expired - Fee Related
- 1997-05-21 PE PE1997000400A patent/PE68898A1/es not_active Application Discontinuation
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4791111A (en) * | 1985-12-23 | 1988-12-13 | Janssen Pharmaceutica, N.V. | [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles having anti-microbial properties |
| US5039676A (en) * | 1990-05-11 | 1991-08-13 | Schering Corporation | Tri- and tetra-substituted-oxetanes and tetrahydrofurans and intermediates thereof |
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