CN1246058A - 包含环孢菌素a的无油药物组合物 - Google Patents
包含环孢菌素a的无油药物组合物 Download PDFInfo
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Abstract
本发明提供了一种包含药物组合物的硬明胶胶囊,该药物组合物含有环孢菌素A,HLB值至少为10的表面活性剂,基本上不含任何油,且当存在亲水相时,该亲水相为聚乙二醇和/或低级链烷醇,条件是所存在的任何低级链烷醇的存在量低于除去硬明胶胶囊的组合物总重量的12%。
Description
本发明涉及包含环孢菌素A作为活性药物的新型药物组合物,环孢菌素A也被称作ciclosporine(在下文中称为环孢菌素)。
迄今为止很少有含环孢菌素的药物组合物已被商业应用于人类。因此在美国只有SANDIMMUNE和NEORAL(用于微乳剂的环孢菌素)被批准。
这些制剂被制成口服溶液或软明胶胶囊形式。这些软明胶胶囊需要特殊的制备工艺。
本发明的组合物为含有环孢菌素的组合物,它们符合美国或其它地区的批准要求,并且可被制成以硬明胶胶囊给药的形式。这种胶囊为本领域所熟知,可以用传统的方法制备和填充。
一方面本发明提供了一种口服药物组合物,其包含环孢菌素A和(i)HLB值至少为10的表面活性剂,和可任选的(ii)增粘剂,和/或(iii)亲水相,该亲水相为聚乙二醇和/或低级链烷醇,条件是所存在的任何低级链烷醇的存在量低于该组合物总重量的12%,优选低于10%或8%,该组合物适于填充入硬明胶胶囊中和作为其中心填充物(centre-fill)且基本上不含任何其它油类。
本发明组合物基于应用很少几种组分,例如表面活性剂(包括通常来源于其制备的相关副产品),可任选的增粘剂(增稠剂),以及如果需要,另外的亲水相(除存在于表面活性剂中之外的),该亲水相选自聚乙二醇和/或低级链烷醇,其中所述低级链烷醇的存在量低于该组合物重量的12%,例如8%。
以前提出的环孢菌素组合物有以下缺点:它们在硬明胶胶囊中不稳定(例如2-3年后不稳定),生物利用率或变化性与SANDIMMUNE和NEORAL相似。本发明的组合物有很好的稳定性。胶囊不易变脆。
该组合物优选含有较少其它赋形剂。这具有减小体积的优越性。因此除存在于表面活性剂中的那些之外,优选存在少于5%,更优选少于2%或1%的亲脂性组分(油),或亲水性组分,例如链烷醇(如乙醇或丙二醇)。
该组合物可以含有聚乙二醇。例如当通过聚乙氧基化制备或单独加入时,聚乙二醇可以作为表面活性剂的一部分。其存在量可以为制剂的1-40%。优选聚乙二醇在37℃为液体,例如分子量在200-600道尔顿之间。
在环孢菌素制剂中可存在通常剂量的环孢菌素,例如每重量剂型25mg;50mg;100mg。剂型例如为本领域已知的硬明胶胶囊。
本发明提供了新型环孢菌素药物制剂,其适应或基本上减少迄今为止本领域在环孢菌素的治疗中遇到的困难。具体地说,已发现本发明的组合物允许制备含有足以方便口服给药的高浓度的环孢菌素的固体、半固体和液体组合物,而同时可以得到改善的药效,例如,在生物利用率特征方面。
更具体地说,已发现本发明的组合物可进行有效的环孢菌素给药,同时可提高再吸收/生物利用率水平,并且降低接受环孢菌素治疗的个体患者以及个体间所获得的再吸收/生物利用率水平的差异。应用本发明的教导,可得到降低用于个体患者的剂量之间以及个体/个体患者组之间所达到的血液/血清环孢菌素浓度差异的环孢菌素剂型。因此本发明能够降低达到有效治疗所需的环孢菌素剂量水平。另外,它可以使接受环孢菌素治疗的个体以及接受相同治疗的患者组所需的连续每日剂量更为标准化以及最优化。
随着个体患者剂量率和血液/血清响应浓度的更为标准化,以及对患者组给药和其响应参数的更为标准化,可以降低监控需求,因此基本上降低了治疗费用。
通过所需的环孢菌素剂量的降低/所达到的生物利用率特征的标准化,本发明还提供了使接受环孢菌素治疗的患者不良副作用发生率降低的方法,特别是肾毒性反应。
本发明组合物体积小,但稳定性好,因此可以增加患者的顺应性。
表面活性剂优选被FDA批准,例如GRAS表面活性剂,例如:
1.1 聚乙氧基化蓖麻油,例如,天然或氢化植物油与乙二醇的反应产物,即聚氧乙烯乙二醇化天然或氢化植物油,例如聚氧乙烯乙二醇化天然或氢化蓖麻油。这些产品可以通过已知方法得到,例如,通过天然或氢化蓖麻油或其馏分与环氧乙烷以例如约1∶35到1∶60的摩尔比反应制得,并且任选除去产品中的游离聚乙二醇成份,例如按照德国Auslegeschriften 1,182,388和1,518,819公开的方法。尤其适合的是商品名为Cremophor的各种表面活性剂。更为适合的是产品Cremophor RH 40,其皂化值约50-60,酸值≤1,碘值≤1,水含量(Fischer)≤2%,nD 60=约1,453-1,457,HLB=约14-16;Cremophor RH 60,其皂化值约40-50,酸值≤1,碘值≤1,水含量(Fischer)约4.5-5.5%,nD 25=约1,453-1,457,HLB=约15-17;Cremophor EL,分子量(通过蒸汽渗透压测定法)=约1630,其皂化值约65-70,酸值=约2,碘值=约28-32,nD 25=约1,471(参见Fiedler loc. cit. pp. 326-327)。同样适用于该类的包括商品名为Nikkol的各种表面活性剂,例如Nikkol HC0-60。产品Nikkol HC0-60为氢化蓖麻油和环氧乙烷的反应产物,其具有以下性质:酸值=约0.3;皂化值=约47.4;羟值=约42.5;pH(5%)=约4.6;色度APHA=约40;熔点=约36.0℃;冰点=约32.4℃;水含量(%,KF)=约0.03;
这些产品含有大约70-90%的“亲水部分”,即甘油聚乙二醇脂肪酸酯,以及聚乙二醇脂肪酸酯和聚乙二醇与甘油乙氧基化物的亲水部分。参见例如Karl Muller,表面活性剂,Year 3,Issue 2,p.37-45。
优选该表面活性剂为聚乙氧基化氢化蓖麻油Cremophor RH。
1.2 例如通过环氧乙烷和山梨醇脂肪酸酯共聚合制备的聚氧乙烯-脱水山梨醇-脂肪酸酯(多乙氧基醚)及其酐类,例如单-和三-月桂基,棕榈基,硬脂基和油基酯,例如以商品名Tween已知和市售的产品(参见Fiedler loc. cit. pp. 1300-1304),包括产品Tween:20[聚氧乙烯(20)脱水山梨醇单月桂酸酯]40[聚氧乙烯(20)脱水山梨醇单棕榈酸酯]60[聚氧乙烯(20)脱水山梨醇单硬脂酸酯]80[聚氧乙烯(20)脱水山梨醇单油酸酯]65[聚氧乙烯(20)脱水山梨醇三硬脂酸酯]85[聚氧乙烯(20)脱水山梨醇三油酸酯]21[聚氧乙烯(4)脱水山梨醇单月桂酸酯]61[聚氧乙烯(4)脱水山梨醇单硬脂酸酯]和81[聚氧乙烯(5)脱水山梨醇单油酸酯]。
这类产品中尤其适用于本发明组合物的为上面的产品Tween 40和Tween 80;
1.3 例如通过脂肪酸和环氧乙烷反应制备的聚氧乙烯脂肪酸酯,例如硬脂酸-40-聚烃氧基酯,例如已知商品名为Myrj(参见Fiedler loc. cit. p. 834)的市售聚氧乙烯硬脂酸酯以及已知商品名为Cetiol HE.(参见Fiedler loc. cit. p. 284)的市售聚氧乙烯脂肪酸酯;这类产品中尤其适用于本发明组合物的为Myrj 52,其D25=约1.1.,熔点=约40-44℃,HLB=约16.9,酸值=约0-1,皂化值=约25-35;
1.4 例如月桂酸,硬脂酸,油酸,异硬脂酸的聚乙氧基化甘油基脂肪酸单酯,例如可以商品名Tagat O或L得到的那些。
1.5 饱和C10-C22,例如C18取代的,例如羟基脂肪酸的聚氧乙烯单酯;例如12羟基硬脂酸PEG,例如PEG约600-900,例如660道尔顿MW,例如德国Ludwigshafen的BASF公司的SOLUTOL H515。
1.6 聚氧乙烯-聚氧丙烯共聚物,poloxamers,例如以商品名Pluronic和Emkalyx已知和市售的那些(参见Fiedler loc.cit. p. 956-958)。这类产品中尤其适用于本发明组合物的为产品Pluronic F68(poloxamer 188)。
1.7 丙二醇单-和二-脂肪酸酯如丙二醇二辛酸酯,丙二醇二月桂酸酯,丙二醇羟基硬脂酸酯,丙二醇异硬脂酸酯,丙二醇月桂酸酯,丙二醇蓖麻醇酸酯,丙二醇硬脂酸酯等(参见Fiedler loc.cit. p. 1013及以下)。特别优选的为以商品名Miglyol 840已知和市售的丙二醇辛酸癸酸二酯(参见Fiedler loc. cit. p.809)。Miglyol 840的脂肪酸含量为C6max约3%,C8约65-80%,C10约15-30%,C12max约3%,酸值=max.0.1,碘值=约320-340,碘值=max.1。
离子型表面活性剂实例包括:
2.1 琥珀酸二辛基酯,磺基琥珀酸二辛基酯钠,琥珀酸二-[2-乙基己基]酯或十二烷基硫酸钠。
2.2 磷脂,特别是卵磷脂(参见Fiedler loc. cit. p. 731-733)。适用于本发明组合物的卵磷脂尤其包括大豆卵磷脂。
2.3 胆汁盐,例如碱金属盐,例如牛磺胆酸钠。用作表面活性剂组分的其它亲脂性表面活性剂的实例例如为:
2.1 天然植物油甘油三酯和聚亚烷基多元醇的酯基转移作用产物。这些酯基转移作用产物为本领域熟知,可以按照美国专利号3,288,824描述的一般方法制备。它们包括各种天然(例如非氢化的)植物油如玉米油,核油,杏仁油,花生油,橄榄油和棕榈油和它们的混合物与聚乙二醇(特别是平均分子量在200-800间的聚乙二醇)的酯基转移作用产物。优选的产品为通过2摩尔份的天然植物油甘油三酯和1摩尔份的聚乙二醇(例如平均分子量在200-800间)的酯基转移作用制备。这类各种形式的酯基转移作用产物以商品名Labrafil已知和市售[参见Fiedler loc.cit. 707]。特别适于用作本发明组合物组分的产品为LabrafilM 1944 CS,为核油和聚乙二醇的酯基转移作用产物,其酸值=约2,皂化值约145-175,碘值=约60-90;和Labrafil M 2130CS,为C12-C18-甘油酯和聚乙二醇的酯基转移作用产物,其熔点=约35-40℃,酸值≤2,皂化值=约185-200,碘值≤3;
2.2 单-,二-和单/二-甘油酯,特别是辛酸或癸酸和甘油的酯化作用产物。这类产品中优选的是例如包含辛酸/癸酸单-和二-甘油酯或者主要或基本上由其组成的那些,如以商品名Imwitor(参见loc. cit. pp. 645)市售的产品。这类产品中特别适用于本发明组合物的为Imwitor 742,它是约60 p. p. w辛酸和40 p. p.w癸酸混合物和甘油的酯化作用产物。Imwitor 742典型地为黄色结晶物质,在约26℃为液体;酸值=max.2;碘值=max.1;皂化值=约235-275;甘油单酯%=约40-50%;游离甘油=max.2%;熔点=约24-26℃;未皂化物=0.3%max.;过氧化值=max.1;
2.3 脱水山梨醇脂肪酸酯,例如以商品名Span已知和市售的产品,例如包括脱水山梨醇-单月桂基,-单棕榈基,-单硬脂基,-三硬脂基,-单油基和-三油基酯(参见Fiedler loc. cit.pp. 1139-1140);
2.4 季戊四醇脂肪酸酯和聚亚烷基二醇醚,例如季戊四醇--二油酸酯,-二硬脂酸酯,-单月桂酸酯,-聚乙二醇醚和-单硬脂酸酯以及季戊四醇脂肪酸酯(参见Fiedler loc. cit. pp. 923-924);
2.5 甘油单酯,例如甘油单油酸酯,甘油单棕榈酸酯和甘油单硬脂酸酯,例如以商品名Myvatex,Myvaplex和Myverol已知和市售的产品(参见Fiedler loc. cit. p. 836),和乙酰化,例如单-和二-乙酰化甘油单酯,例如以商品名Myvacet已知和市售的产品(参见Fiedler loc. cit. pp. 835);
2.6 甘油三醋酸酯或(1,2,3)-甘油三醋酸酯(参见Fiedler loc.cit. pp. 952);和
2.7 甾醇和它们的衍生物,例如胆甾醇和它们的衍生物,特别是植物甾醇,例如含有谷甾醇,菜油甾醇或豆甾醇和它们的环氧乙烷加合物的产品,例如大豆甾醇和它们的衍生物,如以商品名Generol已知的产品(参见Fiedler loc. cit. pp. 554和555),特别是产品Generol 122,122 E5,122 E10和122E25。
应理解表面活性剂可以是复杂的混合物,含有其制备中所产生的副产品或未反应的初始产品,例如聚氧乙基化作用可能含有另一个副产品,例如聚乙二醇。
本发明的组合物也可含有增稠剂(也称为增粘剂)。
适合的增稠剂可以为本领域熟知和使用的产品,包括,例如可使组合物易于填充且防止渗漏的可药用聚合物和无机增稠剂,例如触变剂。这些也应具有在胃液或水中或在pH 1-2下迅速溶解(例如在5分钟内)的性质,例如以下类型:
3.1 水溶性聚乙二醇琥珀酸生育酯(TPGS),例如聚合度约为1000,例如可从美国Eastman Fine Chemicals Kingsport,Texas得到。
3.2 水溶性纤维素和纤维素衍生物,包括烷基纤维素,例如甲基-,乙基-和丙基-纤维素;羟烷基纤维素,如羟丙基纤维素和羟丙基烷基纤维素,如羟丙基甲基纤维素;酰化纤维素,如醋酸纤维素,醋酸邻苯二甲酸纤维素,醋酸琥珀酸纤维素和邻苯二甲酸羟丙基甲基-纤维素;以及它们的盐,如羧甲基纤维素钠。适合用于本发明的上述产品的实例是熟知的和市售的产品,例如商品名为Klucel和Methocel(参见Fiedler,loc. cit.,pp. 688和790)的产品;
3.3 水溶性聚乙烯吡咯烷酮,包括:例如聚-N-乙烯基吡咯烷酮和乙烯吡咯烷酮的共聚物,如乙烯吡咯烷酮-醋酸乙烯酯的共聚物,尤其是低分子量的共聚物。适合用于本发明的上述化合物的实例为熟知并且市售的那些,例如商品名为Kollidon(或,在美国商品名为Povidone)(参见Fiedler,loc. cit.,pp. 694-696)的化合物,尤其是产品Kollidon 30和90;
3.4 少量无机增稠剂,例如硅镁土、膨润土和硅酸盐,包括亲水性二氧化硅产品,例如烷基化(例如甲基化)硅胶,特别是胶状二氧化硅产品如熟知并且市售的商品名为Aerosil[参见药物赋形剂手册,loc. cit.,pp. 253-256]的产品,特别是产品Aerosil130,200,300,380,O,OX 50,TT 600,MOX 80,MOX 170,LK 84和甲基化Aerosil R 972。
该组合物也可以含有一种或多种其它成分(例如0.1-5%),具体地说包括抗氧化剂[例如抗坏血酸基棕榈酸酯,叔丁基羟基茴香醚(BHA),二丁基羟基甲苯(BHT)和生育酚类,例如-生育酚(维生素E)],调味剂等。应用抗氧化剂,特别是使用生育酚,特别有利。
本发明组合物各成分的相对比例,根据所涉及的组合物的特殊类型当然也会变化很大。本领域的技术人员通常能够确定任一个特殊实例中的有效比例。因此,以下描述的所有比例和相对重量范围应当理解为仅是优选的或单个的发明教导,不是为了以其最宽范围限制本发明。
a) 环孢菌素的存在量,通常占除去硬明胶胶囊的组合物总重量的5-30%之间,更适合的约为10-25%。
b) 如果存在聚乙二醇,则其量通常占除去硬明胶胶囊的组合物总重量的约15-30%;
c) 除去表面活性剂之外作为增稠剂的任何其它赋形剂的存在量优选占除去硬明胶胶囊的组合物总重量的大约0.1-5%。
上面的组合物可以另外加入增稠剂,尽管如同以前指出的,通常这是不太优选的。增稠剂的加入量可以根据终产物需要的稠度变化,例如是否为增稠的可流动形式,例如用于填充胶囊。加入量当然也由选择的增稠剂的性质决定。通常增稠剂组分(4)(如果加入)的存在量至多约占组合物总重量的25%,更适合的是至多占组合物总重量的大约15或20%,例如为组合物总重量的大约0.5或5到15或20%。
该组合物也可以包括其它添加剂或组分,例如前面描述的。具体地说,它们可以包含抗氧化剂(例如至多约占组合物总重量的0.5或1%),和甜味剂或调味剂(例如至多约占组合物总重量的2.5或5%)。
优选不含其它赋形剂。因此组合物的体积较小,可以填充1, 2或3号胶囊。
口服给药时,发现本组合物表现出尤为有利的特性,例如通过人或小猎犬的标准实验得到的结果的一致性和高水平生物利用率两方面。尤其是和其它制剂体系相对照,例如如同本领域已知的,已发现这些组合物与表面活性物质相容,例如存在于胃肠道的胆汁盐。那就是说,它们完全分散于含有这类天然表面活性剂的含水体系中,因此能够就地形成稳定、不产生沉淀或其它细微颗粒结构破裂的微乳液体系。在任何特定时间或对任何给定个体,该体系口服给药的功能不会受是否相对存在胆汁盐影响和/或破坏。因此,该组合物代表本发明一个尤为优选的实施方案。在标准临床实验或狗实验中,采用标准放射性免疫检测环孢菌素,可以得到其生物利用率特征。优选的胶囊具有短的Tmax。该组合物在用水稀释时优选形成胶束溶液,其中可以检测到例如直径在10-150nm之间的微滴。上述组合物优选以可口服的硬明胶胶囊作为壳制成单位剂型。当组合物呈单位剂形时,各单位剂形合适的是含有5或10至约200mg环孢菌素,更优选为大约15或25至150mg环孢菌素,例如25,50或100mg环孢菌素。因此本发明的单位剂形适合于每天给药1次,2次或3次直到5次(例如,依赖于治疗的特殊目的,治疗阶段等),每单位剂形适当含有例如大约25,50或100mg环孢菌素。
赋形剂的进一步详细说明在Fiedler中给出。
下列非限制性实施例说明本发明。实施例1:硬明胶胶囊环孢菌素A 100mg表面活性剂(Cremohhor RH或Tween) 300mg实施例2:
如实施例1,但另外包含10mg TPGS。
各组合物在人和狗体内的生物利用率曲线与NEORAL的表现类似,例如AUC,Tmax和Cmax。
硬明胶胶囊至少稳定2年,并始终保持良好状态。实施例3:硬明胶胶囊环孢菌素A 50mg表面活性剂(Cremohhor RH或Tween) 300mg1,2-丙二醇或乙醇 组合物总重量的8%实施例4:硬明胶胶囊环孢菌素A 50mg表面活性剂(Cremohhor RH或Tween) 300mgPEG 300 组合物总重量的30%
Claims (11)
1.一种含有药物组合物的硬明胶胶囊,所述药物组合物含有环孢菌素A与HLB值至少为10的表面活性剂,基本上不含任何油,且在存在亲水相时,该亲水相为聚乙二醇和/或低级链烷醇,条件是所存在的任何低级链烷醇的存在量低于除去硬明胶胶囊的组合物总重量的12%。
2.如权利要求1所述的硬明胶胶囊,其中存在的低级链烷醇的存在量低于除去硬明胶胶囊的组合物总重量的8%。
3.如权利要求1或2所述的硬明胶胶囊,其中表面活性剂为聚氧乙烯-脱水山梨醇-脂肪酸酯。
4.上述任一权利要求所述的硬明胶胶囊,进一步包括能够溶解于胃液或水中的增稠剂。
5.上述任一权利要求所述的硬明胶胶囊,其中环孢菌素的存在量为除去硬明胶胶囊的组合物总重量的10-25%。
6.上述任一权利要求所述的硬明胶胶囊,除表面活性剂外包含作为增稠剂的其他赋形剂,含量为除去硬明胶胶囊的组合物总重量的0.1-5%。
7.上述任一权利要求所述的硬明胶胶囊,其中存在亲水相。
8.如权利要求7所述的硬明胶胶囊,其中亲水相为聚乙二醇和/或丙二醇。
9.如权利要求7所述的硬明胶胶囊,其中亲水相为聚乙二醇和/或乙醇。
10.如权利要求1所述的硬明胶胶囊,包含亲水相,该亲水相含有权利要求1定义的聚乙二醇和/或低级链烷醇,且当存在聚乙二醇时,该聚乙二醇加热到37℃时为液体,表面活性剂为聚氧乙烯脱水山梨醇脂肪酸酯或聚乙氧基化蓖麻油或聚氧乙烯脂肪酸酯。
11.如权利要求10所述的硬明胶胶囊,其中药物组合物为溶解有环孢菌素的半固体或液体。
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1998
- 1998-01-28 KR KR10-2003-7005807A patent/KR20040004416A/ko not_active Application Discontinuation
- 1998-01-28 AU AU62141/98A patent/AU737053B2/en not_active Ceased
- 1998-01-28 TR TR1999/01686T patent/TR199901686T2/xx unknown
- 1998-01-28 CZ CZ19992663A patent/CZ295207B6/cs not_active IP Right Cessation
- 1998-01-28 SG SG200104053A patent/SG115386A1/en unknown
- 1998-01-28 HU HU0001013A patent/HUP0001013A3/hu unknown
- 1998-01-28 CN CN98802163A patent/CN1246058A/zh active Pending
- 1998-01-28 AT AT98904156T patent/ATE275963T1/de not_active IP Right Cessation
- 1998-01-28 CN CNA2005100666723A patent/CN1679917A/zh active Pending
- 1998-01-28 IL IL13079798A patent/IL130797A0/xx active IP Right Grant
- 1998-01-28 CA CA002278675A patent/CA2278675A1/en not_active Abandoned
- 1998-01-28 GB GB9917521A patent/GB2335854B/en not_active Expired - Fee Related
- 1998-01-28 KR KR1020057012172A patent/KR20050084502A/ko active Search and Examination
- 1998-01-28 US US09/284,391 patent/US6475519B1/en not_active Expired - Fee Related
- 1998-01-28 DE DE29824679U patent/DE29824679U1/de not_active Expired - Lifetime
- 1998-01-28 KR KR1019997006094A patent/KR20000069900A/ko active Search and Examination
- 1998-01-28 NZ NZ336900A patent/NZ336900A/en unknown
- 1998-01-28 RU RU99118508/14A patent/RU2211047C2/ru not_active IP Right Cessation
- 1998-01-28 ES ES98904156T patent/ES2229473T3/es not_active Expired - Lifetime
- 1998-01-28 SK SK1020-99A patent/SK285019B6/sk not_active IP Right Cessation
- 1998-01-28 EP EP03007982A patent/EP1331002A3/en not_active Withdrawn
- 1998-01-28 PL PL98334850A patent/PL190420B1/pl not_active IP Right Cessation
- 1998-01-28 PT PT98904156T patent/PT988046E/pt unknown
- 1998-01-28 GB GB0024188A patent/GB2355195B/en not_active Expired - Fee Related
- 1998-01-28 BR BR9807528-4A patent/BR9807528A/pt not_active Application Discontinuation
- 1998-01-28 EP EP98904156A patent/EP0988046B1/en not_active Revoked
- 1998-01-28 DE DE19882037T patent/DE19882037T1/de not_active Ceased
- 1998-01-28 DE DE69826272T patent/DE69826272T2/de not_active Revoked
- 1998-01-28 WO PCT/EP1998/000453 patent/WO1998033512A1/en not_active Application Discontinuation
- 1998-01-28 JP JP10532524A patent/JP2000516256A/ja not_active Withdrawn
- 1998-01-29 ID IDW990766A patent/ID26696A/id unknown
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1999
- 1999-07-05 IL IL130797A patent/IL130797A/en not_active IP Right Cessation
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2000
- 2000-09-26 HK HK00106122A patent/HK1027745A1/xx not_active IP Right Cessation
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2001
- 2001-11-06 US US09/992,584 patent/US6723339B2/en not_active Expired - Fee Related
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2004
- 2004-02-18 US US10/781,069 patent/US20040161458A1/en not_active Abandoned
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2005
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101439015B (zh) * | 2007-11-21 | 2013-02-13 | 因华生技制药股份有限公司 | 有增进生物可利用性的医药组合物 |
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