CN1195289A - 药物组合物 - Google Patents

药物组合物 Download PDF

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CN1195289A
CN1195289A CN96196788A CN96196788A CN1195289A CN 1195289 A CN1195289 A CN 1195289A CN 96196788 A CN96196788 A CN 96196788A CN 96196788 A CN96196788 A CN 96196788A CN 1195289 A CN1195289 A CN 1195289A
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rapamycin
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P·桂塔尔德
B·黑堡林
R·林克
F·里赫特尔
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Abstract

含有一种大环内酯,为一种雷怕霉素或一种子囊霉素和一种载体介质的固态分散体形式的口服药用组合物。

Description

药物组合物
本发明涉及含大环内酯，为一种雷怕霉素或一种子囊霉素的固态分散体的口服药物组合物。
雷怕霉素是一种可以生产的免疫抑制的内酰胺大环内酯，如吸湿性链丝菌属菌。Kesseler，H等人给出了雷怕霉素的结构；1993；Helv.Chim.Acta；76：117。雷怕霉素是一种非常有效的免疫抑制剂并还具有抗癌和杀真菌的活性。但是它做为药物的应用却受到它很低且易变的重物利用率的限制。此外，雷怕霉素在含水溶剂，如水中的溶解度很低，使它难以制成稳定的药物组合物。大量雷怕霉素的衍生物是已知的。在世界知识产权组织(WO)94/02136中公开了一些16-O-取代的雷怕霉素，其内容在此引入作为参考。40-O-取代的雷怕霉素已在以下的专利中叙述过，如美国专利5258389和WO 94/09010(O-芳基和O-烷基雷怕霉素)；  WO 92/05179(羧酸酯)，美国专利5118677(酰胺酯)，美国专利5118678(甲氨酸酯)，美国专利5 100 883(氟化酯)，美国专利5151413(乙缩醛)，美国专利5120842(甲硅烷基醚)，WO 93/11130(亚甲基雷怕霉素和衍生物)，WO 94/02136(甲氧基衍生物)，WO 94/02385和WO 95/14023(链烯基衍生物)，全部在此引入作为参考。32-O-二氢或取代的雷怕霉素已在美国专利5256790中加以叙述，在此引入作为参考。
在专利合作条约(PCT)申请号EP 96/02441中叙述了更多的雷怕霉素的衍生物，如32-脱氧雷怕霉素在实例1中描述了，16-戊-2炔氧-32(S)-二氢雷怕霉素在实例2和3中叙述了。PCT申请号EP 96/02441的内容在此引入作为参考。
以下把雷怕霉素和其结构相近的类似物和衍生物集体地称之为“雷怕霉素”。
人类口服用的固体雷怕霉素在血液中不能吸收至明显的数量。用常规药物赋形剂制成的简单雷怕霉素的混合物是已知的；但是这类组合物的不利之处在于它们有不可预知的溶解速率，无规律的生物利用率并且不稳定。目前还没有便于口服的雷怕霉素或其衍生物的固态制剂。
因而，本发明的一个方面是提供了一种含雷怕霉素和一种载体介质的固态分散体的药物组合物。
本发明的组合物提供了一种方便服用并且稳定的高生物利用率的药剂。
用于本发明组合物的雷怕霉素可以是任何一种雷怕霉素及其衍生物，如以上所公开或在上述专利申请中所叙述过的。
用于本发明固态分散体组合物的雷怕霉素可以是雷怕霉素或O取代的衍生物，其中雷怕霉素的环己烷环的羟基被-OR1所取代，其中R1是羟烷基，羟烷氧基烷基，酰氨基烷基和氨基烷基；如在WO 94/09010中叙述的40-O-(2-羟基)乙基-雷怕霉素，40-O-(3-羟基)丙基-雷怕霉素，40-O[2-(2-羟基)乙基氧]乙基-雷怕霉素和40-O-(2-乙酰氨基乙基)-雷怕霉素。雷怕霉素衍生物可以是26-或28-取代的衍生物。
本发明的固态分散体组合物的优选雷怕霉素包括雷怕霉素，40-O-(2-羟基)乙基雷怕霉素，32-脱氧雷怕霉素和16-戊-2-炔氧-32(S)-二氢雷怕霉素。一种更优选的雷怕霉素是40-O-(2-羟基)乙基雷怕霉素(以下称之为化合物X)。
本发明所用的雷怕霉素衍生物的编号参照了在PCT中请WO96/13273第4页公开式A的结构，其内容在此引入作为参考。
本发明所用的词-固态分散体是表示和雷怕霉素，如40-O-(2-羟基)乙基雷怕霉素或雷怕霉素和载体介质的共沉淀物。在固态分散体中，雷怕霉素是无定形或基本无定形的并和载体介质物理地相结合。
本发明的组合物能够以任何方便的形式服用，如片状，胶囊，粒状或在小药囊中的粉状物。
雷怕霉素在组合物中的数量以组合物的重量(％重/重)为基础约为0.01至约30重量％，优选地，其量以组合物总重量为基准，为1至20％重/重。
载体介质的数量按重量可达99.99％，如以组合物的总重量为基础10至95重％。
在一实施方案中，载体介质包括一种水溶性聚合物，优选地一种纤维素的衍生物如羟丙基甲基纤维素(HPMC)，羟丙基甲基纤维素邻苯二甲酸酯，或聚乙烯吡咯烷酮(PVP)。用低表现动态粘度的HPMC可以得到好的结果，如在20℃下低于100cps的2％重量的水溶液，再如低于50cps，优选地低于20cps，例如HPMC 3cps。HPMC是大家都知道并在药物赋形剂手册，第二版，英国药物学会和美国药物协会出版，1994年，第229至232页，其内容在此引入作为参考。HPMC，包括HPMC 3cps，商品名称Pharmacoat 603可自Shinetsu工厂购得。
商品名Povidone的PVP可自市场购得(药物赋形剂手册)，优选一种平均分子量约8000至约50,000 Dalton的PVP。
在另一种实施方案中载体介质包括
-羟基丙基纤维素(HPC)或其衍生物。HPC衍生物的实例包括含水介质如水，在25℃下2％的水溶液低于约400cps，如低于150cps。优选的HPC衍生物的取代度低，其平均分子量低于200,000 Dalton，如在50,000和150,000 Dalton之间。市场上可购得的HPC有Aqualon公司的Klucel LF，Klucel EF和Klucel JF；日本苏打公司的Nisso HPC-L；
-一种聚乙二醇(PEG)。实例有平均分子量在1000和9000 Dalton之间，如约1800和7000之间，如PEG 2000，PEG 4000或PEG 6000(药物赋形剂手册)；
-一种饱和的聚乙二醇化的甘油酯，可从如Gattefossé公司商品名为Gecir如Gelucir 44/14，53/10，50/13，42/12或35/10购得；
一种环糊精，如β-环糊精或α-环糊精。合用的β-环糊精有甲基-β-环糊精；二甲基-β-环糊精；羟基丙基-β-环糊精；葡糖基-β-环糊精；麦芽糖-β-环糊精；磺基-β-环糊精；β-环糊精的磺基-烷基醚，如磺基-C1-4-烷基醚。α-环糊精有葡糖基-α-环糊精和麦芽糖-α-环糊精。
载体介质还可能含一种水溶性或不溶于水的蔗糖或其它可接受的载体或填充物如乳糖，或微晶纤维素。填充物，如果有的话，通常的数量可达约30％重量，如0.5至20重量％，优选地，占组合物重量的约5至约15％。商品微晶纤维素Avicel可自市场，如由FMC公司购得。
载体介质还可以包含一种或多种表面活性剂，如非离子，离子，阴离子或两性表面活性剂。适用的表面活性剂有：
-聚氧乙烯-聚氧丙烯共聚物和嵌段共聚物，已知商品名称是Pluronic或Poloxamer，这是在Fiedler，H.P.的“Lexikon derHilfsstoffe f ür Pharmazie，Kosmetik und angrenzende Gebiete”，EditioCantor，D-7960 Aulendorf，第三次修改和扩大版(1989)，内容在此引入作为参考。一种优选的聚氧乙烯-聚氧丙烯嵌段聚合物是可从BASF公司购得的Poloxamer188；
-乙氧基化的胆甾醇，已知的商品名称Solulan，如Amerchol公司的Solulan C24；
-维生素衍生物如维生素E衍生物，有Eastman公司的生育酚聚乙二醇琥珀酸酯(TPGS)；
-十二烷基硫酸钠或月桂基硫酸钠；
-一种胆汁酸或其盐，如胆酸，乙醇酸或一种盐，如胆酸钠；或
-卵磷酯。
如果在本发明的组合物中有表面活性剂，则其数量一般低于约20％，如1至15％(重量)。
本发明的组合物可以包含一种或多种的崩解剂。崩解剂的实例有ISP公司的商品Polyplasdone(药物赋形剂手册)；Generichcm公司的淀粉甘醇酸钠；FMC公司商品名Ac-di-sol的交联羧甲醚纤维素钠。本发明的组合物还可以包括一种或多种润滑剂如硬脂酸镁或胶态二氧化硅，以组合物的重量为基准，其数量可达约5重量％，如0.5至2重量％。
本发明的组合物包含一种或多种香味剂可能是有利的。
本发明申请人用不含表面活性剂的雷怕霉素组合物获得了好结果。在另一方面，本发明提供一种在此叙述的不含表面活性剂的雷怕霉素的固态分散体。
本发明的组合物可以含抗氧剂和/或稳定剂，其数量可达约1重量％，如在0.05和0.5％(重量)之间。抗氮剂的实例有丁基化的羟基甲苯，DL-α-生育酚，棓酸丙酯。综榈酸维生素C酯和富马酸。丙二酸是一种适用的稳定剂。
在本发明的一个实施方案中，组合物包括达30重量％；如1至20重量％，40-O-(2-羟基)乙基雷怕霉素，和最高达95％，如30至90％重量的HPMC。
本发明组合物中雷怕霉素对载体介质的重量比率一般不超过1∶3，优选地低于1∶4。
在本发明的另一方面，提供了在此叙述的制备固态分散体组合物的方法。
在一个实施方案中，本发明的组合物可以把雷怕霉素和载体介质溶解或悬浮在一个溶剂或溶解剂混合物中而获得。溶剂可以是单一溶剂或溶剂混合物，雷怕霉素和载体介质在溶剂中溶解和悬浮的次序是可以变动的。适于制备本发明固态分散体组合物的溶剂可以是有机溶剂，如一种醇，如甲醇，乙醇或异丙醇；一种酯，如乙酸乙酯；一种醚，如二乙醚；一种酮，如丙酮；或一种卤化烃，如二氯乙烷。一种方便的溶剂混合物是乙醇/丙酮混合物，其乙醇对丙酮的重量比率约1∶10至约10∶1，如1∶5至5∶1。
雷怕霉素和载体介质在溶剂中的典型重量比率为1∶0.1至1∶20。溶剂可以蒸发掉，雷怕霉素就和载体介质共同沉淀下来。所得的残余物可以如在减压下干燥，过滤并研磨。研磨过的分散体可以和其它的赋形剂混合起来，如压成片，或装在小药囊或胶囊中。
在另一个实施方案中，可以把载体介质融解，与雷怕霉素混合，搅拌，可以任选用溶剂或溶剂混合物制备固态分散体组合物。
本发明的固态分散体还可以用喷雾干燥技术制备，如像Lachmann等人在工业制药的理论和实践，1986中所描述的那样。按上述制得的悬浮物经过喷咀分散到一个保持如20至80℃的室中。经过喷咀时，溶剂蒸发，收集分散的细颗粒。
本发明的组合物经研磨后，平均颗粒大小小于0.5mm，如小于约350μm，如约100至约300μm。
本发明的口服组合物对雷怕霉素已知的适应症是有效的，如下述的病痛：
a)治疗和预防器官或组织异体移植的排斥，如治疗心、肺，心-肺，联合，肝，肾，胰，皮肤或角膜移植的接受者。它们也适应防止移植物-对抗-主体的疾病，如在骨髓移植后。
b)治疗和预防自体免疫疾病和炎症，特别是包括自体免疫部分病因学，如关节炎(如风湿性关节炎，关节炎慢性病和关节炎畸形)和风温病等炎症病痛。本发明的化合物可以应用的特定自体免疫病包括自体免疫性血液病(包括如血球溶解性贫血，再生障碍性贫血，纯红细胞贫血和突发性血小板减小症)，全身红斑狼疮，多软骨病，硬皮病，韦格内氏肉芽肿病，皮肤肌炎，慢性活性肝炎，重症肌无力，牛皮癣，斯的二氏综合症，突发口炎性腹泻。自体免疫炎症肠病(包括如溃疡性结肠炎和克罗恩氏病)，内分泌眼病，格雷夫斯病，类肉瘤病，多发性硬化，原发胆汁性肝硬变，幼稚糖尿病(糖尿病I型)，葡萄膜炎(前和后)，干性角膜结膜炎和春季干性角膜炎，间质肺纤维化，牛皮癣关节炎，肾小球性肾炎(带或不带肾病综合症，包括自发的肾病综合症或最小变动肾病)和幼稚性皮肤肌炎。
c)治疗和预防气喘。
d)治疗多药抗药性(MDR)。MDR特别对癌症患者和艾滋病人是有问题的，因为他们不响应常规的化学疗法，Pgp把药送至细胞外面。本发明的组合物可增强其它化学制剂在治疗和控制多药抗药性疾病如多药抗药性癌症或多药抗药性艾滋病。
e)治疗增生性疾病，如肿瘤，皮肤过多症等。
f)治疗真菌感染。
g)治疗和预防炎症，特别能使甾族化合物增强其作用。
h)治疗和预防感染，特别是具有Mip或Mip类似因子的病原体的感染。
i)治疗FK-506和其它结合免疫抑制剂的过量剂量。
本发明的药物组合物可以制成单位剂量形式，如片状、胶囊、粒状，粉状，每个单位剂量含1mg至100mg药物，更优选地，含10至50mg；如15，20，25或50mg。这种剂量形式适于根据疗法的特定目的和治疗期等每天服用1-5次。
准确服用的组合物数量取决于几种因素，如要求的治疗期限和雷怕霉素的释放速度。
药物组合的疗效可经标准临床实验观察到，如已知活性剂的用量给出相应活性剂的血含量；如采用1mg至1000mg之间的剂量，如75kg成年人和标准动物模拟每天5mg至100mg的用量。本组合物对药物物质生物利用率的提高可以在标准动物试验和临床试验中观察到。
所用的药剂形式，如片状，可用涂盖层复盖。适用的涂盖层包括乙酸苯二甲酸纤维素，苯二甲酸羟基丙基甲基纤维素；一种聚甲基丙烯酸共聚物，如Eudragit L.S；或琥珀酸羟基丙基甲基纤维素。
本发明组合物中用的雷怕霉素，如40-O-(2-羟基)乙基雷怕霉素或雷怕霉素，在制成固态分散体之前可以是结晶或无定形的。本发明的一个优点就是雷怕霉素不必是结晶的。雷怕霉素可以和溶剂一起直接使用，不必预先分离。本发明的另一个优点是固态分散体溶解速度大于在简单混合物中的结晶雷怕霉素或无定形雷怕霉素。
在另一方面，本发明提供了一种含子囊霉素和载体介质的固态分散体的药物组合物。
本发明固态分散体组合物中适用的子囊霉素有子囊霉素或其衍生物，如33-表氯-33-脱氧子囊霉素。
目前还没有便于口服的33-表氯-33-脱氧-子囊霉素的固态制剂。因此，在另一方面，本发明提供了一种含33-表氯-33-脱氧-子囊霉素和一种载体介质的固态分散体的药物组合物。
在欧洲申请EP 427680的实例66a中，描述了化合物33-表氯-33-脱氧-子囊霉素。
33-表氯-33-脱氧-子囊霉素将被称作化合物Y。
本发明的子囊霉素，如化合物Y的组合物具有药物的高生物利用率，便于服用并且是稳定的。
子囊霉素，如化合物Y，在组合物中的数量约为0.01至约30％重/重，优选的数量是1至20％重/重。
载体介质可以包含数量为上述重％的任何上面已谈到的组分。适宜的水溶性聚合物环糊精和其它赋形剂如表面活性剂可以用于本发明的33-表氯-33-脱氧-子囊霉素的组合物中。
在一优选方面，本发明提供了一种本申请已叙述过的含表面活性剂和一种子囊霉素如化合物Y的一种固态分散体的组合物。
子囊霉素与载体介质的比率一般不超过1∶3，优选地低于1∶4。
子囊霉素，如化合物Y，固态分散体可以按已叙述的相同方法制备。
本发明公开的化合物Y的口服组合物可用于治疗免疫性间接症的皮肤显现的皮炎和皮肤过于增生症。更具体地，本发明的组合物可用于抗炎和免疫控制剂以及抗皮肤增生剂，预防和治疗炎症及需要免疫抑制的病症，如
a)预防和治疗
-器官或组织移植的排斥，如心脏，肾，肝，骨髓和皮肤，
-移植物-对抗-主体病，如在骨髓移之后，
-自体免疫性疾病如风湿性关节炎，全身红斑狼疮，Hashinoto氏甲状腺病，多处硬化，肌肉无力重症，I型糖尿病和眼葡萄膜炎，
-免疫性间接疾病的皮肤症状；
b)预防和治疗皮肤过于增生疾病，如牛皮癣，特应性皮炎，接触性皮炎和进一步的湿疹性皮炎，皮脂溢皮炎，扁平苔癣，天疱疮，大疱类天疱疮，表皮性大疱，荨麻疹，血管神经性水肿，脉管炎，红斑，皮肤嗜曙红细胞增多，红斑狼疱和痤疮以及
c)斑形脱发。
当本发明的药物组合物是单位剂量时，如片状，胶囊或粉状，每单位剂量可以包括1mg至100mg的药物，更优选地是在10和50mg之间；例如15，20，25或50mg。这种剂量形式适于每天服用1至5次，这取决于疗法的特定目的，治疗的阶段等。
在本发明的一个实施方案中，组合物含30％重量的化合物Y和70％重量的HPMC，如用于治疗牛皮癣，特应性皮炎或接触性皮炎的剂量为每天10至50毫克。
所服用的组合物的确切数量取决于几种因素，如要求的治疗时间和化合物Y的释放速度。
含化合物Y组合物的疗效可由标准的临床试验观察到，如已知的活性剂量给出相应的血中活性剂量；如75公斤成年人和标准动物模特每天1mg至1000mg的活性剂用量。在标准动物实验和临床试验中可以观察到本发明组合物的药物生物利用率提高了。
下面用实例仅对本发明的固态分散体组合做了叙述。
                    实例1
制成了含有下列组份(重量份)的一种固态分散体组合物：
    化合物X            9.1
    HPMC3cps           81.8
    乳糖200筛目        9.1
把雷怕霉素和载体介质溶于乙醇/丙酮混合物中制成了组合物(A型)。无水乙醇和丙酮所用的重量比率为1∶1溶剂蒸发掉，所得的干燥剩余物研磨成平均颗粒大小＜0.5mm的细粉。
                    实例2
制成了含有下列组份(重量份)的一种固态分散体组合物：
化合物X                    16.7
HPMC3cps                   66.7
Poloxamer188(产自BASF)     16.7
组合物(B)型按实例中相似的方式制备。
                    实例3
制成了含有下列组份(重量份)的一种固态分散体：
化合物X                    16.7
HPMC3cps                   66.7
TPGS*                     16.7
组合物(C型)按实例1中相似的方式制备。
*生育酚聚乙二醇琥珀酸酯
                    实例4
制成了含有下列组份(重量份)的一种固态分散体组合物：
化合物X                    10
HPMC3cps                   80
SolulanC24(来自Amerchol)   10
组合物(D型)按实例1中相似的方式制备。
以上A-D型的组合物可以制成片状，装入胶囊，或成粉状并装入小药囊。
鼠服用40-O-(2-羟基)乙基雷怕霉素后的药物动力学
a)服药
0.5ml含化合物X的组合物的水分散体(相当于4.0mg活性组分/鼠)在用连接在聚乙烯管的1ml注射管进行短暂的吸入麻醉时，用胃插入管给药。每种组合物的A，B，C和D型用六只动物。
b)采血样
在实验前一天，向动物的颈静脉中插入一支永久性的插管。由每只鼠收集0.5ml静脉血(颈静脉)并贮存在2.5ml的EDTA管中。两个动物的血样(1和2，2和4，5和6)集中起来，在-80℃下贮存至药物分析时。服药前取血样，服药后10分钟，30分钟，60分钟，120分钟，300分钟，480分钟和1440分钟取血样。
c)生物分析
血样用反相高压液相色谱法分析。
表1给出鼠服用化合物X后收集的药物动力学数量。
表1
总结简介(2-3个集中样的平均值)
                           血浓度
  时间(h)     A型     B型     C型     D型
    0     7     7     7     7
    0.17     118     117     85     68
    0.5     422     131     125     74
    1     375     129     96     66
    2     277     82     89     54
    5     573     92     58     39
    8     496     66     45     34
    24     93     30     34     30
C最大(ng/ml)     573     135     131     81
  T最大(hr)     5.00     0.50     0.50     0.50
  AUC0-8h[(ng/ml).h]     3502     720     565     376
  AUC0-24h[(ng/ml).h]     8213     1487     1192     886
A型造成血中的含量高于那些服用了含表面活性剂的组合物。
狗的研究
在以上有希望的结果之后，用1mg/kg体重的剂量对拴住的猪免狗进行了相对的生物利用率的研究。用每个含化合物X10mg的硬胶囊，用4路拉丁方格设计法向8只狗给药；给药6小时后，给狗喂食，在48小时内测定了血中化合物X的含量。观察到所有的狗都有相同的化合物X的血浓度分布图，化合物X在血中的极限半排出期在10至40小时之内。观察到中等峰值含量为140ng/ml，0-48小时中等AUC含量大约1600ng.h/ml。
                    实例5
制成了含有下列组份(重量份)的一种固态分散体组合物：
化合物Y                         20
HPMC3cps                        80
把化合物Y和载体介质溶解在乙醇/丙酮混合物中制成了组合物(E型)。溶剂蒸发掉，研磨得到的干燥剩余物。
                    实例6
制成了含有下列组份(重量份)的一种固态分散体组合物：
化合物Y                         20
HPMC3cps                        70
Poloxamer188                    10
组合物(F型)按实例5中相同的方式制备。
                    实例7
制成含有下列组份(重量份)的一种固态分散体化合物：
化合物Y                         20
HPMC3cps                        75
月桂基硫酸钠                    5
组合物(G型)按实例5中相同的方式制备。
以上E至G型的组合物可以制成片状，装入胶囊或成粉状并装入小药囊。
鼠服用33-表氯-33-脱氯-子囊霉素的药物动力学
a)服药
0.5ml药物组合物的水分散体(相当于4.0mg活性组分/鼠)在用连接在聚乙烯管的1ml注射管进行短暂的吸入麻醉时，用胃插入管给药。每种组合物的E，F和G型用六只动物。
b)采血样
在实验前一天，向动物的颈静脉中插入一支永久性的插管。由每只鼠收集0.5ml静脉血(颈静脉)并贮存在2.5ml的EDTA管中。两只动物的血样(1和2，3和4，5和6)集中起来，在-80℃下贮存至药物分析时。服药前取血样，服药后10分钟，30分钟，60分钟，120分钟，300分钟，480分的和1440分钟取血样。
c)生物分析
血样用反相高压液相色谱法分析。
结果绘于图1和2中，其中画出了ng/ml(纵座标轴)对时间(小时)(横坐标轴)的曲线。图1示出F型在血中的含量明显地高于服用E型或G型后血液中的含量。图2示出当与食物共用服用时，F型在血中的含量高。
在组合物E，F和G生成时并在贮存6个月后，用X射线衍射测定化合物Y是无定形的。
E，F和G型试验了其相对溶解速度。在0.2重％十二烷基硫酸钠的水溶液中在37℃下搅拌，发现30分钟以后，在每个含10mg化合物Y的研磨组合物中，80％以上的化合物Y释放出并溶解了。92％的化合物Y由E型中释出。做为比较，由相等量的晶体化合物Y中，在30分钟后约5％释放出来。

Claims (10)

1.一种固态分散体形式的含雷怕霉素或子囊霉素和一种载体介质的药物组合物。
2.根据权利要求1的组合物，其中的载体介质含一种水溶性聚合物或一种环糊精。
3.一种固态分散体形式的含雷怕霉素或40-O-(2-羟基)乙基雷怕霉素，和一种含水溶性聚合物的载体介质的药物组合物。
4.根据权利要求3的组合物，其中的聚合物是羟丙基甲基纤维素或聚乙烯吡咯烷酮。
5.根据以上任一项的权利要求的组合物，其中含最高达30％(重量)的雷怕霉素。
6.根据前述任一项权利要求的组合物，其中水溶性聚合物是羟丙基甲基纤维素，其重量可最高达约95％。
7.根据前述任一项权利要求的组合物，其中雷怕霉素和聚合物的比率小于1∶4。
8.一种固态分散体形式的含33-表氯-33-脱氧-子囊霉素和一种载体介质的口服药物组合物。
9.根据权利要求8的组合物，其中该载体介质含一种水溶性聚合物或一种环糊精。
10.根据权利要求8或9的组合物，还含有一种表面活性剂。
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CN105307640A (zh) * 2013-03-19 2016-02-03 诺华股份有限公司 包含依维莫司(everolimus)的药物组合物
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CN103610646A (zh) * 2013-12-05 2014-03-05 江苏奥赛康药业股份有限公司 一种含依维莫司的组合物及其制备方法和含有这一组合物的药物制剂
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CN104721158B (zh) * 2013-12-24 2018-01-30 正大天晴药业集团股份有限公司 一种稳定的依维莫司片剂
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