CN101115758B - 具有增强的溶解性的非晶形的他克莫司固体分散体和包含该分散体的药物组合物 - Google Patents
具有增强的溶解性的非晶形的他克莫司固体分散体和包含该分散体的药物组合物 Download PDFInfo
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- CN101115758B CN101115758B CN2006800040750A CN200680004075A CN101115758B CN 101115758 B CN101115758 B CN 101115758B CN 2006800040750 A CN2006800040750 A CN 2006800040750A CN 200680004075 A CN200680004075 A CN 200680004075A CN 101115758 B CN101115758 B CN 101115758B
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- Prior art keywords
- cyclodextrin
- solid dispersion
- tacrolimus
- acid
- amorphous
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
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Abstract
一种包含他克莫司、取代的环糊精衍生物和有机酸的非晶形的他克莫司固体分散体，所述固体分散体具有高的热力学稳定性和溶解性，可以提供增强的释放速率和生物利用度。
Description
技术领域
本发明涉及一种包含他克莫司(taclolimus)、取代的环糊精衍生物和有机酸的非晶形的他克莫司固体分散体和包含该分散体的药物组合物，该固体分散体表现了他克莫司的增强的生物利用度。
背景技术
分子式(I)为(-)-(1R，9S，13R，14S，17R，18E，21S，23S，24R，25S，27R)-17-烯丙基-1，14-二羟基-12-[(E)-2-[(1R，3R，4R)-4-羟-3-甲氧环己基]-1-甲基乙烯基]-23，25-二甲氧基-13，19，21，27-四甲基-11，28-二氧杂-4-氮杂三环[22.3.1.04.9]二十八碳-18-烯-2，3，10，16-四酮水合物[104987-11-3]的他克莫司(或FK-506)是由Tanaka和Kuroda等(见J.Am.Chem.Soc.，109：5031(1987)和美国专利号4,894,366)发现的小环内酯基(microlide-based)免疫抑制药物。
美国食品与药品管理局已经批准了他克莫司用于抑制移植排斥(普乐可复
胶囊(Fujisawa，Japan))和用于治疗特应性皮炎(普特皮
软膏)的使用。此外，已经证实他克莫司相关化合物对于治疗以下疾病是有用的：例如变态反应性脑脊髓炎、胶原关节炎、阻塞性支气管疾病例如气喘、男性型秃发、糖尿疾病、眼疾例如后葡萄膜炎、局部贫血相关肝损伤、肾小球性肾炎、系统性红斑狼疮、多药耐药、粘膜和血管的炎症、巨细胞病毒感染、特发性血小板减少性紫癜和甲状腺功能亢进症。
他克莫司为白色晶体或结晶粉末，并且完全溶解于有机溶剂例如无水乙醇，但是不溶解于水中。因而，当将水不溶性的他克莫司经口给药时，它的生物利用度不可避免地是低的。
为了克服此问题，韩国专利公布号1987-10073公开了一种商购普乐可复胶囊的制备方法，该方法包括以下步骤：将水溶性的聚合物加入溶解在有机溶剂中的水不溶性的他克莫司中；任选地在那里悬浮添加剂例如赋形剂和崩解剂以获得均匀的悬浮液；和依照常规方法将有机溶剂从那里去除，以获得包含他克莫司和水溶性聚合物的固体分散体组合物。
本发明人出乎意料地发现的是，通过将他克莫司与取代的环糊精衍生物和有机酸一起由喷雾干燥机处理所制备的他克莫司固体分散体，表现了比任何的现有包含羟丙基甲基纤维素的他克莫司制剂更高的活性成分的溶解性和稳定性。
发明概述
因此，本发明的一个目的是提供一种比常规他克莫司制剂表现更高水溶性和生物利用度的他克莫司固体分散体，以及它的制备方法。
本发明的另一个目的是提供一种经口给药用的，包含他克莫司固体分散体的药物组合物。
根据本发明的一个方面，提供了一种包含他克莫司、分子式(II)的取代α-、β-或γ-环糊精衍生物和有机酸的非晶形的他克莫司固体分散体：
其中，
n为在6至8的范围内的整数；和
R为任选地由羟基、羧基或羧基C1-4烷氧基取代的C1-6烷基，，或磺基C1-4烷氧基。
根据本发明的另一个方面提供的是，所述固体分散体进一步包含表面活性剂、水溶性聚合物或药用添加剂。
附图简述
从结合以下附图的本发明的以下说明，本发明的以上和其它的目的和特征将会变得显而易见，该附图分别表示：
图1：结晶他克莫司(1)、实施例1的固体分散体(2)和比较例2的混合物(3)的差示扫描量热计(DSC)的差示热分析图；
图2：实施例1的固体分散体(1)、结晶他克莫司(2)和比较例2的混合物(3)的粉末X-射线衍射的谱图；
图3：普乐可复胶囊(对照物)和在制备实施例1，9和11，以及比较制备实施例1和2中制备的胶囊的饱和溶解度曲线；
图4：普乐可复胶囊(对照物)和在制备实施例1和比较制备实施例1中制备的胶囊的体外释放曲线；
和图5：经口给药的普乐可复胶囊(对照物)和在制备实施例1和比较制备实施例1中制备的胶囊的体内生物利用度曲线。
发明详述
以下详细描述所述包含他克莫司的固体分散体的各个组分：
(1)取代的环糊精衍生物
本发明中采用的分子式(II)的取代的环糊精衍生物在具有增强的水溶性和生物利用度的本发明非晶固体分散体的形成中扮演了至关重要的角色，并且其代表性的实例包括：2-羟乙基-β-环糊精、2-羟丙基-β-环糊精、2，6-二甲基-β-环糊精、磺丁基醚-7-β-环糊精、(2-羧基甲氧基)丙基-β-环糊精、2-羟乙基-γ-环糊精和2-羟丙基-γ-环糊精，并且2-羟乙基-β-环
(II)
糊精、2-羟丙基-β-环糊精、2，6-二甲基-β-环糊精和磺基丁基醚-7-β-环糊精
是优选的。该取代的环糊精衍生物可以组合使用。
其中，
n为在6至8的范围内的整数；和
R为任选地由羟基、羧基或羧基C1-4烷氧基取代的C1-6烷基，或磺基C1-4烷氧基。
(有机酸)
本发明的有机酸可以是任何一种的已知药用有机酸，该有机酸用于在配制本发明的固体分散时稳定他克莫司。该有机酸的代表性实例包括：异抗坏血酸、柠檬酸、酒石酸、抗坏血酸、乳酸、苹果酸、琥珀酸、乙酸、三氯乙酸、三氟乙酸、二甲基三胺五乙酸、丙酮酸、丙二酸、肉豆蔻酸、苦味酸、甲磺酸、乙磺酸、对氨基苯甲酸、苯磺酸、苯甲酸、乙二胺四乙酸、山梨酸、脂肪酸、葡糖酸、氨基己酸、甘草酸、异硬脂酸、十二烷基苯磺酸、富马酸、马来酸、草酸、丁酸、棕榈酸、磺酸、亚磺酸、甲酸、丙酸、单宁酸、泛酸、天冬氨酸、氨基乙酸、DL-a-氨基丙酸和它们的混合物，并且异抗坏血酸和柠檬酸是优选的。
(3)添加剂
可以将添加剂例如表面活性剂、水溶性聚合物和药用添加剂用于本发明中，以增强本发明固体分散体的流动性和其它的物理性质，并且其实例包括下列各项。
i)表面活性剂
①聚氧乙烯-失水山梨糖醇-脂肪酸酯：
单或三月桂酸酯、棕榈酸酯、硬脂酸酯或油酸酯(
Uniquema)，
②失水山梨糖醇脂肪酸酯：
失水山梨糖醇单月桂酯、失水山梨糖醇单棕榈酯或失水山梨糖醇单硬脂酯(
Uniquema)，
③聚氧乙烯-聚氧丙烯嵌段共聚物(Poloxamers)，
④天然或氢化植物油与乙二醇的反应产物：
聚乙二醇化的天然或氢化蓖麻油(
BASF)，
⑤聚氧乙烯脂肪酸酯：
聚氧乙烯硬脂酸酯(Uniquema)，
⑥二辛基磺基琥珀酸钠或十二烷基硫酸钠，和
⑦甘油单、二和三酯、聚乙二醇单和二酯或聚乙二醇的混合物Gattefosse)
在以上提及的表面活性剂中，聚氧乙烯-聚氧丙烯嵌段共聚物，聚氧乙烯脂肪酸酯，甘油单、二和三酯、聚乙二醇单和二酯、聚乙二醇的混合物，二辛基磺基琥珀酸钠和十二烷基硫酸钠是优选的，并且聚氧乙烯-聚氧丙烯嵌段共聚物是更优选的。
ii)水溶性聚合物
在本发明中，可以任选加入一种或更多种的水溶性聚合物，以改善固体分散体的流动性和其它的物理性质。该水溶性聚合物可以选自：烷基纤维素，例如甲基纤维素；羟烷基纤维素，例如羟甲基纤维素、羟乙基纤维素、羟丙基纤维素和羟丁基纤维素；羟烷基烷基纤维素，例如羟乙基甲基纤维素和羟丙基甲基纤维素；羧烷基纤维素，例如羧甲基纤维素；羧烷基纤维素的碱金属，例如羧甲基纤维素钠；羧烷基烷基纤维素，例如羧甲基乙基纤维素；羧烷基纤维素酯；淀粉；果胶，例如羧甲基支链淀粉钠；甲壳质衍生物，例如脱乙酰壳多糖；多糖，例如藻酸、它的碱金属和铵盐、角叉菜胶(caragenan)、半乳甘露聚糖、黄蓍胶、琼脂、阿拉伯树胶、瓜耳胶和黄原酸胶；聚甲基丙烯酸及其盐；聚甲基丙烯酸及其盐、甲基丙烯酸酯共聚物、氨烷基甲基丙烯酸酯共聚物；聚乙烯醇缩乙醛和二乙基氨基醋酸酯；糖型表面活性剂，例如蔗糖二硬脂酸酯、蔗糖单/二硬脂酸酯和蔗糖单棕榈酸酯；聚乙烯醇；聚乙烯吡咯烷酮和聚乙烯吡咯烷酮-醋酸乙烯酯共聚物；聚环氧烷，例如聚环氧乙烷和聚环氧丙烷；和环氧乙烷-环氧丙烷共聚物。
在以上提及的水溶性聚合物中，烷基纤维素、羟烷基纤维素、羟烷基烷基纤维素和聚乙烯毗咯烷酮是优选的，并且羟丙基甲基纤维素、羟丙基纤维素和聚乙烯吡咯烷酮是更优选的。
iii)药用添加剂
在本发明中，在制备包含固体分散体的经口给药的组合物的过程中，可以任选地加入一种或更多种的药用赋形剂，以改善固体分散体的流动性和其它的物理性质。该药用赋形剂可以选自由乳糖、淀粉、羟基乙酸淀粉钠、聚乙烯聚吡咯烷酮、交联羧甲纤维素钠、麦芽糖糊精、微晶纤维素、磷酸钙、碳酸氢钙和结晶纤维素组成的组。此外，在本发明中可以采用润滑剂，例如硬脂酸、硬脂酸镁和滑石。
在本发明的非晶形的他克莫司固体分散体的制备中，可以采用的作为药物活性成分的他克莫司、取代的环糊精衍生物和有机酸的量对应于在1:0.1～20:0.1～10，优选1:0.1～10:0.1～5的范围内的重量比。表面活性剂或药用添加剂可以以基于他克莫司的20和更少的重量比的量来使用。另外，在本发明的实施例中描述的组合物可以被参考为对本发明效果的优选例证。
本发明的非晶形的他克莫司固体分散体没有在它的DSC扫描中显示任何的吸热峰，也没有在它的粉末X-射线衍射谱中显示结晶折射峰，表明本发明分散体中所包含的他克莫司是稳定的非晶形式。
本发明的固体分散体可以通过包括以下步骤的方法来制备：(a)将取代的环糊精衍生物和有机酸分散或溶解在有机溶剂中；(b)将他克莫司溶解在有机溶剂中；和(c)将以上获得的分散体和溶液混合，随后从那里去除溶剂。
在步骤(a)中，可以任选地将一种或更多种的表面活性剂和药用添加剂溶解或分散在溶液中。可以在步骤(b)中使用的有机溶剂为乙醇、异丙醇、丙酮、乙腈、二氯甲烷、氯仿或任何的适合的有机溶剂。在步骤(c)中，可以通过喷雾干燥、辊筒干燥、溶剂沉淀或冷冻干燥将溶剂去除，以获得非晶形的他克莫司固体分散体。
另外，本发明提供了一种包含与药用载体、赋形剂和添加剂一起的固体分散体，用于经口给药的药物组合物。该药物组合物可以根据任何的常规方法而以粉末、粒状、片剂、软或硬胶囊、丸剂或包衣制剂的形式来配制。例如，可以将以粉末或粒状形式的固体分散体与润滑剂或其它的药物添加剂一起填充进入到硬胶囊中，或者与压片用药物添加剂一起制成片剂形式，然后任选地根据任何的常规方法包衣，以获得包衣制剂。
本发明制剂可以以单独剂量或分开剂量的典型量经口给药。
以下实施例意欲进一步说明本发明而没有限制它的范围。
实施例：他克莫司固体分散体的制备
实施例1
将400mg的2-羟丙基-β-环糊精(Aldrich，USA)、20mg的柠檬酸和20mg的泊洛沙姆(Poloxamer)188(Lutrol F68，BASF)加入到MC(二氯甲烷)和乙醇的混合物中，并且搅拌直至该溶液变为澄清。然后，往那里加入400mg的乳糖并且均匀分散。将溶解于乙醇中的100mg的他克莫司与该分散液混合，并且进行喷雾干燥，同时将喷雾干燥器(迷你喷雾干燥器B-191，Buchi，Switzerland)的入口和出口温度分别维持在60℃和45-50℃，以获得具有列于表1中的成分的他克莫司固体分散体。
实施例2
除采用200mg的2-羟丙基-β-环糊精以外，通过重复实施例1的过程来制备具有列于表1中的成分的他克莫司固体分散体。
实施例3
除采用800mg的2-羟丙基-β-环糊精以外，通过重复实施例1的过程来制备具有列于表1中的成分的他克莫司固体分散体。
表1
实施例4
除采用2，6-二甲基-β-环糊精
W7M Pharma，WAKER)代替2-羟丙基-β-环糊精以外，通过重复实施例1的过程来制备具有列于表2中的成分的他克莫司固体分散体。
实施例5
除采用磺丁基醚-7-β-环糊精
WAKER)代替2-羟丙基-β-环糊精以外，通过重复实施例1的过程来制备具有列于表2中的成分的他克莫司固体分散体。
实施例6
除采用异抗坏血酸代替柠檬酸作为有机酸以外，通过重复实施例1的过程来制备具有列于表2中的成分的他克莫司固体分散体。
表2
实施例7
除采用Myrj52S(Uniqema)代替泊洛沙姆188作为表面活性剂以外，通过重复实施例1的过程来制备具有列于表3中的成分的他克莫司固体分散体。
实施例8
除采用十二烷基硫酸钠代替泊洛沙姆188作为表面活性剂以外，通过重复实施例1的过程来制备具有列于表3中的成分的他克莫司固体分散体。
实施例9
除采用聚乙二醇硬脂酸酯(solutol)代替泊洛沙姆188作为表面活性剂以外，通过重复实施例1的过程来制备具有列于表3中的成分的他克莫司固体分散体。
表3
实施例10
除采用淀粉代替乳糖作为药物添加剂以外，通过重复实施例1的过程来制备具有列于表4中的成分的他克莫司固体分散体。
实施例11
除采用麦芽糊精代乳糖作为药物添加剂以外，通过重复实施例1的过程来制备具有列于表4中的成分的他克莫司固体分散体。
实施例12
除采用微晶纤维素代替乳糖作为药物添加剂以外，通过重复实施例1的过程来制备具有列于表4中的成分的他克莫司固体分散体。
表4
实施例13
除没有采用泊洛沙姆188以外，通过重复实施例1的过程来制备具有列于表5中的成分的他克莫司固体分散体。
实施例14
除没有采用乳糖以外，通过重复实施例1的过程来制备具有列于表5中的成分的他克莫司固体分散体。
实施例15
除没有采用泊洛沙姆188和乳糖以外，通过重复实施例1的过程来制备具有列于表5中的成分的他克莫司固体分散体。
表5
实施例16
除采用10mg的柠檬酸以外，通过重复实施例8的过程来制备具有列于表6中的成分的他克莫司固体分散体。
实施例17
除采用50mg的柠檬酸以外，通过重复实施例8的过程来制备具有列于表6中的成分的他克莫司固体分散体。
实施例18
除采用100mg的柠檬酸以外，通过重复实施例8的过程来制备具有列于表6中的成分的他克莫司固体分散体。
表6
实施例19
除采用800mg的乳酸以外，通过重复实施例1的过程来制备具有列于表7中的成分的他克莫司固体分散体。
实施例20
除采用1,500mg的乳酸以外，通过重复实施例1的过程来制备具有列于表7中的成分的他克莫司固体分散体。
实施例21
除采用2,000mg的乳酸以外，通过重复实施例1的过程来制备具有列于表7中的成分的他克莫司固体分散体。
表7
实施例22
除采用每种10mg的柠檬酸和异抗坏血酸作为有机酸以外，通过重复实施例1的过程来制备具有列于表8中的成分的他克莫司固体分散体。
实施例23
除采用每种200mg的乳酸和微晶纤维素作为药物添加剂以外，通过重复实施例1的过程来制备具有列于表8中的成分的他克莫司固体分散体。
实施例24
除采用每种10mg的泊洛沙姆188和十二烷基硫酸钠作为表面活性剂以外，通过重复实施例1的过程来制备具有列于表8中的成分的他克莫司固体分散体。
表8
实施例25
除采用每种200mg的2-羟丙基-β-环糊精和磺丁基醚-7-β-环糊精以外，通过重复实施例1的过程来制备具有列于表9中的成分的他克莫司固体分散体。
实施例26
除采用200mg的乳酸和200mg的添加的羟丙基甲基纤维素2910作为水溶性聚合物以外，通过重复实施例1的过程来制备具有列于表9中的成分的他克莫司固体分散体。
实施例27
除采用200mg的乳酸和200mg的添加的聚乙烯吡咯烷酮作为水溶性聚合物以外，通过重复实施例1的过程来制备具有列于表9中的成分的他克莫司固体分散体。
表9
比较例1
将与实施例1(见表10)相同的成分简单混合而不喷雾干燥，以获得混合物。
比较例2
除不采用2-羟丙基-β-环糊精以外，通过重复实施例1的过程来制备具有列于表10中的成分的他克莫司固体分散体。
比较例3
除不采用柠檬酸以外，通过重复实施例1的过程来制备具有列于表10中的成分的他克莫司固体分散体。
表10
制备实施例：胶囊制剂的制备
制备实施例1
将940mg的实施例1的固体分散体(他克莫司100mg)、5,495mg的乳糖和65mg的硬脂酸镁均匀混合，并且以相应于1mg的他克莫司的量将所得的混合物填充进入到5号明胶胶囊中，以获得具有列于表11中的成分的胶囊制剂。
制备实施例2
除采用1,340mg的实施例3的固体分散体(他克莫司100mg)和5,095mg的乳糖以外，通过重复制备实施例1的过程来制备具有列于表11中的成分的胶囊制剂。
制备实施例3
除采用940mg的实施例5的固体分散体(他克莫司100mg)以外，通过重复制备实施例1的过程来制备具有列于表11中的成分的胶囊制剂。
表11
制备实施例4
除采用940mg的实施例6的固体分散体(他克莫司100mg)以外，通过重复制备实施例1的过程来制备具有列于表12中的成分的胶囊制剂。
制备实施例5
除采用940mg的实施例8的固体分散体(他克莫司100mg)以外，通过重复制备实施例1的过程来制备具有列于表12中的成分的胶囊制剂。
制备实施例6
除采用940mg的实施例11的固体分散体(他克莫司100mg)以外，通过重复制备实施例1的过程来制备具有列于表12中的成分的胶囊制剂。
表12
制备实施例7
除采用920mg的实施例13的固体分散体(他克莫司100mg)和5,515
mg的乳糖的以外，通过重复制备实施例1的过程来制备具有列于表13中的成分的胶囊制剂。
制备实施例8
除采用540mg的实施例14的固体分散体(他克莫司100mg)和5,895mg的乳糖的以外，通过重复制备实施例1的过程来制备具有列于表13中的成分的胶囊制剂。
制备实施例9
除采用520mg的实施例15的固体分散体(他克莫司100mg)和5,915mg的乳糖的以外，通过重复制备实施例1的过程来制备具有列于表13中的成分的胶囊制剂。
表13
制备实施例10
除采用320mg的实施例15的固体分散体(他克莫司100mg)和6,115mg的乳糖的以外，通过重复制备实施例1的过程来制备具有列于表14中的成分的胶囊制剂。
制备实施例11
除采用微晶纤维素代替乳糖作为药物添加剂以外，通过重复制备实施例1的过程来制备具有列于表14中的成分的胶囊制剂。
制备实施例12
除采用5,195mg的乳糖和300mg的交联羧甲纤维素钠作为药物添加剂以外，通过重复制备实施例1的过程来制备具有列于表14中的成分的胶囊制剂。
表14
制备实施例13
除采用4,845mg的乳糖和650mg的添加的羟丙基甲基纤维素作为水溶性聚合物以外，通过重复制备实施例1的过程来制备具有列于表15中的成分的胶囊制剂。
制备实施例14
除采用4,845mg的乳糖和650mg的交聚维酮作为药物添加剂以外，通过重复制备实施例1的过程来制备具有列于表15中的成分的胶囊制剂。
制备实施例15
除采用4,845mg的磷酸钙和650mg的交聚维酮代替乳糖以外，通过重复制备实施例1的过程来制备具有列于表15中的成分的胶囊制剂。
表15
比较制备实施例1
除采用940mg的比较例1的混合物(他克莫司100mg)以外，通过重复制备实施例1的过程来制备具有列于表16中的成分的胶囊制剂。
比较制备实施例2
除采用540mg的比较例2的固体分散体(他克莫司100mg)和5,895mg的乳糖以外，通过重复制备实施例1的过程来制备具有列于表16中的成分的胶囊制剂。
比较制备实施例3
除采用920mg的比较例3的固体分散体(他克莫司100mg)和5,515mg的乳糖以外，通过重复制备实施例1的过程来制备具有列于表16中的成分的胶囊制剂。
表16
测试例1：热力学稳定性测试
通过研究在其DSC扫描中的吸热峰中的变化来对比较例1的混合物、实施例1的固体分散体和结晶他克莫司分别进行热力学稳定性测试。将表现各个吸热峰的温度表示于表17中，并且将全部的DSC结果表示于图1中。
表17
| 吸热峰温度(℃) | |
| 比较例1 | 127.9 |
| 实施例1 | 无 |
| 结晶他克莫司 | 127.0 |
由表17和图1中可见，本发明的他克莫司固体分散体在其DSC扫描中没有表现出任何突出的吸热峰，因此，它是以非晶形式存在的，该非晶形式在考察的温度范围内是稳定的。
测试例2：X射线粉末衍射分析
在Cu X-射线、40kV和300mA的条件下，采用M18XHF-SRA(Macscience Co.，LTD，Japan)来测定结晶他克莫司、比较例1的混合物和实施例1的固体分散体的X-射线衍射花样，并且将结果表示于图2中。
由图2中可见，本发明的固体分散体中的他克莫司通过喷雾干燥过程而变为非晶的，并且是热力学稳定的。
测试例3：溶解性测试
采用普乐可复胶囊作为对照物对每个制备实施例1、9和11，以及比较制备实施例1和2的制剂进行溶解度测试。将取自每个制剂的包含5mg的他克莫司的样品溶解于10ml的蒸馏水中，并且在25℃水浴中贮存。在贮存以后在1、3、6、15和24小时收集测试样品，并且在以下条件下测量每个样品中的他克莫司的量：
[测试方法：液相色谱仪]
柱-TSK凝胶ODS80TM柱(150mmX4.6mm，5μm)，
流动相-水:异丙醇:四氢呋喃＝5:2:2(v/v/v)，
注射体积-20μl，
流速-控制他克莫司的保留时间为约10分钟，
柱温-50℃，和
检测-220nm。
结果表示于图3中。
由图3中可见，每个本发明的他克莫司的固体分散体都具有比比较制备实施例1的简单混合物显著更高的溶解性。此外，当贮存在25℃水浴中24小时的时候，每个包含采用了环糊精衍生物的固体分散体的制剂都比比较制备实施例2的制剂，或对照物制剂维持了15小时的更高的溶解性。因此，取代的环糊精衍生物的采用抑制了药物在水溶液中的结晶，并且在长的时期保持以非晶的和生物可用的形式。
测试例4：体外释放测试
根据在韩国药典(桨法)中描述的释放测试方法，采用普乐可复胶囊(1mg，Fμjisawa island)作为对照物，对制备实施例1和比较制备实施例1的制剂各个进行体外释放测试，并且在以下条件下分析释放模式：
[释放测试方法]
释放测试系统-Erweka DT80，
释放溶液-在减压下脱气10分钟的900ml的蒸馏水，
释放溶液温度-37±0.5℃，
旋转速率：100rpm，和
样品量-1个胶囊/每个沉锤(sinker)。
[分析方法：液相色谱仪]
柱-Inertsil CN-3(150mmX4.6mm，5μm)，
流动相-水:乙腈:异丙醇＝7:2:1(v/v/v)，
注射体积-300μl，
流速-0.5ml/分钟，
柱温-50℃，和
检测-210nm。
结果表示于图4中。
由图4中可见，包含本发明的非晶形的他克莫司固体分散体的制剂(制剂1)表现了与对照物相类似的释放速率，但是显著高于与其它成分混合的他克莫司制剂(比较制剂1)的释放速率。
测试例5：稳定性测试
在60℃的加速老化条件下，将制备实施例1和比较制备实施例3的制剂与作为对照物的1mg的普乐可复(硬胶囊，Fujisawa island)一起贮存，并且在以下条件下，通过HPLC分析在其杂质和互变异构体的产生中的时间依赖性变化。
柱-纵向连接的2个Supelcosil LC-Diol(250mmX4mm，5μm)，
流动相-正己烷:正丁基氯:乙腈＝7:2:1(v/v/v)，
注射体积-20μl，
流速-控制他克莫司的保留时间为约15分钟，
柱温-25℃，和
检测-225nm。
结果表示于表18中。
表18
由表18中可见，在苛刻的老化条件下，在包含取代的环糊精衍生物和有机酸的本发明的制剂(制备实施例1)中的他克莫司，比对照物或比较制备实施例3的制剂稳定得多，并且可以抵抗互变异构物质或杂质的产生。
测试例6：体内吸收测试
采用对照物对每个制备实施例1和比较制备实施例1的制剂进行体内吸收测试，以研究本发明化合物的经口给药的生物利用度。
将分配有各个制剂的5只雄性Sprague-Dawley大鼠(重量：每只250g；14-15个星期)适应超过4天，同时允许自由获得食物和水。然后将该大鼠禁食48小时，同时允许它们自由获得水。
用测试或对照物制剂，以相应于10mg/kg他克莫司的量，连同水对大鼠经口给药。在给药前和给药后0.5、1、1.5、2、3、4、5、7和24小时从大鼠采集血样。
向200μl的每个血样中加入400μl的0.2M ZnSO4和MeOH(2:8(v/v))的混合物，并且将该混合物摇动。将该混合物在12,000rpm离心30秒以获得上层清液，将该上层清液过滤通过0.22μm的过滤器，并且在以下条件下通过LC-MS分析：
柱-Waters MS C18(150mm X2.1mm具有保护柱)，
流动相-浓度梯度(65％MeOH→-95％MeOH)，
注射体积-30μl，
流速-0.3ml/分钟，和
检测-SIR类型m/z：826.7(Na加合物)。
结果表示于表19和图5中。
表19
由表19和图5中可见，根据本发明制备的制剂在所有的方面中表现了比普乐可复胶囊(对照物制剂)更高的生物利用度。因此，本发明中采用的取代环糊精和有机酸的结合应用产生了通过在先技术不能实现的有益效果。
虽然关于以上特别实施方案而描述了本发明，但是需要认识到的是，可以进行不同的更改和变化，并且该更改和变化也落入由后附权利要求所定义的本发明的范围中。
Claims (11)
1.一种非晶形的他克莫司固体分散体，其包含他克莫司、分子式(II)的取代α-、β-或γ-环糊精衍生物和有机酸：
其中，
n为在6至8的范围内的整数；和
R为任选地由羟基、羧基或羧基C1-4烷氧基取代的C1-6烷基，或磺基C1-4烷氧基；
其中所述有机酸选自柠檬酸和异抗坏血酸。
2.按照权利要求1所述的非晶形的他克莫司固体分散体，其中他克莫司∶取代的环糊精衍生物∶有机酸的重量比在1∶0.01-20∶0.1-10范围内变化。
3.按照权利要求1所述的非晶形的他克莫司固体分散体，所述分散体进一步包含表面活性剂、水溶性聚合物或药用添加剂。
4.按照权利要求1所述的非晶形的他克莫司固体分散体，其中所述取代的环糊精衍生物选自由2-羟乙基-β-环糊精、2-羟丙基-β-环糊精、2，6-二甲基-β-环糊精、磺丁基醚-7-β-环糊精、(2-羧基甲氧基)丙基-β-环糊精、2-羟乙基-γ-环糊精和2-羟丙基-γ-环糊精组成的组。
5.按照权利要求4所述的非晶形的他克莫司固体分散体，其中所述取代的环糊精衍生物选自由2-羟乙基-β-环糊精、2-羟丙基-β-环糊精、2，6-二甲基-β-环糊精和磺丁基醚-7-β-环糊精组成的组。
6.按照权利要求3所述的非晶形的他克莫司固体分散体，其中所述表面活性剂选自由聚氧乙烯-失水山梨糖醇-脂肪酸酯，失水山梨糖醇脂肪酸酯，聚氧乙烯-聚氧丙烯嵌段共聚物，天然或氢化植物油与乙二醇的反应产物，聚氧乙烯脂肪酸酯，二辛基磺化琥珀酸钠，十二烷基硫酸钠，甘油单、二和三酯、聚乙二醇单和二酯、和聚乙二醇的混合物组成的组。
7.按照权利要求3所述的非晶形的他克莫司固体分散体，其中所述水溶性聚合物选自由甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丁基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素和它们的碱金属、羧甲基乙基纤维素、淀粉、果胶、甲壳质衍生物、多糖、聚丙烯酸和它们的盐、聚甲基丙烯酸和它们的盐、甲基丙烯酸酯共聚物、氨烷基甲基丙烯酸酯共聚物、聚乙烯醇缩乙醛、二乙基氨基醋酸酯、蔗糖二硬脂酸酯、蔗糖单/二硬脂酸酯和蔗糖单棕榈酸酯、聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯吡咯烷酮-醋酸乙烯酯共聚物、聚环氧烷、和环氧乙烷与环氧丙烷的共聚物组成的组。
8.药物组合物，其包含权利要求1的非晶形的他克莫司固体分散体、表面活性剂、水溶性聚合物和药用添加剂。
9.一种制备权利要求1的非晶形的他克莫司固体分散体的方法，所述方法包括以下步骤：(1)将取代的环糊精衍生物和有机酸分散或溶解在有机溶剂中，其中所述有机酸选自柠檬酸和异抗坏血酸；(2)将他克莫司溶解在有机溶剂中；和(3)将以上获得的分散体和溶液混合，随后通过喷雾干燥从混合物去除溶剂。
10.按照权利要求9所述的方法，其中在步骤(2)中采用的溶剂选自由乙醇、异丙醇、丙酮、乙腈、二氯甲烷、氯仿和它们的混合物组成的组。
11.按照权利要求9所述的方法，其中将表面活性剂、水溶性聚合物或药用添加剂进一步加入到步骤(1)的溶液中。
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| KR1020050010302 | 2005-02-04 | ||
| KR10-2005-0010302 | 2005-02-04 | ||
| KR1020050010302A KR100678824B1 (ko) | 2005-02-04 | 2005-02-04 | 용해성이 증가된 무정형 타크로리무스 고체분산체 및 이를포함하는 약제학적 조성물 |
| PCT/KR2006/000397 WO2006083130A1 (en) | 2005-02-04 | 2006-02-03 | Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same |
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| KR (1) | KR100678824B1 (zh) |
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| FR2913018A1 (fr) * | 2007-02-23 | 2008-08-29 | Sanofi Aventis Sa | Solution solide amorphe contenant un derive de pyrazole-3-carboxamide sous forme amorphe et des excipients stabilisateurs |
| LT2167033T (lt) | 2007-05-30 | 2017-08-10 | Veloxis Pharmaceuticals A/S | Kartą per dieną vartojama geriamoji vaisto forma, apimanti takrolimą |
| US12083103B2 (en) | 2007-05-30 | 2024-09-10 | Veloxis Pharmaceuticals, Inc. | Tacrolimus for improved treatment of transplant patients |
| CN101909673B (zh) * | 2007-12-31 | 2012-12-26 | 诺沃-诺迪斯克有限公司 | 电子监控的注射设备 |
| CL2008000374A1 (es) * | 2008-02-05 | 2008-04-04 | Igloo Zone Chile S A | Composicion farmaceutica que comprende un polvo para suspension oral de tacrolimus o una de sus sales, hidratos o solvatos y excipientes farmaceuticamente aceptables; procedimiento de preparacion de dicha composicion farmaceutica; y uso para la preve |
| CA2715802A1 (en) * | 2008-02-28 | 2009-09-03 | Bial - Portela & C.A., S.A. | Pharmaceutical composition for poorly soluble drugs |
| WO2009118356A2 (en) * | 2008-03-25 | 2009-10-01 | Formac Pharmaceuticals N.V. | Preparation method for solid disupersions |
| US20230101012A1 (en) * | 2008-05-30 | 2023-03-30 | Veloxis Pharmaceuticals, Inc. | Stabilized tacrolimus composition |
| RS55118B1 (sr) | 2010-02-17 | 2016-12-30 | Veloxis Pharmaceuticals As | Stabilizovana takrolimus kompozicija |
| CA2835232C (en) * | 2011-07-01 | 2017-02-14 | Fondazione Istituto Insubrico Di Ricerca Per La Vita | A complex of amorphous tomoxiprole and cyclodextrin with fast dissolution rate and process for the preparation thereof |
| KR101986683B1 (ko) * | 2012-12-13 | 2019-06-10 | 한미약품 주식회사 | 테트라졸 유도체를 활성 성분으로 포함하는 용해도가 개선된 고체 분산체 |
| CN103479600B (zh) * | 2013-09-17 | 2018-01-19 | 成都盛迪医药有限公司 | 一种他克莫司固体分散体 |
| CN105616365B (zh) * | 2014-11-08 | 2019-04-05 | 山东新时代药业有限公司 | 一种依维莫司片剂 |
| CN106860408B (zh) * | 2015-12-14 | 2021-06-22 | 山东新时代药业有限公司 | 一种格列美脲片 |
| CN106880597B (zh) * | 2015-12-14 | 2022-06-07 | 山东新时代药业有限公司 | 一种依维莫司片 |
| CN106860407B (zh) * | 2015-12-14 | 2021-07-30 | 山东新时代药业有限公司 | 一种利伐沙班片 |
| CN106880617B (zh) * | 2015-12-14 | 2021-08-31 | 山东新时代药业有限公司 | 一种他克莫司胶囊 |
| CN106880598B (zh) * | 2015-12-14 | 2021-08-31 | 山东新时代药业有限公司 | 一种依折麦布片剂 |
| CN105803806A (zh) * | 2016-04-21 | 2016-07-27 | 安徽皖翎羽绒制品有限公司 | 一种具有长效屏蔽电磁辐射功效羽绒的处理方法 |
| CN106226430A (zh) * | 2016-07-31 | 2016-12-14 | 合肥远志医药科技开发有限公司 | 一种他克莫司制剂的有关物质检测方法 |
| CA3099901C (en) | 2018-07-13 | 2024-03-19 | Council Of Scientific & Industrial Research | Solid dispersion comprising an anticancer compound for improved solubility and efficacy |
| CN109528738A (zh) * | 2018-12-24 | 2019-03-29 | 陕西师范大学 | 甘草酸在制备促进髓鞘再生抑制神经炎症药物的应用 |
| CN111830168B (zh) * | 2020-07-23 | 2022-07-22 | 吉林医药学院 | 一种泊洛沙姆的lc-hr-ms/ms定量分析方法 |
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| BE1009856A5 (fr) * | 1995-07-14 | 1997-10-07 | Sandoz Sa | Composition pharmaceutique sous la forme d'une dispersion solide comprenant un macrolide et un vehicule. |
| TW426516B (en) * | 1996-12-06 | 2001-03-21 | Fujisawa Pharmaceutical Co | An oral pharmaceutical composition in solid dispersion containing water-insoluble tricyclic compounds |
| RU2214244C9 (ru) * | 1998-03-26 | 2020-07-29 | Астеллас Фарма Инк. | Препараты с замедленным высвобождением |
| KR20030041577A (ko) * | 2001-11-20 | 2003-05-27 | 디디에스텍주식회사 | 난용성 약물과 치환된 시클로덱스트린을 함유하는고체분산체 및 이를 함유하는 약제학적 조성물 |
| CN100589809C (zh) * | 2002-06-13 | 2010-02-17 | 诺瓦提斯公司 | 季铵环糊精化合物 |
| WO2005004848A1 (en) * | 2003-07-09 | 2005-01-20 | Chong Kun Dang Pharmaceutical Corp. | The solid dispersion of tacrolimus |
| ATE531368T1 (de) * | 2003-08-29 | 2011-11-15 | Veloxis Pharmaceuticals As | Tacrolimus enthaltende zusammensetzungen mit modifizierter freisetzung |
| WO2005020994A1 (en) * | 2003-08-29 | 2005-03-10 | Lifecycle Pharma A/S | Solid dispersions comprising tacrolimus |
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| US4916138A (en) * | 1986-04-02 | 1990-04-10 | Fujisawa Pharmaceutical Co., Ltd. | Solid dispersion composition of FR-900506 substance |
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| HK1111151A1 (en) | 2008-08-01 |
| US20080153866A1 (en) | 2008-06-26 |
| EP1848722A1 (en) | 2007-10-31 |
| JP4825223B2 (ja) | 2011-11-30 |
| JP2008529999A (ja) | 2008-08-07 |
| KR20060089328A (ko) | 2006-08-09 |
| WO2006083130A1 (en) | 2006-08-10 |
| KR100678824B1 (ko) | 2007-02-05 |
| EP1848722A4 (en) | 2012-12-12 |
| CN101115758A (zh) | 2008-01-30 |
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