CN1040746C - 维生素d类似物的新晶形 - Google Patents

维生素d类似物的新晶形 Download PDF

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CN1040746C
CN1040746C CN94190817A CN94190817A CN1040746C CN 1040746 C CN1040746 C CN 1040746C CN 94190817 A CN94190817 A CN 94190817A CN 94190817 A CN94190817 A CN 94190817A CN 1040746 C CN1040746 C CN 1040746C
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calcipotriol
hydrate
crystalline form
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E·T·汉森
N·S·拉特楚·安德森
L·H·灵博格
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    • C07C5/327—Formation of non-aromatic carbon-to-carbon double bonds only
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Abstract

本发明涉及钙泊三醇水合物，一种钙泊三醇的新晶形，具有优越的技术性能和高稳定性。

Description

维生素D类似物的新晶形
本发明涉及一种在结晶悬液制剂的生产中有优越技术特征并具有优越的稳定性能的钙泊三醇水合物-一种钙泊三醇的新晶形。
国际申请NO.PCT/DK86/00081，申请日为1986年7月14日，公开号为WO87/00834，描述了钙泊三醇(INN)(钙泊三烯(US-AN)，(1α，3β，5Z、7E、22E、24S)-24-环丙基-9，10-开环胆甾-5，7-10(19)，22-四烯-1，3，24-三醇)。
钙泊三醇具有优异的生物活性形象，已证明如在局部治疗牛皮癣中非常有用。
由于钙泊三醇在某些溶液中稳定性差，其在某些剂型，特别是霜剂和凝胶中，优选使用结晶悬液。
为了制备适当的结晶悬液制剂，必须能够控制结晶大小，该参数对于得到化合物从制剂中可重复地释放是很重要的。结晶的整体药物在制成最终悬浮液制剂前，一般进行微粒化或进行湿碾磨加工，以减小结晶大小。
对于钙泊三醇，已使用了湿球碾磨加工。当用WO 87/00834中描述的无水晶形进行此加工时，已证明在技术上是困难的。这些结晶不易湿润，在碾磨过程中，它们产生稳定的泡沫，这给得到适当的小而均一的颗粒大小带来了困难。
现令人惊异地发现，当使用在此以前未知的钙泊三醇晶形，即钙泊三醇水合物，代替已知的无水晶形时，可以避免这些技术困难。此水合物在技术上优于无水物；它易于湿润，可顺利地进行湿球碾磨加工。
该新产品是钙泊三醇的单水合物，结晶完美、稳定，特别适用于现代治疗中。
稳定性研究表明钙泊三醇水合物令人惊异地稳定，这由40℃的稳定性数据证明。
在此温度下，无水形式的钙泊三醇显示相当程度的分解，在贮存12个月后，发现30％以上的分解。
相反，本发明的化合物-钙泊三醇水合物-在40℃贮存12个月后没有显示分解。
钙泊三醇单水合物可通过将结晶或非结晶钙泊三醇溶解在有机溶剂如乙酸乙酯或丙酮中，然后加入水和任选地加入非极性溶剂如己烷来制备。
钙泊三醇单水合物应形成局部使用的部分药物制剂，特别是霜剂、或凝胶形式的药物组合物。活性成分的浓度一般将为1-100μg/g。
这些制剂每天可施用一次或多次。
根据本发明制得的制剂包括活性化合物以及药学上可接受的载体和任选的其它治疗成分。载体必须是“可接受的”，意即与制剂的其它成分相容，而不使其接受性变差。
适于局部施用的制剂包括液体或半液体制剂，如搽剂、洗剂、敷剂，水包油或油包水乳剂如霜剂、软膏、糊剂或凝胶；或溶液或悬液。
除了上述提到的成分以外，本发明的制剂还包括一种或多种添加成分，如稀释剂、缓冲液、表面活性剂、增稠剂、润滑剂、防腐剂如羟基苯甲酸甲酯(包括抗氧化剂)、乳化剂等。
在下列非限定性实施例中将进一步说明本发明。
实施例1
将钙泊三醇(2.5g)溶解在50-80℃的乙酸乙酯中，过滤。该溶液用水饱和，自发冷却至室温后，沉淀出了产物。将形成的浆液冷却至0-10℃，过滤。将滤出的产物真空干燥，得到钙泊三醇水合物(2.35g)。
IR光谱(KBr)
该水合物的特征峰分别为1455(m)、1442(m)、1330(W)、1290(m)、1210(m)、1085(m)、907(m)、895(m)和573(W)cm-1。
固态CPMAS(Cross Polarization angle Mugle Spinning)NMR
钙泊三醇水合物的特征共振如下：147.9，146.5，134.8，130.3，129.0，126.5，116.0，109.4，75.5，68.2，67.2，56.9，55.2，47.8，47.5，42.9，42.0，41.3，30.7，28.9，25.6，23.1，22.6，19.5，14.6，6.2和1.9ppm。
示差扫描量热法(DSC)
Perkin Elmer DSC 7仪，20℃/分，约2mg样品，该水合物在近117℃失水，在近169.7℃显示熔化峰。
实施例2
将钙泊三醇(22.7g)溶解在甲醇(200-250ml)中，过滤并真空浓缩，将残余物于50-80℃溶解在乙酸乙酯中(200-250ml)，加入水(2ml)。向形成的溶液中加入钙泊三醇水合物晶种，自动冷却至室温，产物沉淀。从滴液漏斗加入己烷(100ml)，冷却形成的浆液至0-10℃，过滤。
滤出的产物用乙酸乙酯和己烷的1∶1混合物(200ml)洗涤，真空干燥，得到钙泊三醇水合物(19.7g)，表明与实施例1中所述产物相同。
实施例3
将钙泊三醇(120mg)溶解在丙酮(2ml)中，加入水(1.5-3ml)。产物自动结晶，将形成的浆液冷却至0-10℃，过滤，将滤出的产物真空干燥，得到钙泊三醇水合物(100mg)，表明其与实施例1中所述产物相同。
实施例4
霜剂50μg/g
钙泊三醇水合物         50mg
Cetomacrogol 1000      30g
Cetostearylalcohol     60g
氯代烯丙基六铵氯化物   0.5g
丙二醇                 30g
磷酸氢二钠             2g
液体石蜡               50g
白软石蜡               170g
纯水                   加至1000g
在75℃将Cetomacrogol 1000、Cetostearylalcohol、液体石蜡和白软石蜡熔化。将丙二醇溶解在75℃水中，将此溶液与脂肪相混合。将此乳液均质化，并冷却至30℃。将钙泊三醇水合物在部分水相中碾磨，使颗粒大小大部分小于10μm，并悬浮在磷酸氢二钠和氯代烯丙基六铵氯化物的水溶液中。将此悬液加到乳液中，将此霜剂填充在管中。
实施例5
凝胶50μg/g
钙泊三醇水合物         52.2mg
(相当于50mg无水物)
Carbomer               7g
Cetomacrogol 1000      1g
二氮戊环基脲           2g
二氯苄醇               1g
乙二胺四乙酸二钠盐     0.5g
氢氧化钠               3.7g
丙二醇                 30g
纯水                   加至1000g
将Cetomacrogol、二氮戊环基脲、二氯苄醇、乙二胺四乙酸二钠盐和丙二醇溶解在水中。加入Carbomer，高速均化。搅拌下加入溶解在部分水中的氢氧化钠。在一瓶水中用玻璃珠碾磨钙泊三醇水合物，直到得到小于10μm大小的颗粒。将此钙泊三醇水合物悬液加到凝胶中，混合30分钟。将此凝胶装入可折迭管中。

Claims (3)

1.钙泊三醇，(1α，3β，5Z，7E，22E，24S)-24-环丙基-9，10-开环胆甾-5，7，10(19)，22-四烯-1，3，24-三醇，单水合物。
2.含有权利要求1化合物的霜剂或凝胶形式的药物组合物。
3.权利要求2的药物组合物，其中活性成分的含量为1100μg/g组合物。
CN94190817A 1993-01-15 1994-01-07 维生素d类似物的新晶形 Expired - Lifetime CN1040746C (zh)

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GB939300763A GB9300763D0 (en) 1993-01-15 1993-01-15 Chemical compound
GB9300763.1 1993-01-15
PCT/DK1994/000011 WO1994015912A1 (en) 1993-01-15 1994-01-07 New crystalline form of a vitamin d analogue

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CN1040746C true CN1040746C (zh) 1998-11-18

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USRE39706E1 (en) 2007-06-26
DE69406529T2 (de) 1998-05-28
ATE159717T1 (de) 1997-11-15
FI952797A0 (fi) 1995-06-07
US5763426A (en) 1998-06-09
JP3729847B2 (ja) 2005-12-21
FI952797A (fi) 1995-06-07
KR100309751B1 (ko) 2002-11-08
AU663249B2 (en) 1995-09-28
GR3025668T3 (en) 1998-03-31
GB9300763D0 (en) 1993-03-03
DE69406529D1 (de) 1997-12-04
CA2151730A1 (en) 1994-07-21
AU5857394A (en) 1994-08-15
CA2151730C (en) 2005-01-04
FI108638B (fi) 2002-02-28
CN1115979A (zh) 1996-01-31
KR950704249A (ko) 1995-11-17
RU2128646C1 (ru) 1999-04-10
DK0679154T3 (da) 1998-03-30
ES2111287T3 (es) 1998-03-01
JPH08505612A (ja) 1996-06-18
EP0679154A1 (en) 1995-11-02
RU95116650A (ru) 1997-06-10
WO1994015912A1 (en) 1994-07-21
EP0679154B1 (en) 1997-10-29
NZ259679A (en) 1996-11-26

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