CN1030920C - 孕二烯酮糠酸酯-水合物的制备方法 - Google Patents

孕二烯酮糠酸酯-水合物的制备方法 Download PDF

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CN1030920C
CN1030920C CN91108910A CN91108910A CN1030920C CN 1030920 C CN1030920 C CN 1030920C CN 91108910 A CN91108910 A CN 91108910A CN 91108910 A CN91108910 A CN 91108910A CN 1030920 C CN1030920 C CN 1030920C
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袁沛浩
查尔斯·埃克哈特
特里萨·埃林格
南希·莱文
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Abstract

本发明涉及新的孕二烯酮糠酸酯-水合物及其制备方法和含所述化合物的药用组合物。

Description

孕二烯酮糠酸酯一水合物的制备方法
本发明涉及一种物质的新的组合物及其制备方法和药用制剂，所述物质是9α，21-二氯-16α-甲基-1，4-孕二烯-11β，17α-二醇-3，20-二酮-17-(2′-糠酸酯)一水合物，也称做孕二烯酮糠酸酯一水合物。
众所周知，孕二烯酮糠酸酯可用于治疗炎症。该化合物可按美国专利4,472,393号所公开的方法制备，该专利本文引作参考文献。
当将含无水孕二烯酮糠酸酯的含水药用组合物(如混悬液)按下述方法进行稳定性试验时：在室温下和35℃下搅拌4星期，形成一种结晶物质，观察到该物质不同于混悬液中的无水孕二烯酮糠酸酯晶体。我们设计了几个试验以测定结晶物质的性质。假设在混悬液的长期贮存过程中，具有稳定结晶型的孕二烯酮糠酸酯组合物制剂将减少晶体生长的可能性，从而导致更稳定的产物。
本发明提供式I的孕二烯酮糠酸酯一水合物及其制备方法，所述方法为：从饱和的含水的与水混溶的有机溶液中结晶所述化合物，式I为：
本发明还提供孕二烯酮糠酸酯一水合物的含水的稳定的药用组合物。
图1：结晶的孕二烯酮糠酸酯一水合物的红外光谱图
图2：孕二烯酮糠酸酯一水合物结晶的X光衍射图
本发明的孕二烯酮糠酸酯一水合物具有下列特性：分子式         C27H30Cl2O6H2O式量           539.46元素分析(理论值)    C＝66.11％，H＝5.98％，Cl＝13.16％
    (实测值)    C＝59.99％，H＝5.56％，Cl＝13.17％水分析(％H2O)(理论值)3.34
         (实测值)3.31，3.47
孕二烯酮糠酸酯一水合物结晶的x光晶体粉末衍射图的主要参数见表1。
                表I
 角             间距          相对强度
 2θ             d              I/I
 度             (_)
 7.795        11.3324           100
11.595        7.6256              6
12.035        7.3478              3
12.925        6.8437             11
14.070        6.2893             22
14.580        6.0704              5
14.985        5.9072             12
15.225        5.8146             33
15.635        5.6631             96
16.710        5.3011             15
17.515        5.0592             14
18.735        4.7324             12
20.175        4.3978             13
20.355        4.3593              6
20.520        4.3246              4
21.600        4.1108              5
21.985        4.0396             22
22.420        3.9622              8
22.895        3.8811              7
23.245        3.8234             14
23.550        3.7746             13
24.245        3.6680              4
24.795        3.5878             11
24.900        3.5729              5
25.800        3.4503              5
25.985        3.4262              3
26.775        3.3268             84
27.170        3.2794             10
27.305        3.2635              9
   角       间距      相对强度
   2θ       d          I/I
   度       (_)
 27.710    3.2167        5
 28.385    3.1417        7
 29.165    3.0594        1
 29.425    3.0330        2
 29.725    3.0030        2
 30.095    2.9670        7
 30.255    2.9516        3
 30.490    2.9294        10
 30.725    2.9075        6
 31.115    2.8720        3
 31.595    2.8294        47
 32.135    2.7831        6
 32.135    2.7831        7
 33.400    2.6805        2
 33.820    2.6482        2
 34.060    2.6301        8
 34.625    2.5885        4
 34.795    2.5762        2
 35.315    2.5394        1
 36.780    2.4416        21
 37.295    2.4090        2
孕二烯酮糠酸酯一水合物的单晶数据见表II
          表II
        晶体数据α
 晶系           三斜晶
 空间群      P1(c1 1)-No.1
 a(A)             8.481(1)
 b(A)             11.816(2)
 c(A)             7.323(1)
 α(°)           95.00(1)
 β(°)           110.66(1)
 γ(°)           73.27(1)
 V(_3)          657.5(3)
 Dcalcd.(gcm-3)  1.362
α所有测量均使用Enraf-Nonius CAD-4衍射仪(Cu-Kα发射，入射光石墨单色器)。强度数据用通常的洛伦兹和极化作用进行了矫正；还采用了经验吸收矫正。
用直接法(RANTAN)分析晶体结构。从E-图推算出非氢原子的大约位置。用差分傅里叶综合法的谱系对氢原子进行定位，傅里叶综合法是将非氢原子位置温度因子参数和各向异性温度因子参数进行好几次全矩阵最小二剩法调整计算后而进行评价的。氢原子位置和各向同性热参数作为变量包含在较后的最小二剩法的重复单元中，该重复单元也包含消光矫正的精细部分。在PDP11/44和Micro VAX计算机上用Enfra-Nonius结构测定仪(SDP)进行结晶学计算。对于所有的结构因子计算，中性原子散射因子和它们的反常散射矫正因子取自International Tables for X-Ray Crystallography Vo1.IV.TheKnynock Press，Birmingham，England，1974。
孕二烯酮糠酸酯一水合物可以按下述方法制备：使无水孕二烯酮糠酸酯在水和与水混溶的有机溶剂的混合物中形成饱和均相溶液。所述饱和溶液按下述方法制备：在约85℃下，将孕二烯酮糠酸酯溶于与水混溶的有机溶剂中，搅拌下滴加约85℃的热水，从蒸气浴上移出。溶液，搅拌反应物约1小时，然后静置过夜，同时冷却至室温。在室温下搅拌所述溶液，同时加入附加量的水，溶液变得浑浊并有白色沉淀产生。将反应物搅拌一段时间，过滤收集沉淀，产物干燥至恒重。
本发明方法使用的有机溶剂必须是与水混溶的，并且可以溶解孕二烯酮糠酸酯。与水混溶的有机溶剂的例子包括醇类，例如乙醇、异丙醇等；酮类，例如丙酮等；醚类，例如二噁烷等；酯类，例如乙酸乙酯等。优选的溶剂是丙酮和异丙醇。
另一方面，本发明提供了药用组合物，所述组合物包括式I的孕二烯酮糠酸酯一水合物和药学上可接受的惰性载体或稀释剂。
本发明药用组合物可以按照下述方法制备：将孕二烯酮糠酸酯一水合物与任何适合的药用惰性载体或稀释剂混合；制成各种制剂，可以口服、非肠道或局部给药。
特别令人感兴趣的是孕二烯酮糠酸酯一水合物的含水混悬液组合物，例如用于经鼻给药的组合物。每克本发明的水混悬液中可含0.1-10.0mg孕二烯酮糠酸酯一水合物。
本发明含水混悬液组合物特别是可含有：辅助剂和/或赋形剂，例如：混悬剂如微晶纤维素、羧甲基纤维素钠、羟丙基-甲基纤维素；湿润剂如甘油和丙二醇；用于调节PH的酸、碱或缓冲物质如柠檬酸、柠檬酸钠、磷酸、磷酸钠、柠檬酸盐和磷酸盐缓冲液；表面活性剂如多乙氧基醚；灭菌防腐剂如洁尔灭、苯乙醇和山梨酸钾。
下列实施例用来说明本发明，并且是实践本发明方法的最佳实例。显而易见，专业人员可对其进行许多改良而不偏离本发明的目的和范围。
一般试验
样品制成石蜡糊，用5DXB型Nicolet傅里叶变换红外光谱仪做红外吸收光谱图。在型号为APD-3720配备有铜Kα发射源的Philips X光衍射仪上做X光晶体粉末衍射图。用990型Dupont差热扫描量热器测量分解温度。
用费歇尔试剂滴定法测量结晶的孕二烯酮糠酸酯一水合物的水含量。
实施例1
将4.5升乙醇置于配备有适合搅拌器和密封装置的适宜的容器中。搅拌下将27g孕二烯酮糠酸酯的无水粉末溶解于乙醇中。过滤该饱溶液，并以约50ml/min的流速缓慢加入约1.5升的纯水，同时以中等速度搅拌。当溶剂混合物的比例达到1∶3(水∶乙醇)时，停止加水，继续搅拌反应混合物约2小时，以便于品种的形成。继续加水，以约50ml/min的速度加入约7.5升水，直至比例达到2∶1(水∶乙醇)。继续搅拌直至完成结晶，过滤收集晶体，并在室温下用真空干燥器干燥，得到24.83g孕二烯酮糠酸酯一水合物，其红外光谱图和x光衍射图与图1和图2基本相似。
实施例2
将24.3升2-丙醇置于适合的容器中。搅拌下加热(蒸汽浴)至85℃，将340g无水孕二烯酮糠酸酯溶解在2-丙醇中。溶解后，搅拌下用15分钟的时间滴加1950ml热水(85℃)。将热溶液从蒸汽浴上移出，继续搅拌1小时。静置过夜，溶液冷却至室温。搅拌下加入约24升剩余的水；溶液变得浑浊，并且开始产生白色沉淀。将反应混合物搅拌1小时，随后加水。过滤改集白色沉淀，用2升的水洗涤，并且在空气中干燥过夜。在50℃的通风炉中将固体干燥至衡重。得到316.5g孕二烯酮糠酸酯一水合物，重量产率为90％，其红外光谱图和X光衍射图与图1和图2基本相同。
实施例3
孕二烯酮糠酸酯一水合物的鼻用含水混悬液按下法制备：成分                      浓度       典型批
                      mg/g       g/12kg孕二烯酮糠酸酯一水合物    0.5        6.0Avicel RC 591*            20.0       240.0甘油                      21.0       252.0柠檬酸                    2.0        24.0柠檬酸钠                  2.8        33.6多乙氧基醚**              0.1        1.2洁尔灭                    0.2        2.4苯乙醇                    2.5        30.0纯水                      1.0g       12.0kg*Avicel RC-591是FMC的商标名，是微晶纤维素和羧甲基纤维素钠的混合物。**多乙氧基醚是商品名，是指山梨醇和脱水山梨醇与环氧乙烷的共聚物的油酸酯混合物，共聚物中环氧乙烷的用量为每摩尔山梨醇和脱水山梨醇约20摩尔。
将Avicel RC591分散于6kg的纯水中后，加入甘油。将柠檬酸和柠檬酸钠溶于240ml水中，搅拌下将所述溶液加入Avicel-甘油分散液中。在分离器中，搅拌下将多乙氧基醚溶解于约400ml的纯水中。将孕二烯酮糠酸酯一水合物分散于多乙氧基醚水溶液中，然后搅拌下将所述浆液加入Avicel-甘油柠檬酸混合物中。将洁尔灭和苯乙醇溶于纯水后，搅拌下将所述溶液加入混悬液混合物中，将混悬液与纯水混合直至达到12kg。混悬液的最终PH为4.5±0.5。
实施例4
为了防止在X光衍射过程中互相干扰，不加混悬剂、Avicel RC-591制备了下述组合物成分                            浓度
                            mg/g
                       4A    4B    4C孕二烯酮糠酸酯一水合物     0.5   0.5   0.5柠檬酸一水合物             2.0   2.0   2.0柠檬酸钠二水合物           2.8   ---   2.8磷酸二氢钠                 ---   4.0   ---多乙氧基醚                 0.1   0.1   0.1洁尔灭                     0.2   0.2   0.2苯乙醇                     2.5   ---   ---山梨酸钾                   ---   3.4   ---丙二醇                     ---   ---   100.0甘油                       21.0  21.0  21.0按USP纯化水加至            1.0g  1.0g  1.0g
按实施例3的方法制备上述组合物。
将4A、4B和4C三种组合物在35℃下搅拌5天，在室温下再搅拌4星期，评价结晶的稳定性。从混悬液中分离出晶体，并做x光衍射图。结果表明，从三种组合物中收集到的晶体均是孕二烯酮糠酸酯-水合物。
实施例5
制备下述组合物并测定其热稳定性成分                                浓度
                                mg/g
                         5A    5B    5C微晶孕二烯酮糠酸酯一水合物
                         0.5   0.5   0.5柠檬酸一水合物               2.0   2.0   2.0柠檬酸钠二水合物             2.8   ---   2.8磷酸二氢钠                   ---   4.0   ---多乙氧基醚                   0.1   0.1   0.1洁尔灭                       0.2   0.2   0.2苯乙醇                       ---   2.5   ---山梨酸钾                     ---   ---   3.4丙二醇                       100.0 ---   ---甘油                         21.0  21.0  21.0Avicel RC-591                20.0  20.0  20.0按USP纯化水加至              1.0g  1.0g  1.0g
按实施例3的方法制备上述组合物。
将所述组合物在4℃(24小时)和30℃(24小时)交替保持一个月。显微镜分析表明，在上述条件下，没有可检出的孕二烯酮糠酸酯一水合物晶体产生。

Claims (2)

1.制备式(I)的9α，21-二氯-16α-甲基-1，4-孕二烯-11β，17α-二醇-3，20-二酮-17-(2′-糠酸酯)一水合物的方法，
Figure C9110891000021
该方法包括按顺序进行以下步骤：
(a)形成9α，21-二氯-16α-甲基-1，4-孕二烯-11β，17α-二醇-3，20-二酮-17-(2′-糠酸酯)的饱和的与水可混溶的有机溶剂溶液；
(b)加入足量的水使溶剂混合物的比例为1∶1(水∶有机溶剂)，并继续搅拌直至结晶完毕。
2.按照权利要求1的方法，其中有机溶剂选自乙醇、异丙醇、丙酮、二噁烷和乙酸乙酯。
CN91108910A 1990-09-10 1991-09-10 孕二烯酮糠酸酯-水合物的制备方法 Expired - Lifetime CN1030920C (zh)

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ATE113604T1 (de) 1994-11-15
PT98905B (pt) 1998-08-31
HU9300685D0 (en) 1993-06-28
CA2091360A1 (en) 1992-03-11
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NO300548B1 (no) 1997-06-16
BG60755B2 (bg) 1996-02-29
JPH05506667A (ja) 1993-09-30
TW272195B (zh) 1996-03-11
AU663471B2 (en) 1995-10-12
MY106644A (en) 1995-07-31
ES2065701T3 (es) 1995-02-16
EE02962B1 (et) 1997-02-17
NO930693D0 (no) 1993-02-26
NL980012I1 (nl) 1998-05-06
TW229208B (zh) 1994-09-01
CZ281318B6 (cs) 1996-08-14
MX9100990A (es) 1992-05-04
IL99437A0 (en) 1992-08-18
CN1059911A (zh) 1992-04-01
EP0548114B1 (en) 1994-11-02
FI931031A (fi) 1993-03-09
WO1992004365A1 (en) 1992-03-19
AU8497491A (en) 1992-03-30
DE69104991T2 (de) 1995-04-20
OA09772A (en) 1993-11-30
US6180781B1 (en) 2001-01-30
PH30443A (en) 1997-05-09
SI9111497A (sl) 1998-04-30
IE913155A1 (en) 1992-03-11
FI111078B (fi) 2003-05-30
HRP920383A2 (en) 1998-06-30
CZ38393A3 (en) 1994-01-19
ZA917148B (en) 1992-08-26
NZ239711A (en) 1992-09-25
YU149791A (sh) 1994-01-20
EP0548114A1 (en) 1993-06-30
DE19875032I2 (de) 2007-04-19
KR960013445B1 (ko) 1996-10-05
HRP920383B1 (en) 2000-04-30
JPH0725789B2 (ja) 1995-03-22
HK185996A (en) 1996-10-11
DE69104991D1 (de) 1994-12-08
IL99437A (en) 1995-05-29
HU213401B (en) 1997-06-30
MX9203396A (es) 1992-07-31
PL165803B1 (pl) 1995-02-28
NL980012I2 (nl) 2004-11-01
NO930693L (no) 1993-02-26
PT98905A (pt) 1992-09-30
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CA2091360C (en) 1997-04-08
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