CN1106839C - 由糖衣控释的类固醇 - Google Patents

由糖衣控释的类固醇 Download PDF

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CN1106839C
CN1106839C CN96104096A CN96104096A CN1106839C CN 1106839 C CN1106839 C CN 1106839C CN 96104096 A CN96104096 A CN 96104096A CN 96104096 A CN96104096 A CN 96104096A CN 1106839 C CN1106839 C CN 1106839C
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Abstract

一种用于压缩药物片剂的糖衣组合物，它含有糖、负荷剂量的激素类固醇和类固醇释放速率控制量的微晶纤维素。

Description

由糖衣控释的类固醇
过去的三十年中，人们在确认药物从药物片剂中控释速率的方法上已付出了许多努力。将赋形剂掺入药片核芯中以控制其溶解，并由此控制药物的吸收。用聚合物包衣片剂或球以提供药物的缓慢、扩散控释或特定位点释放。
含有多种药物片剂和用胶囊包裹的球状剂型也已有制备，其中的药物从混合物或分离的片层或小球形式存在。这些药物被用来提供多种功能或提供协同作用。常规治疗表明那些使用不止一种不同但可配伍的活性药物情况下，这类片剂特别有用。例如，利尿剂与抗高血压剂一起使用，促孕剂与雌激素联合使用。
根据本发明，提供一种压缩的、糖衣的、含有两种或更多种药理学活性的药物片剂。该压缩片剂可含赋形剂以使药剂快速或缓慢释放。该糖衣中含有治疗量的激素类固醇和激类固醇控释量的微晶纤维素。存在于该片剂核心的药剂可以包括任何常规与激类固醇联合使用的药剂。该糖衣片也可以像通常那样最后进行着色包衣和磨光。
该片剂核芯的内含物在某种意义上与糖衣无关，在压片剂崩解和药的成分溶解发生之前，该糖衣及其中所含的激类固醇就溶解了。因此该核芯片剂的配方中采用的成份可以包括可药用的水溶性和或水不溶性组分，诸如乳糖、磷酸钙、淀粉、碳酸钙、葡萄糖、山梨醇、甘露醇、微晶纤维素、蔗糖、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素、藻酸盐、羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素、交联羧甲基纤维素钠、淀粉羟乙酸钠、硬脂酸镁，硬脂酸、聚乙二醇、十二烷基磺酸钠、烟化二氧化硅、滑石粉等。
含有激素类固醇的糖衣还含有类固醇释放速率控制量的微晶纤维素，在某些情况下，还含有有助于糖衣应用的聚乙烯吡咯烷酮。
该片剂核芯通过压缩类固醇相容的药物和其它可药用赋形剂的混合物来制备，该混合物优选成颗粒的。该片剂核芯可以有不可塑的或可塑的密封包衣，用以修饰核芯所含药物的释放特性，或防止它们受潮和/或氧化。
本发明提供一种改进的压缩片剂，其中除含有一种或多种与外部糖衣中的类固醇在药学上相客的药物的常规内部片剂核芯以外，还有糖衣，该糖衣中含占糖衣重量约0.1％～20％的激素类固醇；占糖衣重量约0.1％～3％的微晶纤维素；占糖衣重量约0％～5％的聚乙烯吡咯烷酮；和糖。以单位剂量为基准，该片剂的负荷糖衣层中含有约0.05mg～50mg，优选约0.1～30mg的激素类固醇。如果需要，可在包封带有类固醇的糖衣层之前的密封包衣层外包覆一惰性的填充糖内包衣层。该含有惰性填料的亚层糖衣可用含约7.5％～15％微晶纤维素的蔗糖制成。该外层糖衣可含有制片剂领域常用的着色剂诸如在二氧化钛或一级、二级或灰色钛。如果需要，该着色剂可以作为单独的包衣层施加在外层糖衣上。最后磨光完成片剂制备。
用于涉及本说明书的糖衣制备的糖是糖产品，诸如从甜菜中甘蔗原料或者经淀粉、糖化物或多糖转化原料得的蔗糖都适于片剂包衣。目前优选的糖是蔗糖。
已知激素类固醇从糖衣中的释放可通过限量的微晶纤维素来控制，微晶纤维素的量为糖衣重量的约0.1％～3％。在糖衣中使用这样少量的微晶纤维素与这种赋形剂作为压缩辅助剂或加速片剂核芯分解的应用不同。在后者情况下，微晶纤维素的浓度可高达15重量％至30重量％。
适于加入本发明糖衣配方的激素类固醇的实例包括：乙酸甲羟孕酮、乙基羟基二降孕甾烯炔酮、甲地妊娠素、二甲去氢孕酮、雌二醇、乙炔雌二醇、乙炔雌二醇三甲醚、雌酮、双烯雌酚、己雌酚、己烯雌酚、孕酮、脱氧炔诺酮、肟炔诺酮、羟孕酮、甲基睾酮、乙基雌烯三醇、去氢甲睾酮、氧甲氢龙、三甲孕酮等。
为说明在不存在和存在微晶纤维素时体外类固醇溶解速率的控制，下列是说明性实施例，但不限制本发明。
实施例1
用无孔的或有孔的包衣盘将含有下述固体的糖衣包在片剂核芯上：
蔗糖，NF                87％
聚乙烯吡咯烷酮          3％
乙酸甲羟孕酮，USP       10％
根据<711>USPXX，P.959(1980)测定类固醇的溶解速率，用装置2，在50rpm溶解在37℃ 0.54％十二烷基磺酸钠水溶液中，重复试验六次(方法A)。CV表示以百分比表示的这些试验之间的变化系数。
时间(分)            释放的类固醇的百分比(CV％)
  5                            93(5.2)
  10                           94(5.3)
  30                           95(5.3)
  60                           95(5.4)
  120                          95(5.4)
实施例2
用USP装置1在100rpm将用上述相同方法及相同糖衣包衣的片剂溶于37℃ 0.13％十二烷基磺酸钠的0.1NHCL溶液中，试验六次(方法B)。这一研究的结果如下：
时间(分)            释放的类固醇的百分比(CV％)
  5                           83(6.0)
  10                          85(5.8)
  30                          85(6.2)
  60                          85(6.1)
  120                         85(6.2)
实施例3
用相同方法及相同成分的糖包衣的其它片剂在37℃、0.12％十二烷基磺酸钠0.1N HCL溶液中使用SOTAXDissotest装置以5.7ml/分流速进行经流溶解试验(方法C)。三次试验的结果分别是：
时间(分)         释放的类固醇的百分比(CV％)
  30                     90.9(2.9)
  60                     94.2(3.0)
  90                     95.3(2.9)
  120                    96.0(3.0)
  210                    97.4(3.0)
  300                    98.9(3.6)
通过这些体外研究，清楚地表明在这里作为典型激素类固醇的甲羟孕酮从糖衣中释放得非常迅速。
实施例4
为了比较及详细说明本发明糖衣意想不到的性质，用含有下列固体的糖衣包衣片剂核芯：
蔗糖，NF                  86.5％
微晶纤维素                0.5％
PVP                       3.0％
乙酸甲羟孕酮，USP         10.0％
使用含微晶纤维素的糖包衣的片剂及方法A进行试验，得到三次实验的体外溶解数据：
时间(分)            释放的类固醇的百分比(CV％)
  5                       19.5(49.5)
  10                        29.9(32.8)
  30                        50.0(23.0)
  60                        61.6(19.5)
  120                       74.2(19.2)
实施例5
用另外的以上述相同方法制备的由含微晶纤维素的糖包衣的片剂采用方法B进行六次试验，所得数据如下：
时间(分)           释放的类固醇的百分比(CV％)
  5                        2.3(34.4)
  10                       8.2(27.0)
  30                       17.9(16.1)
  60                       26.5(13.6)
  120                      32.7(16.6)
实施例6
采用方法C，用糖衣中含微晶纤维素的片剂进行三次试验，所得数据如下：
时间(分)             释放的类固醇的百分比(CV％)
  30                          2.8(34.4)
  60                          4.1(24.8)
  90                          5.1(22.3)
  120                         6.4(22.3)
  210                         11.0(19.4)
  300                     14.3(11.0)
这些数据清楚地表明，糖衣中的少量微晶纤维素(糖衣固体重量的0.5％时)可明显延迟激素类固醇的释放。
实施例7
制备糖衣片剂，其中糖衣含有0.0％、0.5％或2％的微晶纤维素与3·0％聚乙烯吡咯烷酮、10.0％乙酸甲羟孕酮和蔗糖结合。这些片剂给禁食的四条警犬喂食，在0、0.5、1、1.5、2、3、5、8、12、16和24小时测定类固醇的血浆水平。数据结果用曲线表示，计算的24小时期间的曲线下面积(AUC)并测定到达最大血浆浓度的时间如下：微晶纤维素％     AUC(0～24小时)    tmax(hr)    Cmax
               ng×hr/ml                  (ng/ml)
0.0              345             0.6       37.8
0.5              294             1.0       36.9
2.0              294             1.1       24.6
由这些狗的体内数据明显看出，当糖衣中微晶纤维素的浓度从0.0增至0.5％至2.0％，激素类固醇的生物利用率出现了明显的变化。这样，掺入糖衣中的激素类固醇的释放速率就可以由掺入糖衣中的非常少量的微晶纤维素来控制。
实施例8
制备糖衣片，其中糖衣含有0.25％、0.5％或0.8％的微晶纤维素与0.5％聚乙烯吡咯烷酮、5.0％乙酸甲羟孕酮和蔗糖结合。在37℃的的0.54％十二烷基磺酸钠溶液中用USP崩解装置(USPXX，<201>，p958)(1980)对这些片剂进行体外溶解试验。所得试验数据如下：
溶解的乙酸甲羟孕酮的百分比(CV％)时间(分)  0.25％微晶纤维素  0.5％微晶纤维素  0.8％微晶纤维素15         97.8(5.2)         72.6(9.5)        32.4(15.2)30         98.8(5.3)         89.9(6.3)        62.8(8.2)45         99.3(5.2)         95.2(5.6)        76.6(6.9)60         99.1(5.2)         98.3(5.7)        84.8(6.6)90         99.9(5.3)         100.9(6.0)       94.4(6.9)120       100.3(5.6)         102.4(5.3)       98.0(7.1)
对这些剂型也进行了人体生物利用度测定研究。这些剂型以交换(cross-over)设计施用于十二例健康女性。在0.5、1、1.5、2、2.5、3、4.5、6、8和12小时采集血样，分析血浆中的乙酸甲羟孕酮。所得数据如下：微晶纤维素   AUC(0～12小时)    tmax(hr)    Cmax(ng/ml)0.25％      26.0±14.3*      2.9±1.3    4.24±3.00.5％       25.8±10.5       3.2±1.2    3.88±1.870.8％       13.2±4.0        3.9±1.6    1.99±0.73*平均值±1标准偏差
体外溶解和人体内生物利用度数据清楚地表明激素类固醇药物的释放特性和生物利用度是由糖衣中的微晶纤维素浓度控制的。实施例9
将蔗糖基质中含有5mg二甲去氢孕酮、o.4％微晶纤维素和0.5％聚乙烯吡咯烷酮的糖衣包于密封的并用糖包衣的片剂核芯上。使用USPXX的<711>，p959(1980)描述的溶解测试方法，用装置2，在37℃ 50r.p.m，900ml 0.54％十二烷基磺酸钠进行测试来比较这种剂型与含5mg，二甲去氢孕酮的快速崩裂压缩片剂的体外溶解情况。所得数据如下：
释放的二甲去氢孕酮的平均百分比(CV％)
时间(分)    常规快速崩片      糖衣中含二甲去氢孕酮
                              的糖衣片
  15          95(2.0)                6(11.2)
  30          95(2.9)                11(6.9)
  45          97(1.6)                15(6.4)
  60          97(1.9)                18(6.6)
  120         98(1.9)                25(6.2)
结果表明当激素掺入含0.4％的微晶纤维素的糖衣中时大大降低了二甲去氢孕酮溶解。
本发明优选的实施方案是压缩片剂，其中的片剂核芯含有单位剂量的雌激素化合物或其混合物，含量为0.1mg～5mg，更优选为约0.3mg～2.5mg，与稳定的赋形剂压助剂和填充剂结合。最理想的是结合于片剂核芯的雌激素包括自然发生结合的雌激素产品，如已知的PremarinR。在压缩处上的糖衣上包覆另外一层糖衣，该糖衣含有约1mg～50mg，优选1.5mg～30mg的乙酸甲羟孕酮，再加上着色包衣，最后是磨光包衣。

Claims (7)

1.一种压缩糖衣药物片剂，它含有糖、激素类固醇和0.1％-3％重量的微晶纤维素。
2.权利要求1的压缩糖衣药物片剂，其中糖是蔗糖。
3.权利要求1的压缩糖衣药物片剂，其中所述的激素类固醇是乙酸甲羟孕酮或二甲去氢孕酮。
4.权利要求1的压缩糖衣药物片剂，它含蔗糖，0.1％-3％重量的微晶纤维素、从0％-5％重量的聚乙烯吡咯烷酮、0.1％-20％重量的激素类固醇和水溶液。
5.权利要求1的压缩糖衣药物片剂，它包括含有结合的雌激素的片剂核芯和糖衣，其中所述的糖衣与激素类固醇和微晶纤维素结合。
6.权利要求5的压缩糖衣药物片剂，其中所述的片剂核芯含有0.1mg-5.0mg结合的雌激素，并且所述的糖衣含有1.0mg-50mg所述的激素类固醇。
7.权利要求5的压缩糖衣药物片剂，其中所述片剂核芯含有0.3mg～2.5mg结合的雌激素，并且所述的糖衣含有1.5mg～30mg乙酸甲羟孕酮。
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