CN1163103A - 类固醇从糖衣中的控制释放 - Google Patents

类固醇从糖衣中的控制释放 Download PDF

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CN1163103A
CN1163103A CN97101231A CN97101231A CN1163103A CN 1163103 A CN1163103 A CN 1163103A CN 97101231 A CN97101231 A CN 97101231A CN 97101231 A CN97101231 A CN 97101231A CN 1163103 A CN1163103 A CN 1163103A
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R·J·巴孔
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Abstract

压缩药物片剂含有片剂核心和糖衣，该糖衣含有一个剂量的激素类固醇和激素类固醇释放速率控制量的微晶纤维素。

Description

类固醇从糖衣中的控制释放
在过去三十年中，已在药物从药片中的释放速率控制方法的鉴定方面作了很大努力。现已将赋形剂加入片剂核心中，以控制药物的溶解，从而控制药物的吸收。片剂和球状体已用聚合物包衣以提供药物的缓慢散布-药物的控制释放或位点特异性释放。
现也已制备了含有不是以混合物形式就是分离的片剂层或球状体的多种药物的片剂和包衣的球状体制剂形式。提供药物以执行多种功能或提供药物协作。这样的片剂在传统治疗使用一种以上的、具有不同效能但相容的药物的情况下尤其有用，例如，利尿药剂经常与抗高血压药剂一起给药，而促孕药剂与雌激素一起给药。
按照本发明提供的药片含有内部压制核心和外部糖衣，其中该压制核心可选地含有无药理学活性的药剂或一种或多种非类固醇的、有药理学活性的、传统上与激素类固醇一起给药的药剂，其改进之处包括在所述糖衣中加入激素类固醇和激素类固醇释放速率控制量的微晶纤维素。压制的片剂核心可以不含任何药剂，或可以含有除类固醇之外的、可与类固醇和任何糖衣中的其它治疗药剂配伍的药剂。因此，本发明的糖衣片剂可以含有一种或多种有药理学活性的药剂，其中对先有的糖衣片剂的改进之处包括在该糖衣中与激素类固醇一起加入激素类固醇释放速率控制量的微晶纤维素。糖衣片剂可以进行有色包衣并与常规包衣片剂一样磨光。
由于在压制片剂核心分解以及核心中存在的任何药物溶解之前，糖衣和含于其中的激素类固醇就溶解了，因此片剂核心的内容物与糖衣无关。用于核心片剂配方中的赋形剂成分可以包括药学上可接受的水溶性物质和/或不溶性物质如乳糖、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、羟丙甲基纤维素、乙基纤维素、交联羧酸纤维素钠、羟基乙酸淀粉钠、硬脂酸镁、硬脂酸、聚乙二醇、十二烷基硫酸钠、煅制二氧化硅、滑石等。
含有激素类固醇的糖衣也含有激素类固醇释放速率控制量的微晶纤维素，在某些情况下，也含有聚乙烯吡咯烷酮以有助于糖衣的应用。
片剂核心通过将混合物进行压制来生产，混合物最好已颗粒化，含有药学上可接受的赋形剂，以及需要时可含有与在糖衣中同激素类固醇释放速率控制量的微晶纤维素一起加入的与类固醇相容的治疗药物。片剂核心可含有设计的未增塑或增塑密封衣，以对任何含于该核心的药物的药物释放特性进行修正，或保护药物以防潮和/或防氧化。无药物核心是那些传统上在药理学研究中用作安慰剂的核心。
本发明提供改进的压制片剂，其中除传统可选的不含药物或含有一种或多种与外部糖衣中的类固醇药学可配伍的药物外，糖衣还含有的激素类固醇的量为大约糖衣重量的0.1-20％、微晶纤维素的量为大约糖衣重量的0.1-3％、聚乙烯吡咯烷酮的量为大约糖衣重量的0-5％以及糖。以单位剂量计算，片剂装料糖衣层载负大约0.01-50毫克、优选大约0.015-40毫克、最优选大约0.02-30毫克总激素类固醇。需要时，在类固醇装料糖衣层之前，在密封衣上应用惰性填料糖内涂层。该含有惰性填料的亚层糖衣可用含有大约7.5-15％微晶纤维素的蔗糖制造。外部糖衣可含有诸如二氧化钛或传统片剂技术中的初级、次级或灰色色调的染料。需要时，也可在外部糖衣层外用染料作为分离衣层。最后使用磨光以进一步完成片剂。
在本说明涉及的糖衣生产中使用的糖是糖产物，如来自甜菜或甘蔗、或淀粉、糖类或多糖转化源的蔗糖，被认为适用于片剂糖衣。目前推荐的糖是蔗糖。
现已发现，激素类固醇从糖衣中的释放可通过将微晶纤维素的量限制在大约糖衣重量的0.1-3％而加以控制。该少量微晶纤维素在糖衣中的使用与该赋形剂作为压制助剂或协助片剂核心分解的应用不同。在后一种情况下，微晶纤维素的浓度可以高达15-30％(重量)。
适用于加入本发明糖衣配方的激素类固醇实例包括，例如，一种或多种下列类固醇：6α-甲基-17α-乙酸基孕甾酮、乙基羟基二降孕甾烯炔酮、乙基羟基二降孕二烯炔酮、二甲去氢孕酮、雌二醇、雌三醇、炔雌醇、炔雌醇甲醚、雌甾酮、双烯雌酚、己雌酚、己烯雌酚、孕甾酮、去氧孕烯、诺孕酯、羟基孕甾酮、炔诺酮、醋炔诺酮、甲基炔诺酮、甲地孕酮、甲基睾丸酮、乙基雌烯醇、1-脱氢-17α-甲基睾丸甾酮、内酯氢龙、trimegestone、dionogest等。另外，可能有或没有典型类固醇功能的组织选择性孕甾酮和/或孕甾酮拮抗物也可加入该技术的配方中。这些包括，但不限于：RU-486、onapristone、ZK-137316、ORG-31730和HRP-2000。需要时，雌激素类固醇和孕激素类固醇可加入糖衣中使用。
为了描述在微晶纤维素缺乏和存在下类固醇体外溶解速率的控制，介绍以下实施例，但不受其限制：
实施例1
使用非穿孔或穿孔的包衣盘，将含有以下固体的糖衣施用于片剂核心上：
蔗糖，NF                             87％
聚乙烯吡咯烷酮                        3％
6α-甲基-17α-乙酸基孕甾酮，  USP    10％
类固醇的溶解速率按照USP XX，p.959(1980)中的<711>，在以下条件进行六次重复试验来确定：用设备2，在水中37℃，以50rpm溶于0.54％十二烷基硫酸钠中进行操作(方法A)。CV代表这些试验之间的不同系数，用百分比表示。
时间(分钟)    释放的类固醇百分数(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
将用上述相同的糖衣以相同方式包衣的片剂，于37℃用UPS设备1，以100rpm在0.1N HCl中溶于0.13％十二烷基硫酸钠中，进行六次试验(方法B)。其结果如下：
时间(分钟)    释放的类固醇百分数(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
用同样糖成分以同样方式包衣的另外的片剂如下进行径流溶解试验：用SOTAX Dissotest Apparatus，在0.1N HCl中于37℃、以5.7mL/分钟的径流速率溶于0.12％十二烷基硫酸钠中(方法C)。三次分离试验的结果如下：
时间(分钟)    释放的类固醇百分数(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)
这些体外研究清楚表明，在这里用作典型激素类固醇的6α-甲基-17α-乙酸基孕甾酮从糖衣中以极快的速率释放。
实施例4
为了进行比较以及描述本发明糖衣的一些出人意料的性质，在片剂核心之上使用含有以下固体的糖衣：
蔗糖，NF                           86.5％
微晶纤维素                          0.5％
PVP                                 3.0％
6α-甲基-17α-乙酸基孕甾酮，USP    10.0％
使用微晶纤维素-含有糖衣的片剂和以下方法A，从三次试验中获得以下体外溶解数据：
时间(分钟)    释放的类固醇百分数(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
用额外的含有微晶纤维素的以上述同样的方式制备的糖衣片剂，按照方法B，六次试验获得以下数据：
时间(分钟)    释放的类固醇百分数(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
用糖衣中含有微晶纤维素的片剂，按照下列方法C，由三次试验获得以下数据：
时间(分钟)    释放的类固醇百分数(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)
从这些数据可明显看出，糖衣中少量的微晶纤维素(在此为糖衣固体重量的0.5％)显著地降低了激素类固醇的释放速率。
实施例7
制备的糖衣片剂含有0.0％、0.5％或2％微晶纤维素与3.0％聚乙烯吡咯烷酮、10.0％6α-甲基-17α-乙酸基孕甾酮和蔗糖。用这些片剂在禁食条件下喂四只警犬，在0、0.5、1、1.5、2、3、5、8、12、16和24小时测定血清类固醇的含量。将其结果绘图，计算24小时周期曲线下的面积，并测定最大血清浓度发生的时间，其结果如下：
微晶纤 AUC(0-24Hrs)                          Cmax
维素％ ngxhr/mL         tmax(Hr)           (ng/mL)
0.0    345              0.6                37.8
0.5    294              1.0                36.9
2.0    294              1.1                24.6
从这些体内警犬数据可明显看出，当糖衣中微晶纤维素从0.0％增至0.5-2.0％时，激素类固醇生物获得性发生显著变化。因此，加入糖衣中的激素类固醇的释放速率可通过将非常少量的微晶纤维素加入糖衣来控制。
实施例8
制备的糖衣片剂的糖衣含有0.25％、0.5％或0.8％微晶纤维素和0.5％聚乙烯吡咯烷酮、5.0％6α-甲基-17α-乙酸基孕甾酮和蔗糖。对这些片剂进行体外溶解试验，即用USP Disintergation Apparatus(USP XX，<201>，p958)(1980)，用0.54％十二烷基硫酸钠溶解介质于37℃进行，获得以下试验数据：
溶解的6α-甲基-17α-乙酸基孕甾酮百分数(CV％)
            0.25％         0.5％        0.8％时间(分钟)    微晶纤维素    微晶纤维素   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)
这些制剂形式也在人类生物获得性研究中进行评价。这些制剂形式按交互设计给12个健康女性研究对象用药。在0.5、1、1.5、2、2.5、3、4.5、6、8、和12小时收集血样，分析血清6α-甲基-17α-乙酸基孕甾酮，获得以下数据：微晶纤维素    AUC(0-12h)     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标准差
从体外溶解数据和体外人类生物获得性数据可清楚看出，激素类固醇的药物释放特性和生物获得性可通过糖衣中微晶纤维素的浓度来控制。
实施例9
将含有5mg二甲去氢孕酮与0.4％微晶纤维素和0.5％聚乙烯吡咯烷酮的蔗糖基质用于密封的糖衣片剂核心。将该制剂形式的体外溶解分布图与含有5mg二甲去氢孕酮用USP XX，p.959(1980)的<711>中描述的、使用设备2用900mL0.54％十二烷基硫酸钠，以50r.p.m.进行操作的溶解试验的分布图进行比较。获得以下数据：
释放的二甲去氢孕酮平均百分比(CV％)
              常规的        糖衣中含有
             快速分解       二甲去氢孕酮时间(分钟)        的片剂         的糖衣片剂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)
当将激素加入含有0.4％微晶纤维素的糖衣中时，清楚地证明了二甲去氢孕酮溶解降低的戏剧性效果。
本发明的一个优选实施例是压制片剂，其中片剂核心含有一个单位剂量的雌激素化合物或其混合物，其量为大约0.1-5.0毫克，或较优选大约0.3-2.5毫克，以及标准赋形剂压制助剂和填料。片剂核心中发现的结合雌激素最好包括自然发生的结合雌激素如大家知道的Premarin。在压制片剂的糖衣外用一含有大约1-50毫克、最好为大约1.5-30毫克6α-甲基-17α-乙酸基孕甾酮的附加糖衣、颜料外衣以及最后是磨光外衣。在其它应用中，优选将非药物核心与含有诸如trimegestone之类的类固醇糖衣、更优选含有诸如trimegestone之类和结合雌激素的类固醇混合物糖衣一起应用。

Claims (7)

1.药片，它含有内部压缩核心和外部糖衣，其中所述压缩核心可选地包括无药理学活性的药剂，或一种或多种传统上与激素类固醇一起给药的非类固醇的、有药理学活性的药物，其改进之处包括在所述糖衣中加入激素类固醇和激素类固醇释放速率控制量的微晶纤维素。
2.药片，它含有非药物压缩核心和糖衣，其改进之处包括在所述糖衣中加入激素类固醇和激素类固醇释放速率控制量的微晶纤维素。
3.权利要求1的药片，其中，存在于所述糖衣中的所述糖是蔗糖。
4.权利要求1的药片，其中，存在于所述糖衣组成中的所述激素类固醇是6α-甲基-17α-乙酸基孕甾酮、乙基羟基二降孕甾烯炔酮、乙基羟基二降孕二烯炔酮、二甲去氢孕酮、雌二醇、雌三醇、炔雌醇、炔雌醇甲醚、雌甾酮、双烯雌酚、己雌酚、己烯雌酚、孕甾酮、去氧孕烯、诺孕酯、羟基孕甾酮、炔诺酮、醋炔诺酮、甲基炔诺酮、甲地孕酮、甲基睾丸酮、乙基雌烯醇、1-脱氢-17α-甲基睾丸甾酮、内酯氢龙、trimegestone或dionogest。
5.权利要求1的药片，其中，存在于所述糖衣中的所述激素类固醇是RU-486、onapristone、ZK-137316、ORG-31730或HRP-2000。
6.权利要求1的药片，其中，所述糖衣含有蔗糖、大约0.1％至大约3％(重量)微晶纤维素、0至大约5％(重量)聚乙烯吡咯烷酮和大约0.1％至大约20％(重量)激素类固醇。
7.权利要求1的药片，其中，所述糖衣含有雌激素类固醇和孕激素类固醇。
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