CN1222077A - 快速溶出的雪花胺氢溴酸盐片剂 - Google Patents

快速溶出的雪花胺氢溴酸盐片剂 Download PDF

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CN1222077A
CN1222077A CN97195512A CN97195512A CN1222077A CN 1222077 A CN1222077 A CN 1222077A CN 97195512 A CN97195512 A CN 97195512A CN 97195512 A CN97195512 A CN 97195512A CN 1222077 A CN1222077 A CN 1222077A
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P·M·V·吉里斯
V·F·V·得肯德
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Abstract

本发明涉及口服给药的速溶片,它含有作为活性成分的治疗有效量的雪花胺氢溴酸盐(1∶1)和药学上可接受的载体,其特征在于所述载体含有作为稀释剂的喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物和崩解剂;也涉及制备此类速溶片的直接压片方法。

Description

快速溶出的雪花胺氢溴酸盐片剂
本发明涉及口服给药的速溶片，它含有作为活性成分的治疗有效量的雪花胺氢溴酸盐(1∶1)和药学上可接受的载体，其特征在于所述载体含有作为稀释剂的喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物和崩解剂；也涉及制备此类速溶片的直接压片方法。
雪花胺为叔胺生物碱，由高加索雪花莲Galantanus woronowi的球茎分离(Proskumina,N.F.和Yakoleva,A.P.1952,Alkaloids ofGalanthus woronowi.Ⅱ.新生物碱的分离。(In Russian.)Zh.ObschcheiKhim.(J.Gen.Chem.)22,1899-1902)。也从普通的雪花莲Galanthusnivalis中分离(Boit,1954)。雪花胺的化学名称为[4aS-(4aα,6β,8aR*)]-4a,5,9,10,11,12-六氢-3-甲氧基-11-甲基-6H-苯并呋喃并(benzofuro)[3a,3,2-ef][2]苯并氮杂-6-醇；该碱性化合物和其氢溴酸盐均为左旋。雪花胺是熟知的乙酰基胆碱酯酶抑制剂，它在烟碱受体部位有活性，而在毒草碱受体部位无活性。它能够穿过人的血脑屏障并且在治疗有效量下无严重的副作用。
雪花胺在东方许多国家的麻醉实践中被广泛用作箭毒反转剂(见Paskow的综述，1986)并且在西方也用于实验中(见Bretagne和Valetta,1965:Wislicki,1967；Consanitis,1971)。
雪花胺在德国和奥地利从70年代起以NivalinTM名称被Waldheim(Sanochemia Gruppe)投放市场用于面部神经痛。
EP-0236684(US-4663318)描述了雪花胺或类似物或其药学上可接受的酸加成盐在制备用于治疗Alzheimer氏痴呆(AD)和相关的痴呆的药物中的用途。该专利仅具有雪花胺可能的剂型的一般的公开。
EP-0449247公开了雪花胺治疗酒精中毒的用途和通过透皮传送系统(TTS)或贴剂的给药方法。类似地，WO-94/16708公开通过透皮传送系统(TTS)或贴剂给予雪花胺治疗尼古丁依赖性的用途。E.Snorrason的许多申请公开雪花胺、其类似物和其药学上可接受的盐用于制备治疗躁狂(US-5336675)、慢性疲劳综合征(CFS)(EP-0515302；US-5312817)和苯并二氮杂治疗的负作用(EP-0515301)。在这些申请和专利如在US-5312817中，给出了雪花胺氢溴酸盐的数种特定的片剂。这些特别制剂如下：
含有1mg雪花胺氢溴酸盐的1片(60mg)的组成雪花胺氢溴酸盐            0.001g磷酸钙                    0.032g乳糖                      0.005g小麦淀粉                  0.0056g微晶纤维素                0.015g滑石粉                    0.0007g硬脂酸镁                  0.0007g
含有5mg雪花胺氢溴酸盐的1片(80mg)的组成；膜包衣组合物未知[NivalinTM,Waldheim,Ltd,Vienna，奥地利](F3)雪花胺氢溴酸盐            0.005g磷酸钙                    0.024g乳糖                      0.004g小麦淀粉                  0.004g微晶纤维素                0.04g滑石粉                    0.002g硬脂酸镁                  0.001g
含有10mg雪花胺氢溴酸盐的1片(120mg)的组成雪花胺氢溴酸盐            0.010g乳糖                      0.040g小麦淀粉                  0.0234g微晶纤维素                0.0374g滑石粉                    0.0036g硬脂酸镁                  0.0012g明胶                      0.0044g
用湿法制粒可以制备这些片剂。
溶出(USP23,<711>溶出，第1791-1793页，装置2(桨状，50rpm,500ml水或缓冲水溶液，37℃)商业可获得
NivalinTM5mg薄膜包衣的片剂(F3)如下：
  时间(min)                  活性成分剂量的计算浓度(重量％)
     H2O   pH4.5USP    pH6.5USP    pH7.5USP   0.1N HCl
    0515304560     0.006.2351.7580.8893.28100.75     0.0021.3886.3397.6398.6099.20     0.005.2543.8879.7887.8890.70      0.0012.8037.7066.1882.7090.93     0.0041.9591.0598.88102.08101.63
为得到政府批准药物投放市场，不仅需要证明所述活性成分具有标示的活性并使用安全，而且必须证明所述活性成分的制剂在不同病人中产生重现性结果。例如，在为片剂形状的固体制剂的情况下，必须保证所述片剂在一定时间内崩解并溶出至一定的程度。在本发明中，提供在30分钟后溶出至少80％的新的雪花胺氢溴酸盐片剂(Q=80％,30’后)(USP23,<711>溶出，第1791-1793页，装置2(桨状，50rpm,500ml纯净水，37℃)。对于此溶出标准的顺应性只有在使用含有崩解剂的特定的稀释剂和第二种崩解剂时才符合。
因此，本发明涉及含有作为活性成分的治疗有效量的雪花胺氢溴酸盐(1∶1)和药学上可接受的载体的片剂，其特征在于所述载体含有作为稀释剂的喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物和崩解剂。所述片剂在30分钟后，溶出至少80％(Q=80％,30’后)(USP23,<711>溶出，第1791-1793页，装置2(桨状，50rpm))。
在最初开始的实验中，用无水乳糖或乳糖一水合物作为稀释剂，用粉状纤维素或微晶纤维素作崩解剂(见实验部分的片剂F1和片剂F2)。在将干燥的混合物送料于压片机上进行直接压片时产生了片剂赋形剂分离的问题，因此引起片剂的组成变化。此外，片剂F1和F2在第一阶段不能符合30’后溶出Q=80％的标准。为了解决这一问题，稀释剂代替喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物(作为MicrocelacTM商标品由商业可得)。此外它在送料于压片机的过程中可以减少分离的倾向，还发现包含上述稀释剂的干法混合物具有良好的流变学性质(可流动性)，以及容易与活性成分和其它的片剂赋形剂混溶。然而，仍然不能符合溶出标准，除非使用很大的膨胀系数的崩解剂，更特别的是如果使用不溶或难溶的交联聚合物如交联聚维酮或交联羧甲基纤维素时更是如此。在本发明的速溶片中所述崩解剂的量方便在约3-约8％(w/w)的范围内，优选约5％(w/w)。
为使混合和直接压片过程更易进行，所述载体还包括助流剂和润滑剂。优选，所述助流剂为胶体无水硅，所述润滑剂为硬脂酸镁。在最初的实验中(见F1和F2)，使用滑石粉作为助流剂，十二烷基硫酸钠作为润湿剂/润滑剂。发现前者可以对所述片剂产生不利影响(延缓所述活性成分的溶出)，后者完全是多余的，可以容易地从所述片剂中省略。
本发明的速溶片含有(基于片芯的总重量)：
(a)2-10％雪花胺氢溴酸盐(1∶1)；
(b)83-93％喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物；
(c)0.1-0.4％的助流剂；
(d)3-8％不溶性交联聚合的崩解剂；和
(e)0.2-1％润滑剂。
所述片剂特别包括：
(a)2-10％雪花胺氢溴酸盐(1∶1)；
(b)83-93％喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物；
(c)约0.2％的胶体无水硅；
(d)约5％交联聚维酮；和
(e)约0.5％的硬脂酸镁。
根据本发明的快速溶出的雪花胺氢溴酸盐(11)片剂另外可选包括其它的赋形剂，例如矫味剂、甜味剂和着色剂。
根据本领域已知的包衣技术可以方便地对雪花胺氢溴酸盐(1∶1)片剂进行薄膜包衣。薄膜包衣片剂比未包衣的片芯更易吞咽，通常易于与其它的片剂区分-特别是当薄膜包衣物含有染料或颜料时，并且具有改善的稳定性(储存期)。在此情况下，可以使用含有膜形成聚合物和增塑剂的混合物，特别是羟丙基甲基纤维素和聚乙二醇，如聚乙二醇6000，作为如前所述薄膜包衣片片芯。速溶片中特别重要的要求是薄膜包衣不应对活性成分自片剂的崩解和溶出有不利影响。所以，适当的薄膜包衣的重量在未包衣片芯的3-8％，特别在4-7.5％的范围内。
如实验部分所示，根据本发明的未包衣片芯和薄膜包衣片(F5,F6,F7)均符合30分钟后Q=80％(USP)的溶出要求。
本发明的片剂适合作为口服给药的单位剂量形式用于需要雪花胺治疗的病人。该片剂适当地包括2-20mg雪花胺(2.563-25.63mg雪花胺氢溴酸盐(1∶1))，特别为4-16mg雪花胺(5.026-20.506mg雪花胺氢溴酸盐(1∶1))。它们最好一天给药三次(t.i.d)，约每8小时一次，或一天二次(b.i.d)，约每12小时一次，因为这些剂量方案在一天的范围内可提供活性成分的治疗血浆浓度。
本发明也涉及制备快速溶出雪花胺氢溴酸盐(1∶1)片剂的制备过程，包括以下步骤：
(ⅰ)将所述活性成分、崩解剂和任选的助流剂与稀释剂干法混合；
(ⅱ)将润滑剂与在步骤(ⅰ)获得的混合物任选混合；
(ⅲ)将在步骤(ⅰ)或步骤(ⅱ)获得的混合物在干燥状态下压制成片剂；并
(ⅳ)任选对步骤(ⅲ)获得的片剂进行薄膜包衣。
干法混合可适当的在行星式混合机中进行：在压片机上直接压制：和在包衣锅中进行薄膜包衣。
实验部分
实施例1：直接压成片剂(F1)
成分：雪花胺氢溴酸盐               5mg乳糖(无水)                   70mg粉末状纤维素                 19mg滑石粉                       4mg十二烷基硫酸钠               1mg胶体无水硅                   0.5mg硬脂酸镁                     0.5mg总重                         100mg
制备：
在行星式混合器中将上述成分紧密混合并在压片机上压制，因此得到每片100mg的片剂。
实施例2：直接压制薄膜包衣片剂(F2)
成分：雪花胺氢溴酸盐               5.13mg(4mg雪花胺)乳糖一水合物                 55.11mg微晶纤维素                   15.2mg滑石粉                       3.2mg十二烷基硫酸钠               0.8mg胶体无水硅                   0.16mg硬脂酸镁                     0.4mg片芯重                       80mghypromellose29105mPas        1.8mg滑石粉                       0.8mg二氧化钛(E171)               0.1mg聚乙二醇6000                 0.3mg纯净水*                     17mg薄膜包衣物重                 3mg总重                         83mg
*该成分在终产物中不存在。
制备：
在行星式混合器中将上述成分紧密混合并在压片机上压制，因此得到每片80mg的片剂。然后在包衣锅中进行片芯的薄膜包衣。
实施例3：直接压制薄膜包衣片剂(F5)
成分：雪花胺氢溴酸盐               5.126mg(4mg雪花胺)喷雾干燥的乳糖一水合物和微晶 221.194mg纤维素(75∶25)的混合物交联聚维酮                   12mg胶体无水硅                   0.48mg硬脂酸镁                     1.2mg片芯总重                     240mghypromellose29105mPas        5.4mg滑石粉                       2.4mg二氧化钛(E171)               0.3mg聚乙二醇6000                 0.9mg纯净水*                     51mg薄膜包衣物重                 9mg总重                         249mg
*该成分在终产物中不存在。
制备：
在行星式混合器中将上述成分紧密混合并在压片机上压制，因此得到每片240mg的片剂。然后在包衣锅中进行片芯的薄膜包衣。
实施例4：直接压制薄膜包衣片剂(F6)
成分：雪花胺氢溴酸盐               23.069mg(18mg雪花胺)喷雾干燥的乳糖一水合物和微晶 203.251mg纤维素(75∶25)的混合物交联聚维酮                   12mg胶体无水硅                   0.48mg硬脂酸镁                     1.2mg片芯总重                     240mghypromellose29105mPas        5.4mg滑石粉                       2.4mg二氧化钛(E171)               0.3mg聚乙二醇6000                 0.9mg纯净水*                     51mg薄膜包衣物重                 9mg总重                         249mg
*该成分在终产物中不存在。
制备：
在行星式混合器中将上述成分紧密混合并在压片机上压制，因此得到每片240mg的片剂。然后在包衣锅中进行片芯的薄膜包衣。
实施例5：各种强度直接压制薄膜包衣片剂(F7a、F7b、F7c、F7d)成分(除特别指明外为mg)       F7a     F7b     F7c     F7d雪花胺氢溴酸盐               5.126   10.253  15.379  20.506(雪花胺)                      (4)      (8)      (12)     (16)喷雾干燥的乳糖一水合物和微晶  51.454   102.907  154.361  205.814纤维素(75∶25)的混合物交联聚维酮                    3        6        9        12胶体无水硅                    0.12     0.24     0.36     0.48硬脂酸镁                      0.3      0.6      0.9      1.2片芯重                        60       120      180      240hypromellose29105mPas         2.5      4        5        6聚乙二醇(μl)                 0.603    0.965    1.207    1.448滑石粉                        0.5      0.8      1        1.2二氧化钛(E171)                0.75     1.2      1.5      1.8着色剂                        0.0032   0.013    0.505    0.130纯净水*                      26.875   43       53.75    64.5薄膜包衣物重                  4.3562   6.978    9.212    10.578总重                          64.3562  126.978  189.212  250.578
*该成分在终产物中不存在。
制备：
在行星式混合器中的上述成分紧密混合并在压片机上压制，因此分别制得每片60、120、180和240mg的片剂。然后在包衣锅中进行片芯的薄膜包衣。
实施例6
对片剂F1、F2、F5(未包衣)、F5(薄膜包衣)、F6(未包衣)、F6(薄膜包衣)和F7a-d(薄膜包衣)进行体外溶出对比研究。所述介质为500mg纯净水，于37℃在装置2(USP23,<711>溶出，第1791-1793页)(桨状，50rpm)中进行。F1
  时间(min)                          活性成分剂量的计算浓度(重量％)
 样品1     样品2  样品3  样品4     样品5     样品6  平均
    0515304560  0.0077.8587.3390.9892.7893.58     0.0059.1078.8884.1587.2888.95  0.0072.4086.7388.4090.3091.00  0.0074.4883.4087.4389.8392.35     0.0076.2389.0891.7893.3096.35     0.0061.3576.3382.2085.8389.83  0.0070.2383.6287.4989.8892.01
F2
   时间(min)                        活性成分剂量的计算浓度(重量％)
    样品1     样品2     样品3     样品4     样品5     样品6     平均
    0515304560     0.0034.4885.2390.5592.8494.40     0.0024.4275.3284.9988.8990.69     0.0033.9279.3987.3190.4592.28     0.0037.3585.2390.3092.4793.91     0.0033.6784.2690.6493.4994.62     0.0033.3373.9383.1188.3889.74     0.0032.8680.5687.8291.0992.60
F5未包衣
    时间(min)                        活性成分剂量的计算浓度(重量％)
    样品1     样品2     样品3     样品4     样品5     样品6     平均
    0515304560     0.0095.5996.1597.4698.1098.17     0.0096.7197.2297.2797.5197.59     0.0095.1097.3797.4997.6897.61     0.0096.6397.2997.5697.7398.12     0.0095.8197.2797.6698.1298.00     0.0096.8597.3997.6898.2798.29     0.0096.1197.1197.5297.9097.96
F5薄膜包衣
   时间(min)                      活性成分剂量的计算浓度(重量％)
  样品1   样品2    样品3   样品4    样品5    样品6     平均
    0515304560   0.0086.2792.7697.2798.1298.05   0.0081.0893.2996.2497.5197.66    0.0089.3792.9095.0796.2796.49    0.0087.8193.3495.2096.6396.66    0.0092.9597.4698.0598.2098.22     0.0086.9393.2794.6195.6896.61    0.0087.4093.8496.0797.0797.28
F6未包衣
  时间(min)                    活性成分剂量的计算浓度(重量％)
   样品1   样品2    样品3    样品4    样品5   样品6     平均
   0515304560    0.0094.0297.1797.4998.1298.53   0.0094.3397.0897.6498.3498.38     0.0093.1897.8498.5398.9299.61    0.0093.5997.3498.0398.36100.09     0.0095.1397.8298.6899.46100.55    0.0093.2997.4797.6298.2198.40     0.0093.9297.4598.0098.5799.26
F6薄膜包衣
 时间(min)                          活性成分剂量的计算浓度(重量％)
   样品1    样品2     样品3    样品4     样品5     样品6      平均
    0515304560     0.0094.6198.1498.8199.74100.24     0.0077.7096.9399.0599.61100.76     0.0095.6399.81100.61100.70100.74     0.0090.5197.3299.5199.59100.13     0.0083.9096.2599.29100.13100.52     0.0078.9495.8697.9799.90100.57     0.0086.8897.3999.2199.95100.50
F7a薄膜包衣
   时间(min)                           活性成分剂量的计算浓度(重量％)
    样品1     样品2     样品3     样品4     样品5     样品6     平均
    01020304560     0.0079.288.391.993.594.0     0.0083.99396.097.598.8     0.0087.194.596.597.197.9     0.0086.493.495.997.298.0     0.0081.089.892.894.595.4     0.0084.793.796.297.898.7     0.0083.792.194.996.397.1
F7b薄膜包衣
   时间(min)                       活性成分剂量的计算浓度(重量％)
    样品1    样品2     样品3    样品4    样品5    样品6     平均
    01020304560     0.0077.288.192.494.896.1    0.0073.086.491.193.395.2     0.0083.391.693.994.795.7    0.0082.391.293.494.995.7    0.0082.193.996.498.299.2    0.0080.790.693.795.095.9     0.0079.890.393.595.196.3
F7c薄膜包衣
   时间(min)                      活性成分剂量的计算浓度(重量％)
    样品1    样品2     样品3     样品4    样品5    样品6    平均
    01020304560     0.0085.996.099.6101.3102.0    0.0092.198.399.5100.2100.5     0.0093.498.398.698.899.0     0.0092.097.898.699.199.2    0.0095.8100.2100.4100.8100.8    0.0093.299.7100.4101.0101.0    0.0092.198.499.5100.2100.4
F7d薄膜包衣
   时间(min)                        活性成分剂量的计算浓度(重量％)
  样品1    样品2    样品3    样品4    样品5  样品6    平均
     01020304560    0.0070.186.094.198.1102.3     0.0082.195.099.0101.8102.1    0.0077.890.694.499.598.2     0.0081.693.396.998.599.4    0.0082.690.894.095.796.5   0.0079.992.697.199.2100.3    0.0079.091.495.998.899.8
F1和F2在阶段1都不能符合30分钟后溶出Q=80％的标准；F5(未包衣)、F5(薄膜包衣)、F6(未包衣)、F6(薄膜包衣)和F7a-d(薄膜包衣)在阶段1均符合30分钟后溶出Q=80％的标准。

Claims (10)

1．含有作为活性成分的治疗有效量的雪花胺氢溴酸盐(1∶1)和药学上可接受的载体的片剂，其特征在于所述载体含有作为稀释剂的喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物和崩解剂。
2．权利要求1的片剂，其中所述崩解剂为交联聚维酮或交联羧甲基纤维素(croscarmellose)。
3．权利要求1或2的片剂，其中所述载体进一步包括助流剂和润滑剂。
4．权利要求3的片剂，其中所述助流剂为胶体无水硅，且其中所述润滑剂为硬脂酸镁。
5．权利要求1、2、3或4任何一项的片剂，包括基于总重量的重量为：
(a)2-10％雪花胺氢溴酸盐(1∶1)；
(b)83-93％喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物；
(c)0.1-0.4％的助流剂；
(d)3-8％不溶性交联聚合的崩解剂；和
(e)0.2-1％润滑剂。
6．权利要求5的片剂包括
(a)2-10％雪花胺氢溴酸盐(1∶1)；
(b)83-93％喷雾干燥的乳糖一水合物和微晶纤维素(75∶25)的混合物；
(c)约0.2％的胶体无水硅；
(d)约5％交联聚维酮；和
(e)约0.5％的硬脂酸镁。
7．为薄膜包衣的权利要求1、2、3、4、5或6任何一项的片剂。
8．权利要求7的片剂，其中所述薄膜包衣物包括薄膜形成聚合物和增塑剂。
9．权利要求8的片剂，其中所述薄膜包衣物重为未包衣片芯的约3％-约8％。
10．制备权利要求1-9任何一项的片剂的方法，该方法包括下列步骤：
(ⅰ)将所述活性成分、崩解剂和任选的助流剂与稀释剂干燥混合；
(ⅱ)将润滑剂与在步骤(ⅰ)获得的混合物任选混合；
(ⅲ)将在步骤(ⅰ)或步骤(ⅱ)获得的混合物在干燥状态下压制成片剂；并
(ⅳ)任选对步骤(ⅲ)获得的片剂进行薄膜包衣。
CN97195512A 1996-06-14 1997-06-06 快速溶出的雪花胺氢溴酸盐片剂 Expired - Lifetime CN1102390C (zh)

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DK0584185T3 (da) * 1991-05-14 2000-02-07 Ernir Snorrason Behandling af træthedssyndrom med cholinesteraseinhibitorer
US5336675A (en) * 1991-05-14 1994-08-09 Ernir Snorrason Method of treating mania in humans
TW506836B (en) * 1996-06-14 2002-10-21 Janssen Pharmaceutica Nv Fast-dissolving galanthamine hydrobromide tablet

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100438917C (zh) * 2006-07-20 2008-12-03 山东聊城阿华制药有限公司 一种微晶纤维素乳糖的制备方法
CN106822008A (zh) * 2017-01-11 2017-06-13 江苏艾兰得营养品有限公司 一种维生素d速溶制剂及其制备方法

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AR070670A2 (es) 2010-04-28
BG64168B1 (bg) 2004-03-31
HK1019703A1 (en) 2000-02-25
HRP970321A2 (en) 1998-04-30
ES2235234T3 (es) 2005-07-01
DE69732113D1 (de) 2005-02-03
US6099863A (en) 2000-08-08
ZA975281B (en) 1998-12-14
EP0915701A1 (en) 1999-05-19
US6358527B1 (en) 2002-03-19
DK0915701T3 (da) 2005-04-25
SK284620B6 (sk) 2005-07-01
PT915701E (pt) 2005-05-31
AR008237A1 (es) 1999-12-29
ATE285777T1 (de) 2005-01-15
KR20000015851A (ko) 2000-03-15
IL127519A0 (en) 1999-10-28
SI0915701T1 (en) 2005-06-30
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TR199802592T2 (xx) 1999-03-22
CA2257431C (en) 2001-11-20
CN1102390C (zh) 2003-03-05
PL189329B1 (pl) 2005-07-29
NO985815D0 (no) 1998-12-11
EP0915701B1 (en) 2004-12-29
PL330431A1 (en) 1999-05-10
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EA199900026A1 (ru) 1999-06-24
UA62930C2 (uk) 2004-01-15
TW506836B (en) 2002-10-21
DE69732113T2 (de) 2005-12-08
SK169698A3 (en) 1999-10-08
NO985815L (no) 1998-12-11
WO1997047304A1 (en) 1997-12-18
CZ403498A3 (cs) 1999-03-17
EA001193B1 (ru) 2000-12-25
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ID17088A (id) 1997-12-04
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