CN1066624C - 双膦酸的干混制剂 - Google Patents

双膦酸的干混制剂 Download PDF

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CN1066624C
CN1066624C CN93120408A CN93120408A CN1066624C CN 1066624 C CN1066624 C CN 1066624C CN 93120408 A CN93120408 A CN 93120408A CN 93120408 A CN93120408 A CN 93120408A CN 1066624 C CN1066624 C CN 1066624C
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S·R·贝查德
K·A·克雷默
A·V·卡达力
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Abstract

用直接压制/干法混合的片剂制剂的制备方法制备双膦酸及其盐的药用组合物。这些药用组合物可用于治疗包括钙或磷酸盐代谢紊乱，尤其是可用于治疗或预防下列疾病；包括骨吸收，尤其是骨质疏松症，佩吉特氏病，恶性高钙血症和转移性骨疾病。

Description

双膦酸的干混制剂
制药工业采用各种方法来混合片剂制剂中的药剂，尤其是湿法制粒是最普遍的方法之一。
已公开了多种双膦酸，它们可用于治疗和预防涉及骨吸收的疾病，代表性的例子可以见美国专利第3962432号；美国专利第4054598号；美国专利第4267108号；美国专利第4327039号；美国专利第4621077号；美国专利第4624947号；美国专利第4746654号；美国专利第4922077号；和欧洲专利公开第0252504号。但双膦酸的片剂制备的标准方法却遇到了严重的困难。
特别是带有含氮碱性官能基的双膦酸可以与标准制剂的乳糖相互作用，从而导致变色、不稳定及效力降低。这种活性成分的降解在存在水和/或高温的情况下尤为明显。据推测，该配伍禁忌具体是由于美拉德(或“棕黄”)反应，其中双膦酸的游离氨基基团与糖(例如乳糖)的“配糖的”羟基基团反应，最终形成棕色变色的降解物。尽管该问题可以通过不加乳糖而避免，但用乳糖作惰性稀释剂通常是比较理想的。
本发明解决了这个问题，它通过提供一种片剂制剂和方法而避免了制剂中双磷酸和乳糖之间的这种相互作用。此外，本发明也提供配制的有利条件，因为它只需将成分混合而不需在压片前制粒或加水。
本发明的第一个方面是涉及通过直接压制(干法混合)片剂制剂来制备双膦酸的药用组合物的方法。该方法采用将双膦酸与最少量的其它加工助剂混合而不加水。该片剂制剂通过在直接压片前将制剂成分混合而不经水合(即未将另外的水加至该混合物中)来制备。
更具体地来讲，本发明的该方面涉及含双膦酸活性成分的片剂的制备方法，它包括：将该活性成分与稀释剂、干粘合剂、崩解剂以及可与选自下列的一种或多种附加成分混合：压片助剂、矫味剂、增味剂、甜味剂和防腐剂，从而制得混合物；用润滑剂润滑该混合物；并将得到的经润滑的混合物压制成所需的片剂形式。
该公开的方法可用来制备固体剂型、尤其是片剂供药用。
优选的稀释剂包括乳糖。尽管可以使用含水的高流速乳糖，但从连续操作的观点来看，尤其优选无水乳糖。
优选的干粘合剂是纤维素，尤其优选微晶纤维素。微晶纤维素可从FMC公司购得，商名为“Avicel”。
崩解剂可以是若干改性淀粉或改性纤维素聚合物之一，尤其优选交联羧甲醚纤维素钠(crosscarmellose sodium)。交联羧甲醚纤维素钠可以“Ac-di-sol”商品名购得。
优选的润滑剂包括硬脂酸镁。
本发明中可用作活性成分的双膦酸的例子包括下列化合物或其药学上可接受的盐：4-氨基-1-羟基亚丁基-1,1-双膦酸；N-甲基-4-氨基-1-羟基亚丁基-1,1-双膦酸；4-(N,N-二甲氨基)-1-羟基亚丁基-1,1-双膦酸；3-氨基-1-羟基亚丙基-1,1-双膦酸；3-(N,N-二甲氨基)-1-羟基亚丙基-1,1-双膦酸；1-羟基-3-(N-甲基-N-戊基氨基)亚丙基-1,1-双膦酸；1-羟基-2-[3-吡啶基]亚乙基-1,1-双膦酸；和4-(羟基亚甲基-1,1-双膦酸)哌啶。
双膦酸的制备方法可参见例如美国专利第3962432号；美国专利第4054598号；美国专利第4267108号；美国专利第4327039号；美国专利第4407761号；美国专利4621077号；美国专利第4624947号；美国专利第4746654号；美国专利第4922077号和欧洲专利公开第0252504号。具体来讲，4-氨基-1-羟基亚丁基-1,1-双膦酸和4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物的制备方法可以分别参见美国专利第4407761号和美国专利第4922077号。
双膦酸的药学上可接受的盐也可以用在本发明中。双膦酸的碱盐例子包括铵盐，碱金属盐如钾盐和钠盐(包括一钠盐、二钠盐和三钠盐)(这些盐是优选的)，碱土金属盐如钙盐和镁盐，与有机碱形成的盐如二环己胺盐，N-甲基-D-葡糖胺盐和与氨基酸形成的盐如精氨酸盐，赖氨酸盐等。优选无毒且生理上可接受的盐。这些盐可用本领域公知的方法来制备。例如参见美国专利第4922077号。
在本发明中优选的双膦酸是4-氨基-1-羟基亚丁基-1,1-双膦酸。特别优选的双膦酸是4-氨基-1-羟基亚丁基-1,1-双膦酸的钠盐，尤其是4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物。
本发明的另一个方面是直接压制的含双膦酸的药用组合物例如片剂，它由该公开的方法来制备。按重量计，这些药用组合物一般含有约0.5-40％双膦酸活性成分和约60-99.5％未加水的加工助剂。更具体地讲，加工助剂是稀释剂、干粘合剂、崩解剂和润滑剂。优选的加工助剂包括无水乳糖或含水高流速乳糖，微晶纤维素，交联羧甲醚纤维素钠和硬脂酸镁。
优选的药用组合物，按重量计，包含约0.5-40％双膦酸活性成分，约10-80％无水乳糖或含水高流速乳糖，约5-50％微晶纤维素，约0.5-10％交联羧甲醚纤维素钠，和约0.1-5％硬脂酸镁。
优选的药用组合物一般为片剂形式。该片剂可以是例如净重50mg至1g；更优选净重为100-500mg的片剂，以净重为200-300mg的片剂为最佳。
更优选的本发明药用组合物，按重量计，含有约0.5-25％双膦酸，所述双膦酸选自4-氨基-1-羟基亚丁基-1,1-双膦酸和4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物；约30-70％无水乳糖或含水高流速乳糖；约30-50％微晶纤维素；约0.5-5％交联羧甲醚纤维素钠；和约0.1-2％硬脂酸镁。
特别优选的药用组合物，按重量计，含有约1-25％活性成分；约40-60％无水乳糖；约35-45％微晶纤维素；约0.5-2％交联羧甲醚纤维素钠；和约0.1-1％硬脂酸镁。
预计可用于工业开发的优选的药用组合物如下：2.5mg效价游离酸的片剂：
按重量计，约1.63％4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物；约56.87％无水乳糖；约40％微晶纤维素；约1％交联羧甲醚纤维素钠；和约0.5％硬脂酸镁。5mg效价游离酸的片剂：
按重量计，约3.25％4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物；约55.25％无水乳糖；约40％微晶纤维素；约1％交联羧甲醚纤维素钠；和约0.5％硬脂酸镁。25mg效价游离酸的片剂：
按重量计，约1.64％4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物；约42.1％无水乳糖；约40％微晶纤维素；约1％交联羧甲醚纤维素钠；和约0.5％硬脂酸镁。50mg效价游离酸的片剂：
按重量计，约21.8％4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物；约36.7％无水乳糖；约40％微晶纤维素；约1％交联羧甲醚纤维素钠；和约0.5％硬脂酸镁。
本发明药用片剂组合物也可以含有一种或多种附加的制剂成分，它们可以选自药物制剂领域中公知的多种赋形剂。根据片剂所需的性质，可以选择多种成分，它们可以是单独的或混合的，这取决于它们在制备片剂组合物中的已知用途。这样的成分包括稀释剂、压片助剂、崩解剂、润滑剂、粘合剂、矫味剂、增味剂、甜味剂和防腐剂，但并不限于这些。
本文中“片剂”一词是指包括所有形状和大小的压制的药用剂量制剂，包衣或未包衣。可用于包衣的物质包括羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、滑石粉、甜味剂和着色剂。
本发明药用组合物可用于治疗或预防性治疗钙或磷酸盐代谢紊乱和相关的疾病。这些疾病可分成两类：
1．钙盐、主要是磷酸钙的异常(异位)沉淀，组织病理学硬化及骨变形。
2．能有益于减少骨吸收的条件。减少骨吸收应当改善吸收和形成之间的平衡，减少骨损失或导致骨增加。减少骨吸收可以减轻与溶骨损伤有关的疼痛并减少那些损害的发生率和/或生长。
这些疾病包括：骨质疏松(包括由雌激素缺乏、制动术和糖皮质激素所致的和老年性的)，骨营养不良，佩吉特氏病、骨化性肌炎、别赫捷列夫氏病，恶性高钙血症，转移性骨疾病，牙周疾病，胆石病，肾石病，尿石病，尿结石，动脉硬化，并节炎，粘液囊炎，神经炎和手足搐搦。
增加骨吸收可以导致血浆中病理学上的高钙和磷酸盐浓度，这可以通过使用本发明药用组合物而得到缓解。
下列实施例目的在于举例说明本发明但对本发明的范围或精神并无限制。
                 实施例1
4-氨基-1-羟基亚丁基-1,1-双膦酸的5mg效价片剂的制备方法成分                         每片    每400片活性成分(单钠盐三水合物)    6.55mg    26.2g无水乳糖，NF                110.45mg  441.8g微晶纤维素NF                80.0mg    320.0g硬脂酸镁微细粉NF            1.00mg    4.0g交联羧甲醚纤维素钠NFA型     2.00mg    8.0g
将活性成分(相当于每片5mg无水游离酸)与1/3微晶纤维素NF和1/2无水乳糖NF在带状混合器中以20 RPM预混合5分钟。将剩余的2/3微晶纤维素NF和1/2无水乳糖NF加至该预混合物中，将其于20RPM混合10分钟。将交联羧甲醚纤维素钠加至该混合的粉末中并于20RPM混合5分钟。最后将硬脂酸镁通过90目筛加至该混合物中并于20RPM再混合5分钟。将该润滑后的混合物压制成5mg活性成分的片剂。
                     实施例2
4-氨基-1-羟基亚丁基-1,1-双膦酸的2.mg效价片剂的制备方法
成分                     每片活性成分(单钠盐三水合物)    3.26mg无水乳糖，NF                113.74mg微晶纤维素NF                80.0mg硬脂酸镁微细粉NF            1.00mg交联羧甲醚纤维素钠NFA型     2.00mg
用实施例1的方法制备片剂。
                     实施例3
4-氨基-1-羟基亚丁基-1,1-双膦酸的10.0mg效价片剂的制备方法。
成分                         每片活性成分(单钠盐三水合物)       13.05mg无水乳糖，NF                   103.95mg微晶纤维素NF                   80.0mg硬脂酸镁微细粉NF               1.00mg交联羧甲醚纤维素钠NFA型        2.00mg
用实施例1的方法制备片剂。
                  实施例4
4-氨基-1-羟基亚丁基-1,1-双膦酸的40.0mg效价片剂的制备方法
成分                      每片活性成分(单钠盐三水合物)     51.21mg无水乳糖，NF                 64.79mg微晶纤维素NF                 80.0mg硬脂酸镁微细粉NF             1.00mg交联羧甲醚纤维素钠NFA型      2.00mg
用实施例1的方法制备片剂。
                   实施例5
4-氨基-1-羟基亚丁基-1,1-双膦酸的25mg效价片剂的制备方法。成分                           每片        每400片活性成分(单钠盐三水合物)      32.75mg      131.0g无水乳糖，NF                  84.25mg      337.0g微晶纤维素NF                  80.0mg       320.0g硬脂酸镁微细粉NF              1.00mg       4.0g交联羧甲醚纤维素钠NFA型       2.00mg       8.0g
用实施例1的方法制备片剂。
                   实施例6
4-氨基-1-羟基亚丁基-1,1-双膦酸的50mg效价片剂的制备方法。成分                         每片       每400片活性成分(单钠盐三水合物)     65.5mg     163.75g无水乳糖，NF                 110.0mg    275.0g微晶纤维素NF                 120.0mg    300.0g硬脂酸镁微细粉NF             1.5mg      3.75g交联羧甲醚纤维素钠NFA型      3.0mg      7.5g
用实施例1的方法制备片剂。
                   实施例7稳定性研究
在不同的条件下用不同的赋形剂制备活性成分的片剂制剂(相当于每片5mg无水游离的4-氨基-1-羟基亚丁基-1,1-双膦酸)。按照实施例1的方法制备直接压制的片剂，按照下述方法制备湿颗粒的片剂。在敝开式盘的条件下并于40℃/75％(相对湿度)对片剂进行稳定性研究，结果如下：
1．用湿法制粒制备的并含有无水乳糖的制剂在2周内出现片剂变色。
2．用湿法制粒制备的并含有含水乳糖的制剂在4周内出现片剂变色。
3．用直接压制(干法混合)制剂制备的制剂在4周以后未出现片剂变色。活性成分的测定证实：在相同的时间内无效价损失或降解。表Ⅰ表明了直接压制的制剂相对于湿法制粒的制剂的稳定性特征。
                   表1
5mg试样稳定性抽样的3个月数据
(Three-Month Data of 5mg Probe Stability Lots)
                 (a)直接压片条件               开始时测定的百分数
          敞开式盘            HDPE/CRC瓶
         cpd    加合物      MK-0217  加合物40℃        101.2％  ----       99.8％   ----40℃/75％RH 102.9％  ----       98.5％   ----
                            100.9％* ----60℃        100.6％  ----       101.3％  ----RT/90％RH   103.5％  ----       102.1％  ----*重复值
           (b)．湿法制粒条件            开始时测定的百分数
        敝开式盘         HDPE/CRC瓶
        epd    加合物    MK-0217    加合物40℃        99.7％  ----     97.0％     ----
                         100.0％**  ----40℃/75％RH 84.1％ 15.9％    94.6％     5.6％
                         99.7％**   ----60℃        92.6％ 微量***   94.3％     微量***
                         94.6％**   微量RT/90％RH   101.4％ ----     100.4％    ----
                         99.4％     ----**含有干燥剂***微量表示加合物峰是可检测出的(～5％)，但在实验条件下无法
定量。Cpd=4-氨基-1-羟基亚丁基-1，1-双膦酸。湿法制粒的片剂的制备方法
1)将无水乳糖、alendronate sodium和微晶纤维素在适当大小的混合器中混合。
2)将混合物过#30筛，然后再混合一段时间。
3)将该粉末混合物用适量的水制粒直至出现粘结。
4)将湿团块过#5筛。
5)将湿筛的颗粒置强制空气干燥器于40-50℃干燥直至干燥失重在105℃时小于2％。
6)将干燥颗粒用适宜的筛子过筛。
7)将干筛的颗粒与交联羧甲醚纤维素钠混合，然后与硬脂酸镁混合。
8)用标记的颗粒压制片剂。
尽管上述说明书阐述了本发明的原则并用实施例进行了举例说明，但应当明白，本发明方法包括本文所述的所有临时变动、调整、改良、删节或补充的方法和约定，包括在下述权利要求和其均等物的范围内。

Claims (16)

1．含选自下列的活性成分或其药学上可接受的盐的片剂的制备方法：4-氨基-1-羟基亚丁基-1,1-双膦酸，N-甲基-4-氨基-1-羟基亚丁基-1,1-双膦酸，4-(N,N-二甲氨基)-1-羟基亚丁基-1,1-双膦酸，3-氨基-1-羟基亚丙基-1,1-双膦酸，3-(N,N-二甲氨基)-1-羟基亚丙基-1,1-双膦酸，1-羟基-3-(N-甲基-N-戊基氨基)亚丙基-1,1-双膦酸；1-羟基-2-[3-吡啶基]亚乙基-1,1-双膦酸，和4-(羟基亚甲基-1,1-双膦酸)哌啶；所述制备方法包括：将活性成分与选自无水乳糖和含水高流速乳糖的稀释剂、干粘合剂、崩解剂和可任选的选自下列的一种或多种附加成分混合：压片助剂、矫味剂、增味剂、甜味剂和防腐剂，从而制得混合物，用润滑剂润滑该混合物，并将得到的经润滑的混合物压制成所需的片剂形式。
2．按照权利要求1的方法，其中，活性成分是4-氨基-1-羟基亚丁基-1,1-双膦酸。
3．按照权利要求1的方法，其中，活性成分是4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物。
4．按照权利要求1的方法，其中，干粘合剂是微晶纤维素。
5．按照权利要求1的方法，其中，崩解剂选自改性淀粉、改性纤维素聚合物和交联羧甲醚纤维素钠，或它们的混合物。
6．按照权利要求1的方法，其中，崩解剂是交联羧甲醚纤维素钠。
7．按照权利要求1的方法，其中，润滑剂是硬脂酸镁。
8．含选自下列的活性成分或其药学上可接受的盐的固体剂型：4-氨基-1-羟基亚丁基-1,1-双膦酸，N-甲基-4-氨基-1-羟基亚丁基-1,1-双膦酸，4-(N,N-二甲氨基)-1-羟基亚丁基-1,1-双膦酸，3-氨基-1-羟基亚丙基-1,1-双膦酸，3-(N,N-二甲氨基)-1-羟基亚丙基-1,1-双膦酸，1-羟基-3-(N-甲基-N-戊基氨基)亚丙基-1,1-双膦酸；1-羟基-2-[3-吡啶基]亚乙基-1,1-双膦酸，和4-(羟基亚甲基-1,1-双膦酸)哌啶；其中，该固体剂型用权利要求13的方法制备。
9．一种药用组合物，按重量计，它含有0.5-40％活性成分和60-99.5％主要包括下列物质的赋形剂：无水乳糖或含水高流速乳糖，微晶纤维素，交联羧甲醚纤维素钠和硬脂酸镁；所述活性成分选自以下化合物或其药学上可接受的盐：4-氨基-1-羟基亚丁基-1,1-双膦酸，N-甲基-4-氨基-1-羟基亚丁基-1,1-双膦酸，4-(N,N-二甲氨基)-1-羟基亚丁基-1,1-双膦酸，3-氨基-1-羟基亚丙基-1,1-双膦酸，3-(N,N-二甲氨基)-1-羟基亚丙基-1,1-双膦酸，1-羟基-3-(N-甲基-N-戊基氨基)亚丙基-1,1-双膦酸，1-羟基-2-[3-吡啶基]亚乙基-1,1-双膦酸，和4-(羟基亚甲基-1,1-双膦酸)哌啶。
10．一种药用组合物，按重量计，它含有0.5-40％活性成分，10-80％无水乳糖或含水高流速乳糖，5-50％微晶纤维素，0.5-10％交联羧甲醚纤维素钠和0.1-5％硬脂酸镁；所述活性成分选自下列的化合物或其药学上可接受的盐：4-氨基-1-羟基亚丁基-1,1-双膦酸，N-甲基-4-氨基-1-羟基亚丁基-1,1-双膦酸，4-(N,N-二甲氨基)-1-羟基亚丁基-1,1-双膦酸，3-氨基-1-羟基亚丙基-1,1-双膦酸，3-(N,N-二甲氨基)-1-羟基亚丙基-1,1-双膦酸，1-羟基-3-(N-甲基-N-戊基氨基)亚丙基-1,1-双膦酸，1-羟基-2-[3-吡啶基]亚乙基-1,1-双膦酸，和4-(羟基亚甲基-1,1-双膦酸)哌啶。
11．按照权利要求10的药用组合物，按重量计，它含有0.5-25％的活性成分，30-70％的无水乳糖或含水高流速乳糖，30-50％的微晶纤维素，0.5-5％的交联羧甲醚纤维素钠和0.1-2％的硬脂酸镁。
12．按照权利要求10的药用组合物，其中，活性成分是4-氨基-1-羟基亚丁基-1,1-双膦酸。
13．按照权利要求10的药用组合物，其中，活性成分是4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物。
14．按照权利要求13的药用组合物，按重量计，它含有1-25％的活性成分：4-氨基-1-羟基亚丁基-1,1-双膦酸单钠盐三水合物，40-60％的无水乳糖，35-45％的微晶纤维素，0.5-2％的交联羧甲醚纤维素钠和0.1-1％的硬脂酸镁。
15．由权利要求13的药用组合物制得的片剂。
16．由权利要求10的药用组合物制得的片剂。
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