CN1160076C - 含双膦酸的药用组合物 - Google Patents

含双膦酸的药用组合物 Download PDF

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CN1160076C
CN1160076C CNB991047494A CN99104749A CN1160076C CN 1160076 C CN1160076 C CN 1160076C CN B991047494 A CNB991047494 A CN B991047494A CN 99104749 A CN99104749 A CN 99104749A CN 1160076 C CN1160076 C CN 1160076C
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S·R·贝查德
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K·A·克雷默
A·V·卡达力
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Abstract

一种含双膦酸的药用组合物。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

含双膦酸的药用组合物
本申请是申请号为93120408.9、申请日为1993年12月1日、发明名称为“含双膦酸的药用组合物”的发明专利申请的分案申请。
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合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F MC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20RPM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2.5mg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 5 mg Probe Stability Lots)
                      (a)直接压片
条件                     开始时测定的百分数
                               敝开式盘                         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 (14)

1.一种直接压制片剂形式的药用组合物，按重量计，它包含0.5-40％的4-氨基-1-羟基亚丁基-1，1-双膦酸或其药学上可接受的盐和60-99.5％的赋形剂，所述赋型剂包括选自无水乳糖或含水高流速乳糖的稀释剂、干粘合剂、崩解剂和润滑剂。
2.一种直接压制片剂形式的药用组合物，按重量计，它包含0.5-40％的4-氨基-1-羟基亚丁基-1，1-双膦酸或其药学上可接受的盐和60-99.5％的赋形剂，所述赋型剂由无水乳糖或含水高流速乳糖；微晶纤维素；交联羧甲基纤维素钠和硬脂酸镁组成。
3.一种直接压制片剂形式的药用组合物，按重量计，它包含：
0.5-40％的4-氨基-1-羟基亚丁基-1，1-双膦酸或其药学上可接受的盐；
10-80％的无水乳糖或含水高流速乳糖；
5-50％的微晶纤维素；
0.5-10％的交联羧甲基纤维素钠；和
0.1-5％的硬脂酸镁。
4.按照权利要求3的药用组合物，按重量计，它包含：
0.5-25％的4-氨基-1-羟基亚丁基-1，1-双膦酸或其药学上可接受的盐；
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％的交联羧甲基纤维素钠；和
0.1-2％的硬脂酸镁。
5.按照权利要求1-4中任一项的药用组合物，其中所述的活性成分是4-氨基-1-羟基亚丁基-1，1-双膦酸单钠盐三水合物。
6.按照权利要求1-5中任一项的药用组合物，其中所述的稀释剂是无水乳糖。
7.按照权利要求6的药用组合物，按重量计，它包含：
1-25％的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％的交联羧甲基纤维素钠；和
0.1-1％的硬脂酸镁。
8.含有4-氨基-1-羟基亚丁基-1，1-双膦酸或其药学上可接受的盐的直接压制片剂的制备方法，它包括：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。
9.按照权利要求8的制备方法，其中所述的活性成分是4-氨基-1-羟基亚丁基-1，1-双膦酸单钠盐三水合物。
10.按照权利要求8的制备方法，其中所述的稀释剂是无水乳糖。
11.按照权利要求8的制备方法，其中所述的干粘合剂是微晶纤维素。
12.按照权利要求8的制备方法，其中所述的崩解剂选自：变性淀粉、变性纤维素聚合物、交联羧甲基纤维素钠或它们的混合物。
13.按照权利要求8的制备方法，其中所述的崩解剂是交联羧甲基纤维素钠。
14.按照权利要求8的制备方法，其中所述的润滑剂是硬脂酸镁。
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Families Citing this family (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6096342A (en) 1997-03-12 2000-08-01 The Procter & Gamble Company Dosage forms of risedronate
KR100274734B1 (ko) * 1991-11-22 2000-12-15 제이코버스 코넬리스 레이서 리제드로네이트 지연-방출성 조성물
US5358941A (en) * 1992-12-02 1994-10-25 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids with lactose
US6406714B1 (en) 1992-12-02 2002-06-18 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids
US20010007863A1 (en) * 1998-06-18 2001-07-12 Merck & Co., Inc. Wet granulation formulation for bisphosphonic acids
TW390813B (en) * 1994-04-29 2000-05-21 Merck & Co Inc Wet granulation formulation for bisphosphonic acids
AU4353996A (en) * 1994-12-14 1996-07-03 Bioglan Ireland (R & D) Limited Pharmaceutical tablet formulations for direct compression
EP0824341A4 (en) * 1995-05-12 1999-07-07 Merck & Co Inc PREVENTING TOOTH LOSS THROUGH ADMINISTRATION OF ALENDRONATE OR ITS SALTS
EP0837863A4 (en) * 1995-06-06 1999-06-16 Merck & Co Inc DISODIUM ALENDRONATE PREPARATIONS
ATE289199T1 (de) * 1995-06-06 2005-03-15 Merck & Co Inc Formulierungen mit dem wasserfreien mononatriumsalz von alendronat und deren verwendung zur behandlung von knochenkrankheiten
US6117856A (en) * 1996-02-14 2000-09-12 Binderman; Itzhak Topical bisphosphonates for prevention of bone resorption
DE19615812A1 (de) * 1996-04-20 1997-10-23 Boehringer Mannheim Gmbh Pharmazeutische Zubereitung enthaltend Diphosphonsäuren zur oralen Applikation
AU723357B2 (en) * 1996-10-04 2000-08-24 Merck & Co., Inc. Liquid alendronate formulations
DE19719680A1 (de) 1997-05-09 1998-11-19 Boehringer Mannheim Gmbh Verwendung von Diphosphonsäuren zur präventiven Behandlung von Spätfolgen bei Harnblasenerweiterung oder Harnblasenersatz
IL133405A0 (en) * 1997-06-11 2001-04-30 Procter & Gamble Film-coated tablet for improved upper gastrointestinal tract safety
US20010031244A1 (en) * 1997-06-13 2001-10-18 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
US6432932B1 (en) 1997-07-22 2002-08-13 Merck & Co., Inc. Method for inhibiting bone resorption
US5994329A (en) 1997-07-22 1999-11-30 Merck & Co., Inc. Method for inhibiting bone resorption
IL121623A (en) 1997-08-26 2000-06-29 Unipharm Ltd Process for the preparation of solid oral dosage forms comprising alendronic acid
US6750340B2 (en) 1998-04-02 2004-06-15 Mbc Research, Inc. Bisphosphonate conjugates and methods of making and using the same
US6214812B1 (en) * 1998-04-02 2001-04-10 Mbc Research, Inc. Bisphosphonate conjugates and methods of making and using the same
US6896871B2 (en) 1998-04-02 2005-05-24 Mbc Research, Inc. Biphosphonate conjugates and methods of making and using the same
US7598246B2 (en) 1998-04-02 2009-10-06 Mbc Pharma, Inc. Bisphosphonate conjugates and methods of making and using the same
US8586781B2 (en) 1998-04-02 2013-11-19 Mbc Pharma, Inc. Bone targeted therapeutics and methods of making and using the same
JP4827296B2 (ja) 1998-06-11 2011-11-30 ファルマシア・アンド・アップジョン・カンパニー・エルエルシー デラビルジン錠製剤
US6099865A (en) * 1998-07-08 2000-08-08 Fmc Corporation Croscarmellose taste masking
IL125336A0 (en) 1998-07-14 1999-03-12 Yissum Res Dev Co Compositions for inhibition and treatment of restinosis
US7008645B2 (en) * 1998-07-14 2006-03-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of inhibiting restenosis using bisphosphonates
US6984400B2 (en) * 1998-07-14 2006-01-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of treating restenosis using bisphosphonate nanoparticles
EP0998932A1 (de) 1998-10-09 2000-05-10 Boehringer Mannheim Gmbh Feste pharmazeutische Darreichungsform enthaltend Diphosphonsäure oder deren Salze und Verfahren zu ihrer Herstellung
EP0998933A1 (de) 1998-10-09 2000-05-10 Boehringer Mannheim Gmbh Verfahren zur Herstellung von bisphosphonathaltigen pharmazeutischen Zusammensetzungen zur oralen Applikation
US6331533B1 (en) 1998-11-16 2001-12-18 Merck & Co., Inc. Method for inhibiting dental resorptive lesions
US7205404B1 (en) 1999-03-05 2007-04-17 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
BR0010808A (pt) * 1999-05-21 2002-08-27 Novartis Ag Composições farmacêuticas e usos
AR024462A1 (es) * 1999-07-01 2002-10-02 Merck & Co Inc Tabletas farmaceuticas
AR021347A1 (es) 1999-10-20 2002-07-17 Cipla Ltd Una composicion farmaceutica que contiene acido(s) bisfosfoncio o sal(es) del mismo y un proceso de preparacion de la misma
US6468559B1 (en) 2000-04-28 2002-10-22 Lipocine, Inc. Enteric coated formulation of bishosphonic acid compounds and associated therapeutic methods
PL196485B1 (pl) * 2000-05-11 2008-01-31 Inst Farmaceutyczny Stała doustna kompozycja farmaceutyczna zawierająca aminową pochodną kwasu bisfosfonowego i sposób jej wytwarzania
CZ20002567A3 (cs) * 2000-07-11 2001-12-12 Léčiva, A.S. Tableta vyrobitelná přímým tabletováním, obsahující aktivní látku kyselinu 4-amino-1-hydroxybutyliden-1,1-bisfosfonovou, a způsob její výroby
US6638920B2 (en) 2000-07-21 2003-10-28 Merck & Co., Inc. Compositions and methods of preventing or reducing the risk or incidence of skeletal injuries in horses
GB0029111D0 (en) * 2000-11-29 2001-01-10 Novartis Ag Organic compounds
WO2002055009A1 (en) * 2001-01-12 2002-07-18 Sun Pharmaceutical Industries Limited Spaced drug delivery system
JP5328071B2 (ja) * 2001-04-10 2013-10-30 サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド 時限パルス放出組成物
OA12596A (en) * 2001-05-01 2006-06-08 Pfizer Prod Inc Method for manufacturing a low dose pharmaceuticalcomposition.
PT1392325E (pt) * 2001-05-02 2006-10-31 Novartis Ag Metodo de administracao de bifosfonatos por inalacao no tratamento ou na prevencao da reabsorcao ossea e da osteoporose
WO2003055496A1 (en) * 2001-12-21 2003-07-10 The Procter & Gamble Company Method for the treatment of bone disorders
US20040052843A1 (en) * 2001-12-24 2004-03-18 Lerner E. Itzhak Controlled release dosage forms
NZ534104A (en) * 2001-12-24 2007-03-30 Teva Pharma Dosage form with a core tablet of active ingredient sheathed in a compressed annular body of powder or granular material
IL163666A0 (en) 2002-02-22 2005-12-18 New River Pharmaceuticals Inc Active agent delivery systems and methods for protecting and administering active agents
WO2003086415A1 (en) * 2002-04-05 2003-10-23 Merck & Co., Inc. Method for inhibiting bone resorption with an alendronate and vitamin d formulation
KR20120065435A (ko) * 2002-05-10 2012-06-20 에프. 호프만-라 로슈 아게 골다공증 치료 및 예방용 비스포스폰산
USRE48890E1 (en) 2002-05-17 2022-01-11 Celgene Corporation Methods for treating multiple myeloma with 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione after stem cell transplantation
US7968569B2 (en) 2002-05-17 2011-06-28 Celgene Corporation Methods for treatment of multiple myeloma using 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
ATE461205T1 (de) * 2002-05-17 2010-04-15 Teva Pharma Verwendung von bestimmten lösungsmitteln zur herstellung von bisphosphonsäuren
US20040138180A1 (en) * 2002-10-03 2004-07-15 Barr Laboratories, Inc. Bisphosphonate composition and process for the preparation thereof
US11116782B2 (en) 2002-10-15 2021-09-14 Celgene Corporation Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
US8404716B2 (en) 2002-10-15 2013-03-26 Celgene Corporation Methods of treating myelodysplastic syndromes with a combination therapy using lenalidomide and azacitidine
US20040097468A1 (en) * 2002-11-20 2004-05-20 Wimalawansa Sunil J. Method of treating osteoporosis and other bone disorders with upfront loading of bisphosphonates, and kits for such treatment
BR0309691A (pt) * 2002-12-20 2005-08-02 Hoffmann La Roche Formulação de ibandronato em alta dose
WO2004108067A2 (en) * 2003-04-03 2004-12-16 Sun Pharmaceutical Industries Limited Programmed drug delivery system
US20060051407A1 (en) * 2003-06-27 2006-03-09 Yoram Richter Method of treating ischemia-reperfusion injury
US10517883B2 (en) 2003-06-27 2019-12-31 Zuli Holdings Ltd. Method of treating acute myocardial infarction
EP2612853A1 (en) 2003-09-26 2013-07-10 Exelixis Inc. c-Met modulators and methods of use
NZ546349A (en) * 2003-09-29 2010-03-26 Cipla Ltd Pharmaceutical formulation with improved stability
US6783772B1 (en) * 2003-12-12 2004-08-31 Sanjeev Khandelwal Pharmaceutical preparations containing alendronate sodium
US20050181043A1 (en) * 2004-02-12 2005-08-18 Indranil Nandi Alendronate salt tablet compositions
US20050261250A1 (en) * 2004-05-19 2005-11-24 Merck & Co., Inc., Compositions and methods for inhibiting bone resorption
EP1863450A1 (en) * 2005-03-16 2007-12-12 Elan Pharma International Limited Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations
BRPI0606280A2 (pt) * 2005-03-17 2009-06-09 Elan Pharma Int Ltd composições de bisfosfonato nanoparticulado
US20070059371A1 (en) * 2005-06-09 2007-03-15 Elan Pharma International, Limited Nanoparticulate ebastine formulations
NO347644B1 (no) 2006-05-04 2024-02-12 Boehringer Ingelheim Int Polymorfer
EP1852108A1 (en) 2006-05-04 2007-11-07 Boehringer Ingelheim Pharma GmbH & Co.KG DPP IV inhibitor formulations
PE20080251A1 (es) 2006-05-04 2008-04-25 Boehringer Ingelheim Int Usos de inhibidores de dpp iv
WO2008020305A2 (en) * 2006-08-17 2008-02-21 Aurobindo Pharma Limited Solid dosage forms of bisphosphonic acids
GB0616794D0 (en) 2006-08-24 2006-10-04 Arrow Int Ltd Solid dosage form
US20080132471A1 (en) * 2006-11-21 2008-06-05 Teikoku Pharma Usa, Inc. Bisphosphonate inhalant formulations and methods for using the same
CA2671727C (en) * 2006-12-20 2016-02-16 Genpharm Ulc A composition containing a bisphosphonic acid in combination with vitamin d
US8974801B2 (en) * 2006-12-21 2015-03-10 Amphastar Pharmaceuticals Inc. Long term sustained release pharmaceutical composition containing aqueous suspension of bisphosphonate
ECSP077628A (es) 2007-05-03 2008-12-30 Smithkline Beechman Corp Nueva composición farmacéutica
AR071175A1 (es) 2008-04-03 2010-06-02 Boehringer Ingelheim Int Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante
US20100034752A1 (en) * 2008-08-11 2010-02-11 Toru Hibi Inhalant formulations comprising a bisphosphonate and a pyrazolone derivative and methods for using the same
US20200155558A1 (en) 2018-11-20 2020-05-21 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug
EP2210596A1 (en) 2009-01-22 2010-07-28 Laboratorios Liconsa, S.A. Pharmaceutical composition of ibandronate sodium salt or a hydrate thereof
AU2010249615B2 (en) 2009-05-19 2013-07-18 Celgene Corporation Formulations of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione
TWI462739B (zh) 2010-11-02 2014-12-01 Univ Kaohsiung Medical Ｓｉｌｄｅｎａｆｉｌ－同族物四級銨哌嗪鹽類之製備及醫療用途
AR083878A1 (es) 2010-11-15 2013-03-27 Boehringer Ingelheim Int Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento
KR20210147117A (ko) 2011-02-10 2021-12-06 엑셀리시스, 인코포레이티드 퀴놀린 화합물들의 제조 방법들 및 상기 화합물들을 함유하는 약학 조성물들
AU2012290089B2 (en) 2011-08-01 2016-09-29 Mbc Pharma, Inc. Vitamin B6 derivatives of nucleotides, acyclonucleotides and acyclonucleoside phosphonates
KR102035362B1 (ko) * 2011-12-27 2019-10-22 셀진 코포레이션 (+)-2-[1-(3-에톡시-4-메톡시-페닐)-2-메탄술포닐-에틸]-4-아세틸아미노이소인돌린-1,3-디온의 제제
GB201200868D0 (en) 2012-01-19 2012-02-29 Depuy Int Ltd Bone filler composition
US9993427B2 (en) 2013-03-14 2018-06-12 Biorest Ltd. Liposome formulation and manufacture
EP3105238A4 (en) 2014-02-13 2017-11-08 Ligand Pharmaceuticals, Inc. Prodrug compounds and their uses
WO2016003812A1 (en) 2014-07-02 2016-01-07 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
HUE061382T2 (hu) 2014-08-22 2023-06-28 Celgene Corp Eljárás myeloma multiplex kezelésére immunomoduláló vegyületekkel, antestekkel kombinálva
EP2992885A3 (en) 2014-09-02 2016-05-18 Jansfat Biotechnology Co., Ltd. Method for inhibiting a liver disease
CN107334770A (zh) 2016-05-02 2017-11-10 健脂生物科技股份有限公司 治疗脂质代谢紊乱的组合物及其方法
US10093647B1 (en) 2017-05-26 2018-10-09 Celgene Corporation Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione dihydrate, compositions and methods of use thereof
US10093648B1 (en) 2017-09-22 2018-10-09 Celgene Corporation Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione hemihydrate, compositions and methods of use thereof
US10093649B1 (en) 2017-09-22 2018-10-09 Celgene Corporation Crystalline 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione monohydrate, compositions and methods of use thereof
CN111788196A (zh) 2018-01-09 2020-10-16 配体药物公司 缩醛化合物及其治疗用途

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1036368A (en) * 1963-10-31 1966-07-20 Nat Dairy Prod Corp Method for the manufacture of lactose-containing tablets
DE2534391C2 (de) * 1975-08-01 1983-01-13 Henkel KGaA, 4000 Düsseldorf 1-Hydroxy-3-aminoalkan-1,1-diphosphonsäuren
DE2745083C2 (de) * 1977-10-07 1985-05-02 Henkel KGaA, 4000 Düsseldorf Hydroxydiphosphonsäuren und Verfahren zu deren Herstellung
IT1201087B (it) * 1982-04-15 1989-01-27 Gentili Ist Spa Bifosfonati farmacologicamente attivi,procedimento per la loro preparazione e relative composizioni farmaceutiche
US4639338A (en) * 1984-08-06 1987-01-27 Ciba-Geigy Corporation Preparation of crystalline disodium 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate
US4822609A (en) 1984-12-21 1989-04-18 The Procter & Gamble Company Treatment of osteoporosis
DE3623397A1 (de) * 1986-07-11 1988-01-14 Boehringer Mannheim Gmbh Neue diphosphonsaeurederivate, verfahren zu deren herstellung und diese verbindungen enthaltende arzneimittel
IL84731A0 (en) * 1986-12-19 1988-05-31 Norwich Eaton Pharma Heterocycle-substituted diphosphonic acids and salts and esters and pharmaceutical compositions containing them
DE3767998D1 (de) * 1986-12-20 1991-03-14 Boehringer Mannheim Gmbh Clodronat-haltige arzneimittel und verfahren zur herstellung derselben.
CA1339805C (en) * 1988-01-20 1998-04-07 Yasuo Isomura (cycloalkylamino)methylenebis(phosphonic acid) and medicines containing the same as an active
US5047246A (en) * 1988-09-09 1991-09-10 Bristol-Myers Company Direct compression cyclophosphamide tablet
JP2525478B2 (ja) * 1989-03-01 1996-08-21 帝人株式会社 安定性の改良された活性型ビタミンｄ▲下３▼類固型製剤
US5070108A (en) * 1990-10-12 1991-12-03 Trustees Of The University Of Pennsylvania Methods of treating osteoporosis, increasing bone mineral content and preventing the occurrence of compression fractures in a mammal
US5358941A (en) * 1992-12-02 1994-10-25 Merck & Co., Inc. Dry mix formulation for bisphosphonic acids with lactose

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