CN1154498C - 含有二膦酸类化合物的口服药物组合物的制备方法 - Google Patents
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Abstract
本发明涉及一种含双膦酸盐口服用药物组合物的制备方法,其中所述双膦酸盐以已知方式在流化床制粒机中利用无研磨作用的辅剂湿法制粒,并且其中随后在流化床中干燥颗粒,经具有适当筛网宽度的筛子过筛,进一步利用已知技术加工,制成药物组合物。
Description
技术领域
本发明涉及一种口服用药物组合物的制备方法,该组合物含有氨基烷基-1,1-二膦酸类衍生物或其生理安全盐(此后通称作双膦酸盐类化合物)作为活性物质。
背景技术
双膦酸类化合物在骨疾病和某些钙代谢紊乱症的治疗中至关重要,例如高钙血症、骨质疏松症、肿瘤骨质溶解、佩吉特氏病等。
药物制剂通常不得不满足对含量、内容物均匀性和纯度的苛刻要求。活性物质的特殊性质可能对给药剂型的含量、均匀性和纯度产生不良影响。已知双膦酸盐类化合物是一类强烈趋于与多价金属离子形成复合物的物质。普通的口服用药物制剂常常是在具有金属表面的设备和仪器中生产,因此当加工双膦酸盐时非常易形成复合物的活性物质与可复合材料相接触。当加工中使用了水或含水介质时这种情况特别严重。一种解决方法是干法加工,特别是将组分直接压片,由此在该情况中避免使用湿法制粒。直接压片非常适合制备高剂量的片剂。然而人们已经知道,特别是双膦酸盐的高剂量口服剂型存在相容性的问题,这给口服治疗带来困难。氨基双膦酸类化合物尤其会引起上胃肠道的刺激(H.Fleisch,“骨疾病中的双膦酸盐”,Herbert Fleisch,Berne,1993;126-131页)。另外在直接压片中,当情况是将未粒化粉末填充到明胶胶囊中时,含量会存在上下波动的危险,特别是低剂量或极低剂量的活性物质。因此,虽然存在形成复合物的危险性,湿法制粒是必要的。当采用高速搅拌器时,活性物质与辅剂混合并且用水或粘合剂水溶液湿法制粒。在制备过程中,活性物质非常密切地与设备的金属表面相接触。由于某些药物辅剂的研磨作用进一步增加了形成复合物的危险性。
发明内容
所以,本发明的一个目的是开发一种制备含有双膦酸盐的口服药物组合物的方法,优选每单位剂量含有至多50mg的活性物质,从而减少活性物质在制备组合物中的损失。
因此,根据本发明,通过已知的流化床制粒法(Liebermann等人,“药物剂型”:片剂,第2版,1990,Marcel Dekker,纽约,Basle;Pietsch:“附聚导致的尺寸增大”,Joh Wiley & Sons,Chichester)使双膦酸盐类化合物转化为适合口服应用的剂型。流化床制粒是一种常规湿法制粒方法。然而意外的是,这种方法可以减小活性物质的损失或减少活性物质在制剂中的含量,达到小于6%(重量),优选小于4%(重量)。
所以,本发明涉及一种双膦酸盐类化合物的口服药物组合物的制备方法,其中双膦酸盐是以本身已知的方式、在流化床制粒机中、利用无研磨作用的辅剂湿法制粒,并且其中随后使湿的颗粒在流化床中干燥,经过具有适当筛网宽度的筛子过筛,进而利用已知技术加工制得药物组合物。
因此,湿法制粒过程中形成复合物的上述缺陷在制备低剂量双膦酸盐制剂时不再成为问题。在制备药物组合物时,每单位剂量的双膦酸盐含量适宜至多为50mg,特别是至多10mg。术语“单位剂量”表示不连续的给药形式,即独立片剂或胶囊。
按照本发明通过在已知流化床制粒机中利用在普通制药厂的加工过程中没有研磨作用的辅剂(如二氧化硅),将活性物质制粒可制备所述药物组合物。
优选活性物质以溶液或混悬液与粘合剂水溶液一起喷雾在其它适当的辅剂上并且制粒,或活性物质和辅剂以干粉形式制药流化床制粒机中并且通过将粘合剂水溶液喷雾在粉末混合物中来制粒;另外,也可以将水喷雾在粉末混合物中,在这种情况中粉末混合物中含有粘合剂。
此后,将所得湿颗粒在流化床制粒机中干燥直至原料中含有可接受的残余水分含量,从而进一步用于在其它机器中加工成为药物组合物。
下列双膦酸盐类化合物是可用于本发明的活性物质,它们是游离酸或药物相容性盐或水合物的形式,特别是钠盐:(4-氨基-1-羟基亚丁基)双膦酸盐(阿仑膦酸盐),(二氯亚甲基)双膦酸盐(氯屈二磷酸盐),[1-羟基-3-(1-吡咯烷基)-亚丙基]双膦酸盐(EB-1053),(1-羟基亚乙基)双膦酸盐(羟乙二磷酸盐),[1-羟基-3-(甲基戊基氨基)亚丙基]双膦酸盐(伊班膦酸盐(ibandronate)),[环庚基氨基-亚甲基]双膦酸盐(英卡膦酸盐),(6-氨基-1-羟基亚己基)双膦酸盐(奈立膦酸盐),[3-(二甲基氨基)-1-羟基亚丙基]双膦酸盐(奥帕膦酸盐(olpadronate)),(3-氨基-1-羟基亚丙基)双膦酸盐(氨羟二磷酸二钠(pamidronate)),[1-羟基-2-(3-吡啶基)亚乙基]双膦酸盐(利塞膦酸盐),[[(4-氯苯基)巯基]-亚甲基]双膦酸盐(替鲁膦酸盐),[1-羟基-2-咪唑-(1,2-a)吡啶-3-基亚乙基]双膦酸盐(YH 529),[1-羟基-2-(1H-咪唑-1-基)-亚甲基]双膦酸盐(佐利膦酸盐(zoledronate))。
上述物质及其制各方法是已知的,并且公开在例如下列参考文献:美国专利号4705651(阿仑膦酸盐);美国专利号4927814(伊班膦酸盐);美国专利号3468935、3400147、3475486(羟乙二磷酸盐);O.T.Quimby等人,《有机化学杂志》32,4111(1967)(氯屈二磷酸盐);美国专利号4505321(利塞膦酸盐)和美国专利号4134969和3962432(氨羟二磷酸二钠);美国专利号5130304(EB-1053);美国专利号4970335(英卡膦酸盐);比利时专利号885139(奈立膦酸盐);美国专利号4054598(奥帕膦酸盐);美国专利号4746654、4876248和4980171(替鲁膦酸盐);美国专利号4990503(YH 529)和美国专利号4939130(佐利膦酸盐)。
本发明适宜用来制备含有比例为至多50mg/单位剂量的活性物质的药物组合物,优选至多10mg,特别优选0.1至5mg和0.1至2.5mg/单位剂量。伊班膦酸是特别优选的活性物质,特别是伊班膦酸钠一水合物的形式。
根据本发明,在制粒过程中无研磨作用的辅剂可以是:填充剂,如水合物或无水物形式的乳糖,糖醇如甘露糖醇;压片辅剂,例如微晶或纤维形式的纤维素;和粘合剂,例如聚乙烯吡咯烷酮(PovidoneUSP);或纤维素醚,例如甲基羟丙基纤维素。至少一种辅剂用作粘合剂。
优选至少一种辅剂是乳糖、微晶纤维素或聚乙烯吡咯烷酮。在一个优选实施方案中,采用了1-99%(重量)乳糖,0.1-20%(重量)微晶纤维素,0.1-20%(重量)聚乙烯吡咯烷酮;特别优选25-75%(重量)乳糖,10-20%(重量)微晶纤维素,和2-3%(重量)的聚乙烯吡咯烷酮。
通过已知方法,如果必要利用另外的辅剂,可将颗粒被进一步加工为片剂、咀嚼片、泡腾片、薄膜片、糖衣丸、小药丸或填充在硬明胶胶囊或小药囊中。进一步加工中所用的辅剂是:常规润滑剂,如硬脂酸;崩解剂,如交联聚乙烯吡咯烷酮(Crospovidone USPNF);流动调节剂,例如胶态二氧化硅;压片辅剂等。在一个优选实施方案中,颗粒的进一步加工是利用加入的硬脂酸作为润滑剂,硬脂酸的用量以该给药剂型总重量计为小于5%(重量),特别是0.05至3%(重量)的硬脂酸。
按照本发明通过流化床制粒来制备药物组合物,特别是通过在流化床制粒机中干法加工,可以减少原料和设备表面的密切接触,由此意外地减小活性物质的损失。当单位剂量的活性物质含量较小时这种方法特别适用。这本质上避免了在口服给药剂型的常规制备中所存在的上述缺陷。
本发明现将参考下列实施例进一步详细说明,但不限定本发明。
具体实施方式
实施例1(对照实施例1):
在高速搅拌器/制粒机中制粒后制备伊班膦酸盐2.5mg胶囊(批量45.000个胶囊)。
组分 g
伊班膦酸钠 120.24
乳糖 7934.76
聚乙烯吡咯烷酮 202.50
交联聚乙烯吡咯烷酮(崩解剂) 562.50
硬脂酸(润滑剂) 180.00
每个胶囊中的活性物质含量相当于2.5mg的游离酸。
乳糖、伊班膦酸盐和聚乙烯吡咯烷酮在50%的填充因数下在高速搅拌器/制粒机(Diosna型)中混合2分钟,随后用水制粒8分钟。将湿颗粒在流化床(Aeromatic型设备)中干燥,通过0.8mm筛,与崩解剂和润滑剂混合(Rhoenrad型搅拌器,混合时间为10分钟),并且在胶囊机(MG2/G23型)中包封在2号大小的硬明胶胶囊中但不采用压缩,该胶囊机的容量是20000/小时。
规定的填装重量: 200.0mg
按照工序间控制的实际填装重量: 200.9mg
发现以这种方式制备的胶囊中,活性物质的含量是:94.8%±5.2%(n=10次单独测量)。
实施例2(对照实施例):
在高速搅拌器/制粒机中制粒后制备伊班膦酸盐1.0mg胶囊(批量5000个胶囊)。
组分 g
伊班膦酸钠 5.345
乳糖 999.655
聚乙烯吡咯烷酮 22.500
交联聚乙烯吡咯烷酮(崩解剂) 62.500
硬脂酸(润滑剂) 10.00
每个胶囊中的活性物质含量相当于1.0mmg的游离酸。
乳糖、伊班膦酸盐和聚乙烯吡咯烷酮在高速搅拌器/制粒机(Diosna型)中混合2分钟,随后用水制粒10分钟。将湿颗粒在流化床(Aeromatic型设备)中干燥,通过0.8mm筛,与崩解剂和润滑剂混合(Rhoenrad型搅拌器,混合时间为10分钟),并且在胶囊机(KFM Harro Hofliger型)中包封在2号大小的硬明胶胶囊。
规定的填装重量: 220.0mg
按照工序间控制的实际填装重量: 220.05mg
发现以这种方式制备的胶囊中,活性物质的含量是:94.9%±1.9%(n=10次单独测量)。
实施例3:
在流化床中制粒后制备伊班膦酸盐1.0mg片剂(批量60.000片)。
组分 g
伊班膦酸钠 64.14
乳糖 4405.86
聚乙烯吡咯烷酮 150.00
交联聚乙烯吡咯烷酮(崩解剂) 300.00
硬脂酸(润滑剂) 120.00
微晶纤维素 900.00
胶态SiO2(助流剂) 60.0
每片中的活性物质含量相当于1.0mg的游离酸。
用含有聚乙烯吡咯烷酮和伊班膦酸盐的水溶液在流化床(Aeromatic型)中将乳糖和600g微晶纤维素制粒。湿颗粒在流化床(Aeromatic型设备)中干燥,通过1.0mm筛,与崩解剂、润滑剂、流动调节剂和300g微晶纤维素混合(Turbula型搅拌器,混合时间5分钟)并且在压片机(Korsch型)中转化为片剂,该压片机具有25000片/小时的容量。
规定的填装重量: 100.0mg
按照工序间控制的实际填装重量: 101.3mg
发现以这种方式制备的胶囊中,活性物质的含量是:98.3%±4.2%(n=10次单独测量)。
片剂中的活性物质含量在可接受的界限内。
实施例4:
在流化床中制粒后制备伊班膦酸盐0.1mg片剂(批量150.000片)。
组分 g
伊班膦酸钠 64.14
乳糖 11158.05
聚乙烯吡咯烷酮 375.00
交联聚乙烯吡咯烷酮(崩解剂) 750.00
硬脂酸(润滑剂) 300.00
微晶纤维素 2250.00
胶态SiO2(助流剂) 150.0
每片中的活性物质含量相当于0.1mg的游离酸。
用含有聚乙烯吡咯烷酮和伊班膦酸盐的水溶液在流化床(Aeromatic型)中将乳糖和1500g微晶纤维素制粒。湿颗粒在流化床(Aeromatic型设备)中干燥,通过1.0mm筛,与崩解剂、润滑剂、流动调节剂和750g微晶纤维素混合(Turbula型搅拌器,混合时间10分钟)并且在压片机(Korsch型)中转化为片剂,该压片机具有60000片/小时的容量。
规定的填装重量: 100.0mg
按照工序间控制的实际填装重量: 101.3mg
发现以这种方式制备的胶囊中,活性物质的含量是:98.5%±2.4%(n=10次单独测量)。
片剂中的活性物质含量在可接受的界限内。
Claims (30)
1.一种双膦酸盐口服给药药物组合物的制备方法,其中所述双膦酸盐以已知方式在流化床制粒机中利用无研磨作用的辅剂湿法制粒,随后在流化床中干燥颗粒,经筛网过筛,并且进一步利用已知技术加工,制成每剂量单元含有多至50mg活性物质的药物组合物。
2.根据权利要求1的方法,其中将双膦酸盐溶液或混悬液与粘合剂水溶液一起喷雾在其他辅剂上,进行制粒。
3.根据权利要求1的方法,其中将干粉形式的双膦酸盐和辅剂置于流化床反应釜中,并且通过将水喷雾在粉末混合物中制粒,在这种情况中粉末混合物含有粘合剂;或通过喷雾粘合剂水溶液将含有双膦酸盐的粉末制粒。
4.根据权利要求1-3任一项的方法,其中所用双膦酸盐是阿仑膦酸盐、氯屈二磷酸盐、EB-1053、羟乙二磷酸盐、伊班膦酸盐、英卡膦酸盐、奈立膦酸盐、奥帕膦酸盐、氨羟二磷酸二钠、利塞膦酸盐、替鲁膦酸盐、YH 529或佐利膦酸盐,它们为游离酸、药物相容性盐或水合物的形式,特别是钠盐的形式。
5.根据权利要求4的方法,其中所用双膦酸盐是伊班膦酸盐。
6.根据权利要求1-3任一项的方法,其中至少一种辅剂是乳糖、微晶纤维素或聚乙烯吡咯烷酮。
7.根据权利要求4的方法,其中至少一种辅剂是乳糖、微晶纤维素或聚乙烯吡咯烷酮。
8.根据权利要求5的方法,其中至少一种辅剂是乳糖、微晶纤维素或聚乙烯吡咯烷酮。
9.根据权利要求6的方法,其中采用25-75%重量乳糖,10-20%重量微晶纤维素和2-3%重量聚乙烯吡咯烷酮。
10.根据权利要求7的方法,其中采用25-75%重量乳糖,10-20%重量微晶纤维素和2-3%重量聚乙烯吡咯烷酮。
11.根据权利要求8的方法,其中采用25-75%重量乳糖,10-20%重量微晶纤维素和2-3%重量聚乙烯吡咯烷酮。
12.根据权利要求1-3任一项的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
13.根据权利要求4的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
14.根据权利要求5的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
15.根据权利要求6的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
16.根据权利要求7的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
17.根据权利要求8的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
18.根据权利要求9的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
19.根据权利要求10的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
20.根据权利要求11的方法,其中进一步加工为片剂、胶囊、薄膜片、糖锭剂、小药丸、泡腾片、咀嚼片或将颗粒填充在小药囊中。
21.根据权利要求12的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
22.根据权利要求13的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
23.根据权利要求14的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
24.根据权利要求15的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
25.根据权利要求16的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
26.根据权利要求17的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
27.根据权利要求18的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
28.根据权利要求19的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
29.根据权利要求20的方法,其中进一步的加工是通过向混合物中加入0.05-3%重量硬脂酸来实现。
30.按照权利要求1的方法制备的双膦酸盐的口服给药药物组合物。
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EP98119103.4 | 1998-10-09 | ||
EP98119103A EP0998933A1 (de) | 1998-10-09 | 1998-10-09 | Verfahren zur Herstellung von bisphosphonathaltigen pharmazeutischen Zusammensetzungen zur oralen Applikation |
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CN1154498C true CN1154498C (zh) | 2004-06-23 |
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CNB998112291A Expired - Fee Related CN1154498C (zh) | 1998-10-09 | 1999-10-01 | 含有二膦酸类化合物的口服药物组合物的制备方法 |
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US (1) | US6419955B1 (zh) |
EP (2) | EP0998933A1 (zh) |
JP (1) | JP3725427B2 (zh) |
KR (1) | KR100496086B1 (zh) |
CN (1) | CN1154498C (zh) |
AR (2) | AR019242A1 (zh) |
AT (1) | ATE314075T1 (zh) |
AU (1) | AU744142B2 (zh) |
BR (1) | BR9914368A (zh) |
CA (1) | CA2345818C (zh) |
DE (1) | DE69929219T2 (zh) |
DK (1) | DK1117411T3 (zh) |
ES (1) | ES2255301T3 (zh) |
TR (1) | TR200100888T2 (zh) |
WO (1) | WO2000021541A1 (zh) |
ZA (1) | ZA200102273B (zh) |
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- 1999-10-01 CN CNB998112291A patent/CN1154498C/zh not_active Expired - Fee Related
- 1999-10-01 ES ES99948919T patent/ES2255301T3/es not_active Expired - Lifetime
- 1999-10-01 DE DE69929219T patent/DE69929219T2/de not_active Expired - Lifetime
- 1999-10-01 DK DK99948919T patent/DK1117411T3/da active
- 1999-10-01 KR KR10-2001-7004311A patent/KR100496086B1/ko not_active IP Right Cessation
- 1999-10-01 AT AT99948919T patent/ATE314075T1/de active
- 1999-10-07 AR ARP990105082A patent/AR019242A1/es not_active Application Discontinuation
- 1999-10-07 US US09/413,989 patent/US6419955B1/en not_active Expired - Lifetime
-
2001
- 2001-03-19 ZA ZA200102273A patent/ZA200102273B/en unknown
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2007
- 2007-02-12 AR ARP070100583A patent/AR057636A2/es not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
EP0998933A1 (de) | 2000-05-10 |
TR200100888T2 (tr) | 2001-07-23 |
DE69929219T2 (de) | 2006-08-17 |
JP3725427B2 (ja) | 2005-12-14 |
WO2000021541A1 (en) | 2000-04-20 |
ATE314075T1 (de) | 2006-01-15 |
JP2002527399A (ja) | 2002-08-27 |
AR019242A1 (es) | 2001-12-26 |
ZA200102273B (en) | 2002-06-19 |
KR100496086B1 (ko) | 2005-06-20 |
EP1117411A1 (en) | 2001-07-25 |
CA2345818C (en) | 2006-01-03 |
ES2255301T3 (es) | 2006-06-16 |
DK1117411T3 (da) | 2006-04-24 |
CN1319016A (zh) | 2001-10-24 |
EP1117411B1 (en) | 2005-12-28 |
KR20010073202A (ko) | 2001-07-31 |
CA2345818A1 (en) | 2000-04-20 |
AR057636A2 (es) | 2007-12-12 |
US6419955B1 (en) | 2002-07-16 |
BR9914368A (pt) | 2001-08-07 |
AU744142B2 (en) | 2002-02-14 |
DE69929219D1 (de) | 2006-02-02 |
AU6199099A (en) | 2000-05-01 |
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