CN1112185C - 含有能与水结合赋形剂的固体药物组合物 - Google Patents
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Abstract
本发明涉及一固体药物组合物,该组合物含有重量百分比低于7%的油或油性物质,小剂量的活性组份,和一可与水结合的,不溶于水的,不交联的聚合物赋形剂,该赋形剂的平均颗粒尺寸大于150μm。该组合物可通过一简单方法获得,方法包括,将可与水结合的,不溶于水的,不交联的聚合物赋形剂与活性组份混合,该活性组份溶解或分散于油或油性物质中,其水分散体中或水中。
Description
本发明涉及一种固体药物组合物,其含有重量百分比低于7%的油或油性物质,小剂量的活性组份及一种能与水结合的,不溶于水的,不交联的聚合物赋形剂,以及该固体组合物的制备方法。
许多固体药物组合物在现有技术中是已知的,如Genaro等的标准参考书,Remingtonis Pharma-ceutical Sciences,(第18版,Mack Publishing Company,1990,特别参考第8部分,第89章:药物制剂及其制造)。通常的片剂或胶囊是由含有活性组合物和添加剂或赋形剂的颗粒制成。这些赋形剂包括稀释剂,粘合剂,助流剂,润滑剂,以及类似物质。制备片剂的普通方法为湿法制粒,干法制粒和直接压片。这些方法各有其缺点,特别是配方采用小剂量的活性组合物时。例如,湿法制粒中的活性组合物通常溶解或分散于液相,其通常为造成环境问题的有机溶剂。干法制粒中采用小剂量的活性组合物时,极难使活性含量均匀。直接压片法并非普遍适用,只有在具备形成优良片剂的物理要求,特别是具备良好的附着和流动性能组份才能用。只有极少数组份具备所需性能。由于提高造片操作效率和采用最少占地面积和劳动以降低费用的显著优点,因此需要一种非常简单的方法制备用于片剂和胶囊的载药载体颗粒。另外,若将小剂量的有效组份压缩于片剂中,含出现含量不均的问题。现有的采用小剂量活性组份制备片剂的方法存在复杂性,环境问题、或缺乏再生产能力的缺陷。由Vervaet等披露了一种改进方法(Int.J.Pharmaceutics 108(1994)207-212),由微晶纤维素Avicel PH-101和PEG-40氢化蓖麻油制备丸剂。这些组合物含有7-21%的氢化蓖麻油和颗粒尺寸相当小的微晶纤维素,并需经制粒、压制成形和球化而获得丸剂。PCT专利申请WO 94/23700也披露了含有Avicel PH-101的组合物。I.Ullah等(Pharmaceutical Techology,1987年9月,48-54)和C-M Chen等(Drug Development and In-dustrial Pharmacy,16(3),1990,379-394)披露了另一种需经制粒的方法。根据这些方法通过将药物和一干粘合剂(如能将残存水分吸收的微晶纤维素)混合而获得一种湿活性化干制粒法。EP598,337披露了含有具备水膨胀性但非水溶性的交联的聚合物和油的药物组合物。但这些组合物的流动性不充分。
本发明提出一种用于获得载药载体颗粒的溶液,无需经制粒步骤,即采用一种固体药物组合物,该组合物含有重量比低于7%的油或油性物质,小剂量的活性组份及一种不溶于水的,不交联的聚合赋形剂,该赋形剂能与水结合,平均颗粒尺寸大于150μm。
将能与水结合的,不溶于水的,不交联的聚合物赋形剂为加入剂量单元中以提高该混合物和生成的剂量单元的的体积的稀释剂。本发明的优选稀释剂为具有吸水性能的载体材料,用于混合含有溶解或分散的小剂量活性组份的乳化体或油相。优选的载体材料为不溶于水的纤维素或淀粉,如非晶或微晶纤维素或附聚淀粉,或其混合物。载体材料的平均颗粒尺寸大于150μm(微米),优选至少180μm。载体材料由典型组成为重量百分比20-99%的所得药物组合物制成,该组合物含有除可与水结合的载体材料之外的任何适用的药物活性辅料。辅料包括填充剂,稀释剂,崩解剂,粘合剂,着色剂,润滑剂,及其类似物质。优选的可与水结合的,不溶于水的,不交联的聚合物赋形剂为适于商业用途的Avicel PH-200。
含有活性组份的油或油性物质的优选溶点低于40℃。优选的药物组合物含有重量为0.005-5%剂量的活性组份。
活性组份可为任何活性组份,优选甾族化合物。优选的甾族制剂由孕激素、雌激素和其混合物中选出。更优选的孕激素是从甲烯甲炔诺,3-酮-甲烯甲炔诺Org 30659(17α-17-羟基-11-亚甲基-19降孕-4,15-二烯-20-炔-3-酮),左旋甲基炔诺酮和孕二烯酮中选出的,雌激素是从乙炔雌二醇(EE),雌二醇和炔雌甲醚中选出的。通常使用孕激素和雌激素的混合物。最优选片剂含有甲烯甲炔诺或乙炔雌二醇或其混合物。其它适用的活性组份例如有左旋甲状腺氨酶,甲状腺素,洋地黄毒甙和地高辛。
用于使孕激素和雌激素溶解或悬浮的油类可源自天然、半合成或全合成。来自植物的固定油类主要含有(混有)甘油酯类。例如花生油,蓖麻油,芝麻油,分馏椰子油(饱和植物脂肪酸甘油酯),油酸乙酯,玉米油,Gelucire(部分甘油酯和聚缩甘油脂肪酸),及其类似物质。其它适用的液相为液体石蜡,二甲基硅油,甘油三乙酸酯,单-或双-甘油酯和聚乙二醇的酯类,丙二醇,聚甘油,甘油,或甘油基。油或油性物质含量的典型组成为低于用于片剂或胶囊的混合物重量的7%,优选低于4%,更成选为从0.1至4%。活性化合物亦可含于油性物质和水中。乳化体为该类混合物一例。如油含量为0%(即组合物中不含油),优选使用活性组合物的水溶液或分散体。可应用已知的技术和成份制备含有活性化合物,油,油性物质和任选水的适用的混合物。乳化剂可为增粘剂类如糖,聚乙二醇,明胶,羟丙基纤维素(HPC),支链淀粉,淀粉,羧甲基纤维素(CMC),羟丙基甲基纤维素(HPMC),聚乙烯吡咯烷酮,树胶类如阿拉伯树胶和瓜耳胶,纤维素骨架和淀粉骨架的材料,及其类似物质。用于稳定乳化体的还有具有离子源性质的乳化剂(十二烷基硫酸钠,二辛基磺基琥珀酸钠,溴代十六烷基三甲基鎓)和具有非离子源性的乳化剂〔甘油单硬脂酸酯,甘油单油酸酯,脱水山梨醇单硬脂酸酯(Span类),聚氧乙烯脱水山梨醇单硬脂酸醚(Tween类,聚山梨酸酯),PEG-脂肪酸酯(如硬脂酸-50-聚烃氧基酯),PEG-脂肪醇醚(Cetomacrogol类)及其类似物质〕。
此处可以避免液相(含活性化合物)的组合物和组分浓缩物在搅拌中与载体材料的附聚过程。例如通过加入高浓缩的增粘乳化剂造成的附聚会引起混合物流动性不够理想。因此应当避免任何附聚反应。能与水结合的,不溶于水的聚合物赋形剂和所应用水的数量之比优选应高于5∶1,更优选高于10∶1,这样一方面为了避免流动性的减弱,另一方面避免了干燥步骤。能改善流动性的材料属于助流剂,例如,在配方中加入二氧化硅,十二烷硫酸镁,氧化镁可降低微粒间的摩擦并可减少在压片过程中材料从较大孔隙向较小孔隙流动所产生的问题。含有孕激素的组合物可进一步含有着色剂,崩解剂,润滑剂,可改善药物释放特性的赋形剂和其它添加剂。
本发明制备固体药物组合物的方法的特点在于可将小剂量的活性组份溶解或分散于油或油性物质中,水分散体中,或水中,然后与可与水结合的,不溶于水的,不交联的聚合物赋形剂混合,该赋形剂的平均颗粒尺寸大于150μm。其后该固体药物组合物可与更多的能与水结合的,不溶于水的,不交联的聚合物赋形剂或其它任何适宜的药物活性辅料进行任意混合,则所得的固体组合物可被任意压制成片剂或填充入胶囊。
本发明中制备方法的优点在于其简单和安全。活性物质优选地悬浮、分散、乳化或溶解于油或油性物质中,然后用混合器将该液体与可与水结合的,不溶于水的,不交联的聚合物赋形剂相混合。未必需干燥。可任意加入助流剂以改善流动性,如加入氧化硅。通常混合液未必需加入润滑剂,可直接用于压制片剂或制造胶囊。未必需经用于改善流动性的制粒步骤或通过降低分离改善均匀性的步骤。
本发明中的组合物具有各种超过现有组合物的优点,即,过程简单,无需制粒,附聚,干燥和与润滑剂混合;以及过程安全,无需有机溶剂;并且该过程可在封闭体系中进行。本发明药物组合物中的活性组份的稳定性及含量均匀性为良好到优秀。
可根据一般已知的工艺制备片剂和胶囊,例如Gennaro等的参考书,Remington′s Pharmaceutical Sciences,(第18版,MackPublising Company,1990,特别参考第8部分:药物制剂及其制造)。
通过以下实施例对发明进行进一步说明:
实施例1
将活性组份制成均一混合物(重量/片)甲烯甲炔诺 150μg乙烯雌二醇(EE) 30μgMiglyol 812 1.3μg水 3.68μgAvicelPH-200 58.99mg甲基纤维素MHB-50 0.07mg二氧化硅 0.81mg
活性组份悬浮于Miglyol(饱和植物脂肪酸三酸甘油酯)中。然后用Ultra Turrax混合器将该油与甲基纤维素的水溶液混合5分钟。在高剪切混合器(Gral 10)中将该乳化体与微晶纤维素Avicel PH-200-同进行均质以制备用于直接压片的混合物。加入胶状二氧化硅,在Turbula混合器中混合10分钟。用Korsch PH106旋转式压片机压制出重65mg的片剂。
实施例2
由微晶纤维素与甲烯甲炔诺和EE按照实施例1中描述的方法制备的混合物,所应用的乳化剂含下列组份(重/片):
用于乳化体的(每片)克数 | |
Mtglyol 812花生油 oil芝麻油羧甲基纤维素-钠甲基纤维素MHB-50司盘-80吐温-80阿拉伯树胶水 | 1 2 3 4 5 6 7 8 9 10 111.30 1.30 - - - - - - - 1.30 -- - 1.30 1.30 1.30 - - - - - 1.30- - - - - 1.30 1.30 1.30 1.30 - -0.04 - 0.04 - - 0.04 - - - - -- - - 0.07 - - 0.07 - - - -- 0.13 - - 0.13 - - 0.13 - - -- 0.13 - - 0.13 - - 0.13 - - -- - - - - - - - 0.2 0.2 0.23.66 3.46 3.68 3.66 3.46 3.68 3.66 3.46 3.53 3.53 3.53 |
混入胶状二氧化硅之后将该混合物压片。
实施例3
将活性组份制成均一混合物,含有下列组合物(每片):Org OD-14 0.3mgMiglyol 812 1.3mgAvicel PH-200 63.4mg
将活性化合物Org OD-14〔(7α,17α)-17-羟基-7-甲基-19-去孕-17-孕-5(10)-烯-20-炔-3-酮〕与油混合。然后在Gral 10高剪切混合器中将该油相与全部微晶纤维素一起均质化。将最终混合物压制成每片重65mg的片剂。
实施例4
用以下组合物按实施例1中描述的方法制备片剂:Org 30659 60μgEE 20μgMiglyol 812 1.3μg甲基纤维素MHB-50 0.02mg水 1.20mgAvicel PH-200 61.75mgμg二氧化硅 0.65mgμg
实施例5
将活性组份制成均一混合物(重/片):甲烯甲炔诺 150μg乙炔雌二醇(EE) 30μg羟丙基纤维素(HPC) 150μg水 4.95mgPrimojel(淀粉羟乙酸钠) 2.65mgAvicel PH-200 57.06mg
将HPC溶解于水中制成3%的HPC溶液。在Ultra Turrax混合器中经5分钟混合使活性组份悬浮于该溶液中。在高剪切混合(Gral10)器中将甲烯甲炔诺/EE的悬浮体与微晶纤维素Avicel PH-200和Primojel-同均质化,制备用于直接压片的混合物。在Ko-rsch PH106旋转式压片机中压制成每片重65mg的片剂。实施例6
将活性组份制成均一混合物(重/片)甲烯甲炔诺 150μg乙炔雌二醇(EE) 30μg羟丙基纤维素(HPC) 150μgGelucire35/10 2.44mg水 2.44mg十二烷基硫酸钠(SLS) 0.32mgAvicel PH-200 58.67mg二氧化硅 0.81mg
将Gelucire加热至50℃,然后使活性组份悬浮其中。用UltraTurrax将该混合物与HPC溶液混合5分钟。在高剪切混合器(Gral10)中将甲烯甲炔诺/EE的乳化体微晶纤维素PH-200和SLS-同均质化,制备用于直接压片的混合物。加入胶状二氧化硅,在Erweda混合器中混合1分钟。在Korsch PH106旋转式压片机中压制成每片重65mg的片剂。
实施例7
按照实施例1中描述的组合物和步骤制备片剂。将含有150μg甲烯甲炔诺(未包衣片)和60μg Org30659(包衣片)的两组片剂进行比较。片剂须经加速保存条件。其稳定性的结果见下表(RH=相对湿度)。
保存3个月后的甲烯甲 保存1个月后的Org炔诺% 30659(%) |
40℃/50%相对湿度 - 97.840℃/外界 98.9 -40℃/75%RH 100.0 97.350℃/75%RH 100.4 - |
结果表明,在加速保存条件下,片剂中的两种孕激素均具有良好的稳定性。
实施例8
将含有本发明中可与水结合的,不溶于水的,不交联的聚合物赋形剂(Avicel PH-200)的组合物,与一含有可与水结合的,不溶于水的,平均粒径小于150μm的不交联的聚合物赋形剂(Avicel PH-102)的组合物,及与含有EP598,337中提到的可与水结合的,不溶于水的,交联的聚合物赋形剂(交联聚乙烯吡啶酮)的组合物进行比较,每种组合物含有或不含油相(miglyol):组合物 (量:克)
*羟丙基纤维素#交联聚乙烯吡啶酮
饱和植物脂肪酸组合物二酸甘油脂) | HPC* | 水 | AvicelPH-200 | 总量mass | |
812 | |||||
A | 0 | 0.5 | 15.5 | 183.8 | 200 |
B | 4.0 | 0.4 | 11.6 | 183.8 | 200 |
组合物 | miglyol812 | HPC* | 水 | AvicelPH-102 | 总量mass |
C | 0 | 0.5 | 15.5 | 183.8 | 200 |
D | 4.0 | 0.4 | 11.6 | 183.8 | 200 |
组合物 | miglyol812 | HPC* | 水 | Polyplas-doneXL 10# | 总量mass |
E | 0 | 0.2 | 7.8 | 92.0 | 100 |
F | 2.0 | 0.2 | 5.8 | 92.0 | 100 |
通过测定每秒流经漏斗的该组合物的克数可测定出其流动性,漏斗的直径为9.0mm。组合物B,D,和F为8%的乳化体(2%miglyol),组合物A,C和E为8%的HPC溶液:
组合物 | 流动性克/秒g/s |
AB | 2.971.49 |
CD | 00 |
EF | 00 |
Claims (8)
1.一种固体药物组合物,该组合物含有:重量百分比低于7%的油或油性物质,0.005-5%重量的甾族化合物作为活性组份,及一可与水结合的,不溶于水的,不交联的聚合物赋形剂,该赋形剂的平均颗粒尺寸大于150μm。
2.权利要求1中的固体药物组合物,其含有重量百分比低于4%的油或油性物质。
3.权利要求1或2中的固体药物组合物,其所含油或油性物质的熔点低于40℃。
4.权利要求1或2中的任一固体药物组合物,其含有可与水结合的,不溶于水的,不交联的聚合物赋形剂,该赋形剂的平均颗粒尺寸至少为180μm。
5.权利要求1或2中的任一固体药物组合物,其所含的可与水结合的,不溶于水的,不交联的聚合物赋形剂为纤维素或淀粉。
6.权利要求1或2中的任一固体药物组合物,其所含的活性组份为甲烯甲炔诺,乙炔雌二醇,或其混合物。
7.权利要求1-6中的任一固体药物组合物的制备方法,其特征为,将小剂量的活性组份溶解或分散于油或油性物质中,其水分散体中,或水中,然后与一可与水结合的,不溶于水的,不交联的聚合物赋形剂混合,该赋形剂的平均颗粒尺寸大于150μm,其后该固体药物组合物可与更多的可与水结合的,不溶于水的,不交联的聚合物赋形剂或其他活性的药物辅料进行任意混合,然后所得的固体组合物可被任意压制成片或填充入胶囊。
8.权利要求7中的方法,其中所含可与水结合的,不溶于水的,不交联的聚合物赋形剂与过程中引入的水量的选择为大于5∶1。
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EP94203017 | 1994-10-17 | ||
EP94203017.2 | 1994-10-17 |
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CN1130064A CN1130064A (zh) | 1996-09-04 |
CN1112185C true CN1112185C (zh) | 2003-06-25 |
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US (1) | US6187339B1 (zh) |
EP (1) | EP0707848B1 (zh) |
JP (1) | JPH08268914A (zh) |
KR (1) | KR100388932B1 (zh) |
CN (1) | CN1112185C (zh) |
AT (1) | ATE211647T1 (zh) |
AU (1) | AU688581B2 (zh) |
BR (1) | BR9504400A (zh) |
CA (1) | CA2159419C (zh) |
DE (1) | DE69524917T2 (zh) |
DK (1) | DK0707848T3 (zh) |
ES (1) | ES2171498T3 (zh) |
FI (1) | FI117121B (zh) |
HK (1) | HK1001886A1 (zh) |
HU (1) | HU221427B (zh) |
IL (1) | IL115445A (zh) |
MX (1) | MX9504252A (zh) |
PT (1) | PT707848E (zh) |
RU (1) | RU2152802C2 (zh) |
TR (1) | TR199501246A2 (zh) |
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- 1995-10-13 EP EP95202770A patent/EP0707848B1/en not_active Expired - Lifetime
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- 1995-10-16 AU AU34267/95A patent/AU688581B2/en not_active Ceased
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EP0598337A2 (en) * | 1992-11-13 | 1994-05-25 | VECTORPHARMA INTERNATIONAL S.p.A. | Pharmaceutical compositions including a drug, a cross-linked polymeric substance, an oil, and a surface active agent |
Also Published As
Publication number | Publication date |
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HUT75247A (en) | 1997-05-28 |
DE69524917D1 (de) | 2002-02-14 |
DE69524917T2 (de) | 2002-08-29 |
FI954905A0 (fi) | 1995-10-16 |
EP0707848B1 (en) | 2002-01-09 |
AU3426795A (en) | 1996-05-02 |
ES2171498T3 (es) | 2002-09-16 |
HU9502985D0 (en) | 1995-12-28 |
KR960013373A (ko) | 1996-05-22 |
JPH08268914A (ja) | 1996-10-15 |
AU688581B2 (en) | 1998-03-12 |
HU221427B (en) | 2002-10-28 |
US6187339B1 (en) | 2001-02-13 |
DK0707848T3 (da) | 2002-04-15 |
HK1001886A1 (en) | 1998-07-17 |
IL115445A0 (en) | 1995-12-31 |
BR9504400A (pt) | 1997-05-27 |
ATE211647T1 (de) | 2002-01-15 |
KR100388932B1 (ko) | 2003-09-19 |
CA2159419C (en) | 2006-07-04 |
FI117121B (fi) | 2006-06-30 |
CN1130064A (zh) | 1996-09-04 |
PT707848E (pt) | 2002-06-28 |
RU2152802C2 (ru) | 2000-07-20 |
EP0707848A1 (en) | 1996-04-24 |
FI954905A (fi) | 1996-04-18 |
TR199501246A2 (tr) | 1996-06-21 |
IL115445A (en) | 1999-08-17 |
MX9504252A (es) | 1997-01-31 |
CA2159419A1 (en) | 1996-04-18 |
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