CN1305381A - 环磷酰胺包衣片剂 - Google Patents
环磷酰胺包衣片剂 Download PDFInfo
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- CN1305381A CN1305381A CN99807433A CN99807433A CN1305381A CN 1305381 A CN1305381 A CN 1305381A CN 99807433 A CN99807433 A CN 99807433A CN 99807433 A CN99807433 A CN 99807433A CN 1305381 A CN1305381 A CN 1305381A
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- cyclophosphamide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及以环磷酰胺作为活性化合物的包衣片剂,其中在片芯中包含环磷酰胺、一种或多种填充剂、一种或多种干燥粘合剂但不是预膨胀淀粉、流动调节剂和润滑剂。在本发明优选的实施方案中,该膜片剂的片芯包含乳糖一水合物、D-甘露醇或CaHPO4作为填充剂,非预膨胀玉米淀粉或超细纤维素作为干燥粘合剂,包含高分散二氧化硅作为流动调节剂,和硬脂酸镁、硬脂酸、棕榈酸硬脂酸甘油酯、聚乙二醇、滑石或单山萮酸甘油酯作为润滑剂。
Description
本发明涉及环磷酰胺膜包衣片剂及其制备方法。本发明可用于药物工业。
环磷酰胺是具有很广抗肿瘤谱的治疗剂,并且已在化疗中使用了几十年来治疗实体瘤例如乳腺癌、支气管癌和生血组织增殖。
迄今为止,已知的药物制剂是使用各种辅料例如甘露醇或尿素的片剂、包衣片剂、以及冻干制剂。
EP0519099中描述了通过直接制片法制备的、包含环磷酰胺和预膨胀淀粉的片剂。
因为环磷酰胺有害健康,所以出于该原因,与环磷酰胺直接接触有潜在危险,依据EP0519099制备的片剂是用作压制包衣片的片芯,并由此通过第二制片技术来包衣。该操作在技术上是复杂的。此外还需要特殊制片机械来制备压制包衣片剂。
因此需要简单且经济的制备包含环磷酰胺的口服固体药物剂型的方法。
其中需要考虑,为了防止与该细胞毒活性化合物直接接触,必须将药物剂型包衣。
此外还已知环磷酰胺在化学上是不稳定的,因此还必须考虑药物剂型的稳定性。
令人惊奇的是,不使用预膨胀淀粉也能制备包含环磷酰胺的膜包衣片剂。
合适的辅料是以在实施例1中提及的相容性研究为基础选择的。在该研究中惊奇地发现,在预膨胀淀粉存在下、环磷酰胺的稳定性没有什么差异。
此外还令人惊奇的是,尽管由于制备操作,该活性化合物在包衣过程中受到水分和热的影响,但是膜包衣片剂成品仍具有足够的稳定性。
实施例1研究环磷酰胺与不同制片辅料的相容性。
将53.5mg环磷酰胺与86.5mg(辅料1-10)或3.0mg(辅料11-18)混合并压片。将压制片在31℃贮存6个月。通过氯化物测定来评价活性化合物的降解。
所得结果总结在下表中。
辅料功能 | 辅料 | 环磷酰胺降解 | 褪色 | |
填充剂 | 1 | 无水乳糖 | 2.52 | ++ |
2 | 磷酸钙 | 3.85 | - | |
3 | 无水磷酸钙 | 2.02 | - | |
4 | Emcompress(CaHPO4) | 1.50 | ||
5 | D-甘露醇 | 1.15 | - | |
6 | 乳糖一水合物 | 0.70 | - | |
填充剂/干燥粘合剂/崩解促进剂 | 7 | 微晶纤维素 | 1.50-1.73* | - |
8 | 纤维素(Elcema) | 0.85-1.32* | -+ | |
9 | 预膨胀淀粉 | 1.02 | -+ | |
10 | 玉米淀粉 | 0.75 | - | |
崩解促进剂 | 11 | 交联聚乙烯吡咯烷酮 | 1.5 | ++ |
流动调节剂 | 12 | 高分散二氧化硅 | 0.46-1.72* | -+ |
流动调节剂/润滑剂 | 13 | 硬脂酸镁 | 1.51 | -+ |
14 | 硬脂酸 | 0.94 | -+ | |
15 | 棕榈酸硬脂酸甘油酯 | 0.82 | - | |
16 | 聚乙二醇 | 0.68 | - | |
17 | 滑石粉 | 0.55 | - | |
18 | 单山萮酸甘油酯 | 0.30 | - |
*根据类型实施例2制备片剂的片芯(50mg环磷酰胺)直接制片
将0.535mg环磷酰胺、0.390mg乳糖一水合物、0.400mg超细纤维素、0.200mg玉米淀粉、0.040mg滑石和0.020mg高分散二氧化硅过筛并均化。然后加入0.015mg硬脂酸镁并混合。将以这种方式制得的物质加工成片剂:重量: 160mg硬度: >30N崩解度: <10分钟
实施例3制备膜包衣片剂(50mg环磷酰胺)
将11.83g聚乙二醇和2.37g聚山梨酸酯80溶于75.21g水中。将1.9g羧甲基纤维素钠溶于80.0g水。把上述溶液混合。然后加入23.67g滑石、23.67g二氧化钛和0.24g二甲硅油(simeticone),将该混合物均化。然后加入17.73g 30%浓度的丙烯酸乙酯/异丁烯酸甲酯共聚物在水中的分散液。然后在适当装置中用所制得的悬浮液对片芯喷雾:膜包衣片剂的理论重量:166mg
实施例4确定环磷酰胺膜包衣片剂的稳定性
3个月后环磷酰胺的降解 | ||
26℃/60%RH | 31℃/40% | |
第1批 | 0.30 | 4.12 |
第2批 | 0.17 | 2.36 |
预计在低于25℃条件下贮存时该膜包衣片剂的稳定性可最高达3年。
Claims (4)
1.以环磷酰胺作为活性化合物的膜包衣片剂,其中在片芯中包含环磷酰胺、一种或多种填充剂、一种或多种干燥粘合剂但不是预膨胀淀粉、流动调节剂和润滑剂。
2.权利要求1的膜包衣片剂,其中在片芯中包含乳糖一水合物、D-甘露醇或CaHPO4作为填充剂,非预膨胀玉米淀粉或超细纤维素作为干燥粘合剂,包含高分散二氧化硅作为流动调节剂,和硬脂酸镁、硬脂酸、棕榈酸硬脂酸甘油酯、聚乙二醇、滑石或单山萮酸甘油酯作为润滑剂。
3.权利要求2的膜包衣片剂,其中的片芯可包含单独的或以任意所需混合物形式的辅料。
4.权利要求1-3任一项的膜包衣片剂,其中在片芯中包含的每份环磷酰胺与乳糖一水合物、超细纤维素、非预膨胀玉米淀粉、滑石、高分散二氧化硅和硬脂酸镁的比例如下:
乳糖一水合物 0.2-1.5,优选0.5-1,特别是0.73;
超细纤维素 0.2-1.5,优选0.5-1,特别是0.74;
非预膨胀玉米淀粉0.1-1.5,优选0.2-0.7,特别是0.37;
滑石 0.01-1.5,优选0.05-0.08,特别是0.07;
高分散二氧化硅 0.01-0.1,优选0.01-0.5, 特别是0.04;
硬脂酸镁 0.01-0.1,优选0.01-0.05,特别是0.03。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19826517.4 | 1998-06-15 | ||
DE19826517A DE19826517B4 (de) | 1998-06-15 | 1998-06-15 | Verfahren zur Herstellung von Filmtabletten mit Cyclophosphamid als Wirkstoff und daraus hergestellte Cyclophosphamid-Filmtablette |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1305381A true CN1305381A (zh) | 2001-07-25 |
CN1177590C CN1177590C (zh) | 2004-12-01 |
Family
ID=7870877
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998074330A Expired - Fee Related CN1177590C (zh) | 1998-06-15 | 1999-06-08 | 环磷酰胺包衣片剂 |
Country Status (29)
Country | Link |
---|---|
US (1) | US20010046504A1 (zh) |
EP (1) | EP1089739B1 (zh) |
JP (1) | JP4891478B2 (zh) |
KR (1) | KR100679872B1 (zh) |
CN (1) | CN1177590C (zh) |
AR (1) | AR019670A1 (zh) |
AT (1) | ATE310523T1 (zh) |
AU (1) | AU771284B2 (zh) |
BG (1) | BG65253B1 (zh) |
BR (1) | BR9911276A (zh) |
CA (1) | CA2333682C (zh) |
CO (1) | CO5070588A1 (zh) |
CZ (1) | CZ302157B6 (zh) |
DE (3) | DE19826517B4 (zh) |
DK (1) | DK1089739T3 (zh) |
ES (1) | ES2255276T3 (zh) |
HK (1) | HK1037959A1 (zh) |
HU (1) | HU226528B1 (zh) |
IL (2) | IL139944A0 (zh) |
NO (1) | NO325154B1 (zh) |
NZ (1) | NZ508888A (zh) |
PL (1) | PL193398B1 (zh) |
RU (1) | RU2236231C2 (zh) |
SK (1) | SK286185B6 (zh) |
TR (1) | TR200003702T2 (zh) |
TW (1) | TWI242450B (zh) |
UA (1) | UA75566C2 (zh) |
WO (1) | WO1999065499A1 (zh) |
ZA (1) | ZA200006998B (zh) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT500063A1 (de) | 1999-11-23 | 2005-10-15 | Sandoz Ag | Beschichtete tablettenkerne |
NZ535455A (en) | 2002-02-21 | 2009-08-28 | Biovail Lab Int Srl | Controlled release dosage forms |
DE102005008797A1 (de) * | 2005-02-25 | 2006-09-07 | Baxter International Inc., Deerfield | Trofosfamid-haltige Filmtabletten und Verfahren zu deren Herstellung |
US9452980B2 (en) | 2009-12-22 | 2016-09-27 | Hoffmann-La Roche Inc. | Substituted benzamides |
JO3659B1 (ar) * | 2010-06-02 | 2020-08-27 | Astellas Deutschland Gmbh | أشكال جرعات بينداموستين عن طريق الفم وإستخداماته العلاجية |
UA112170C2 (uk) | 2010-12-10 | 2016-08-10 | Санофі | Протипухлинна комбінація, що містить антитіло, яке специфічно розпізнає cd38, і бортезоміб |
EP2745833A1 (en) * | 2012-12-21 | 2014-06-25 | Institut Gustave Roussy | Soluble, dispersible or orodispersible tablets comprising cyclophosphamide |
EP3197438A4 (en) | 2014-09-26 | 2018-06-20 | Intas Pharmaceuticals Ltd. | Pharmaceutical composition having improved content uniformity |
KR102415797B1 (ko) | 2016-03-17 | 2022-07-04 | 에프. 호프만-라 로슈 아게 | Taar의 작용제로서 활성을 갖는 5-에틸-4-메틸-피라졸-3-카복스아미드 유도체 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5047246A (en) * | 1988-09-09 | 1991-09-10 | Bristol-Myers Company | Direct compression cyclophosphamide tablet |
US5110814A (en) * | 1989-01-11 | 1992-05-05 | Asta Pharma Ag | Azelastine and its salts used to combat psoriasis |
UA26305A (uk) * | 1990-07-16 | 1999-08-30 | Аста Медіка Аг | Таблетка, спосіб її одержаhhя, граhулят та спосіб одержаhhя граhулята |
ES2063412T3 (es) * | 1990-07-16 | 1995-01-01 | Asta Medica Ag | Tableta y granulado que contienen como principio activo mesna. |
RO113611B1 (ro) * | 1990-08-03 | 1998-09-30 | Asta Pharma Ag | Preparate solide de ifosfamida, administrate oral si procedeu de obtinere |
DE4433764A1 (de) * | 1994-09-22 | 1996-03-28 | Asta Medica Ag | Darreichungsformen enthaltend alpha-Liponsäure, feste Salze von R-Thioctsäure mit verbesserter Freisetzung und Bioverfügbarkeit |
EP0827498B1 (en) * | 1996-02-22 | 2003-06-18 | Samjin Pharmaceutical Co., Ltd. | New antiviral substituted pyrimidinedione homocarbocyclic nucleoside derivatives and methods for the preparation thereof and compositions containing the same as active ingredients |
JPH11322596A (ja) * | 1998-05-12 | 1999-11-24 | Shionogi & Co Ltd | 白金錯体および環状リン酸エステルアミドを含有する抗癌剤 |
US20040034099A1 (en) * | 2002-06-27 | 2004-02-19 | Ramsey Beverly J. | Pharmaceutical composition |
-
1998
- 1998-06-15 DE DE19826517A patent/DE19826517B4/de not_active Expired - Fee Related
-
1999
- 1999-06-08 PL PL99344832A patent/PL193398B1/pl not_active IP Right Cessation
- 1999-06-08 KR KR1020007014142A patent/KR100679872B1/ko not_active IP Right Cessation
- 1999-06-08 CZ CZ20004489A patent/CZ302157B6/cs not_active IP Right Cessation
- 1999-06-08 AT AT99927902T patent/ATE310523T1/de active
- 1999-06-08 DK DK99927902T patent/DK1089739T3/da active
- 1999-06-08 RU RU2001101903/15A patent/RU2236231C2/ru not_active IP Right Cessation
- 1999-06-08 WO PCT/EP1999/003920 patent/WO1999065499A1/de active IP Right Grant
- 1999-06-08 ES ES99927902T patent/ES2255276T3/es not_active Expired - Lifetime
- 1999-06-08 CN CNB998074330A patent/CN1177590C/zh not_active Expired - Fee Related
- 1999-06-08 AU AU45085/99A patent/AU771284B2/en not_active Ceased
- 1999-06-08 TR TR2000/03702T patent/TR200003702T2/xx unknown
- 1999-06-08 EP EP99927902A patent/EP1089739B1/de not_active Expired - Lifetime
- 1999-06-08 JP JP2000554378A patent/JP4891478B2/ja not_active Expired - Fee Related
- 1999-06-08 DE DE59912829T patent/DE59912829D1/de not_active Expired - Lifetime
- 1999-06-08 SK SK1858-2000A patent/SK286185B6/sk not_active IP Right Cessation
- 1999-06-08 HU HU0102788A patent/HU226528B1/hu not_active IP Right Cessation
- 1999-06-08 IL IL13994499A patent/IL139944A0/xx active IP Right Grant
- 1999-06-08 CA CA002333682A patent/CA2333682C/en not_active Expired - Fee Related
- 1999-06-08 NZ NZ508888A patent/NZ508888A/en not_active IP Right Cessation
- 1999-06-08 BR BR9911276-0A patent/BR9911276A/pt not_active Application Discontinuation
- 1999-06-09 TW TW088109644A patent/TWI242450B/zh not_active IP Right Cessation
- 1999-06-10 DE DE29921466U patent/DE29921466U1/de not_active Expired - Lifetime
- 1999-06-11 CO CO99036819A patent/CO5070588A1/es unknown
- 1999-06-15 AR ARP990102862A patent/AR019670A1/es not_active Application Discontinuation
- 1999-06-15 US US09/333,256 patent/US20010046504A1/en not_active Abandoned
- 1999-08-06 UA UA2001010222A patent/UA75566C2/uk unknown
-
2000
- 2000-11-27 IL IL139944A patent/IL139944A/en not_active IP Right Cessation
- 2000-11-28 ZA ZA200006998A patent/ZA200006998B/en unknown
- 2000-12-12 NO NO20006325A patent/NO325154B1/no not_active IP Right Cessation
-
2001
- 2001-01-10 BG BG105139A patent/BG65253B1/bg unknown
- 2001-11-12 HK HK01107939A patent/HK1037959A1/xx not_active IP Right Cessation
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