CN85101689A - 硝苯吡啶制剂及其制备方法 - Google Patents
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- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- General Health & Medical Sciences (AREA)
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Abstract
本发明涉及新的具有改善了生物利用率的固体硝苯吡啶制剂。该制剂按重量比含有1份硝苯吡啶和1.0—20份，最好是2.0—15份的易溶于水的填料和适量的其他惯用的辅助剂和赋形剂。
Description
本发明涉及新的具有改善了生物利用率的固体硝苯吡啶制剂。该制剂含有硝苯吡啶和易溶的填料，也涉及其制备的方法和作为药剂的使用。尤其可用作冠状动脉和血压的药剂。
已经公开了硝苯吡啶对血液循环具有很强的效应（参阅英国专利1173862）。由于硝苯吡啶的溶解度很小在医药产品的药物制剂中引起许多困难。这在对这些活性化合物的专门配方的许多专利和专利申请中是明显的。例如美国专利3784684论及含有硝苯吡啶的专门可吞食的明胶胶囊，用该胶囊能更有利地使用硝苯吡啶对冠状动脉血栓的作用。再者，英国专利1456618对同样说到确有好的硝苯吡啶生物利用率的固体约用制剂进行了描述并提出了权利要求。而且DT-OS（德国公开说明书）2822882描述了固体剂型。讲到用某些加溶剂和表面活性剂补偿了该活性化合物的微溶性。此外，在欧洲公开说明书（1247）讲到用聚乙二醇和某些多孔载体改善二羟基吡啶的可吸收的能力。
同样，在文献中描述了各种方法以改善生物利用率，该利用率直接与改善溶解度有关。除了化学结构上的改变，例如引入改善溶解度的取代基，还描述了许多涉及改善活性化合物物理性质的方法。例如，提出了减少活性化合物的颗粒度，改变晶体结构。制成盐的形式，加入湿润剂。与其他物质结合，使用生物载体，形成固体分散体（共沉淀）或制备表面被吸附物〔参阅S.H.耶尔考夫斯基：药物和制剂科学（S.H.Yalkowskay.Drugs and the pharmaceutical science），12，135-180（1981）;和J.波尔德门：配方和剂型的制备，埃尔西维亚/北荷兰：生物药物出版社，1977.215-219页（J.Poldermann：Furmulation and preperation of dosage forms，Elsever/North-Holland Biomedical press，1977.215-219）〕。
迄今，用特殊措施以补偿硝苯吡啶的低溶解度以及同时确保有好的生物利用率的一切尝试都有许多缺点。使用表面活性物质，加溶剂和某些具有特殊表面的载体，例如多孔性的，往往会导致该制剂相当大量的给药方式，为便于吞嚥这种类型的片剂或胶囊往往要制成例如椭球形或长椭球形的特殊形式。但是在制剂重量大于400毫克时，也不是总能达到令人满意的结果。也不是更经常地服用较小的制剂能满意解决的。
本发明涉及新的具有改善生物利用率的固体硝苯吡啶制剂，按重量比，该制剂含有1分硝苯吡啶和1.0-20分，最好是2.0-15分易于溶解的填料，和适当的其他惯用辅助剂和赋形剂。
特别有兴趣的是，按本发明的硝苯吡啶制剂含有以下物质作为易溶于水的填料。例如乳糖、蔗糖、果糖、葡萄糖、甘露醇或山梨醇这样的糖或糖醇;和（或）诸如镁、钙、钾、钠或铵盐这类的盐;也可以是阴离子：例如氯化物、碳酸盐、柠檬酸盐、酒石酸盐、乳酸盐、乙酸盐或碳氢酸盐。
生理学上可接受的，在25℃时，溶解度至少每100毫升水为15克，最好是每100毫升水为20克的一切物质均可用作易溶于水的填料。
特别可以提到的是甘露醇、乳糖、氯化钠和柠檬酸钾。
按本发明的制剂是将硝苯吡啶和易溶于水的填料一起粒化，需要时再将颗粒压成片剂进行制备的。
按本发明所用的硝苯吡啶最好是用结构式Ⅱ：
的叉化合物与通式Ⅲ
的烯胺化合物在具有1-4个碳原子的低级醇中，在40-100℃的温度时反应而制备的。
一种可取的不同方法，是用共沸蒸馏法除去反应中的水，化合物Ⅱ和Ⅲ可以用等摩尔量的，也可以用稍过量的烯胺化合物Ⅲ。
叉化合物Ⅱ是用等摩尔量的酮羧酸酯与O-硝基苯甲醛在有1-4个碳原子的低级醇作溶剂并有催化剂量的哌啶乙酸盐存在时，在温度为20到60℃之间时进行反应而制得的。式Ⅲ的烯胺化合物是由酮羧酸酯与氨在低级醇（1-4个碳原子），最好是异丙醇中，温度在0-40℃之间时反应而制得的。反应剂氨也能用水溶液状态的氨。
从现有技术来看，很意外的是，在将硝苯吡啶与上述提及的易溶于水的填料一起粒化时，释放可以大大的增加，这样在生物利用率方面就会有效的改善。这效果不取决于外加辅助剂的存在，按照现有技术的知识，这些辅助剂，例如配位剂或表面活性剂是增加释放的速率。
在释放试验中，在以下的条件下使用美国药典的搅槽法进行（USP paddle method）
900毫升0.1N的盐酸
搅拌转动是100转/分
按本发明的制剂（例1的产品）在一小时后，硝苯吡啶的释放率达到100%。常规硝苯吡啶片相应的制剂。其中所用的硝苯吡啶是相同的晶体结构。并含有相同的辅助剂，一小时后释放率只有43%。从表1看到的释放的改进是明显的。
表1
从含有硝苯吡啶药片的体外释放
（美国药典搅槽法）
释放时间 以所用剂量的百分比表示硝苯吡啶的累积
〔小时〕 例1的药片 对照例的药片
0.25 95% 18%
0.5 100% 30%
1 100% 43%
对照例：
100克硝苯吡啶，2080克玉米淀粉，1150克粉状纤维素和50克乳糖在行星式搅拌机中搅拌5分钟，用聚乙烯基吡咯烷酮/吐温80的水溶液（固体含量为200克/5克）粒化15分钟。潮湿的组合物通过粗锉（内嵌有φ2.0毫米的筛网）并在流化床干燥器中干燥到最后水含量约为5%。
干燥的颗粒过筛（1.0毫米筛孔的筛网）使之均匀，并与15克硬脂酸镁剧烈搅拌。然后将颗粒压成重360毫克的片剂。
实施例
例1
100克硝苯吡啶，1580克玉米淀粉，1400克乳糖和300克粉状纤维素在行星式搅拌机中搅拌5分钟。用聚乙烯基吡咯烷酮/吐温80的水溶液（固体含量为200克/5克）粒化15分钟。潮湿的组合物通过粗锉（内嵌有φ2.0毫米的筛网），并在流化床干燥器中干燥到最后的水含量约为4.5%。干燥的颗粒过筛（1.0毫米筛孔的筛网）使之均匀，并与15克硬脂酸镁剧烈搅拌。然后将颗粒压制成重360毫米的片剂，片剂可用保护衣包裹。
例2
200克硝苯吡啶，3160克玉米淀粉，1800克乳糖和700克粉状纤维素在流化床成粒机（Glatt WSG5）中加热，先用十二烷基硫酸钠的水溶液（含量10克）喷洒。然后粉末用羟基丙基甲基纤维素的水溶液（含有400克）粒化并干燥到最后水含量约为4.5%，过筛（筛孔为φ0.8毫米）并与20克硬脂酸镁在立方混合器中混合。将要压制的颗粒加工成重314.5毫克的片剂，并用不透明的胶膜在Accela包衣机中包衣。
例3
1000克甘露醇，400克硝苯吡啶，600克粉状纤维素和40克十二烷基硫酸钠在搅拌成粒机（例如LOEdige MGT30）中搅拌1分钟，用淀粉糊（淀粉含量为200克）在成粒机中粒化5分钟，转子的速度为200转/分。用Ⅱ型切碎机装置（chopper settingⅡ）得到约200-300微米的平均粒度，颗粒通过粗锉（内嵌有筛网φ2.0毫米）并在流化床干燥器中（例如Glatt WST5）干燥到最后水含量约为4.0%。干燥的颗粒与100克硬脂酸镁在混合器中混合10分钟，然后压制成具有平均直径9毫米，重约237毫克的片剂。
生产的片剂可以再用不透明的胶膜层包衣，该膜层含有，例如红色氧化铁作光保护层。
例4
500克乳糖，200克硝苯吡啶，450克粉状纤维素，400克玉米淀粉，650克碳酸钙，20克吐温80和50克硬脂酸镁在立方混合器中混合，然后干压（Alexander WP50磨;压榨压力为35巴），片状物先压碎，再用1.25毫米的筛网使颗粒均匀，并与25克硬脂酸镁和200克玉米淀粉均匀混和，制成的颗粒压成重250毫克并具有直径9毫米的片剂。
得到的片剂能直接使用，也可以外包一层保护衣，该保护衣由羟基丙基甲基纤维素，聚乙二醇和氧化铁或生理上允许的其他色素或有色胶膜。
例5
750克甘露醇，300克硝苯吡啶，855克玉米淀粉，975克碳酸镁，150克予先转化成糊状的玉米淀粉和600克粉状纤维素在行星式搅拌机（Collette MP20）中搅拌8分钟，在继续加入250毫升2.0%浓度的十二烷基硫酸钠水溶液后，随着搅拌速度的增大粒化15分钟。湿润的组合物进行磨锉。在流化床干燥器中干燥到最后水含量约3.8%并过筛1筛孔为1.0毫米）使之均匀。在75克硬脂酸镁中混合后得到最后的混合物，压制成重247毫米的片剂。
所得片剂可以包上不透日光的包衣，当然这种颗粒也能装入硬的明胶胶囊中。
Claims (9)
1、具有改善生物利用率的固体硝苯吡啶制剂，该制剂按重量比含有1分硝苯吡啶和1.0-20分易溶于水的填料和适量的惯用辅助剂和赋形剂。
2、按权利要求1的硝苯吡啶制剂，按重量比含有2-15分易溶于水的填料。
3、按权利要求1-2的硝苯吡啶制剂，含有作为水溶性填料的乳糖（或）甘露醇。
4、按权利要求1-3的硝苯吡啶制剂，是颗粒状的。
5、按权利要求1-3的硝苯吡啶制剂，是成片剂，涂层片剂或包衣片剂形式的。
6、按权利要求1的硝苯吡啶制剂的制备方法，其特征在于，按重量比，1分硝苯吡啶和1.0-20分的易溶于水的填料和适量的辅助剂和赋形剂一起粒化，这些颗粒进一步加工成惯常服用的型式。
7、按权利要求6的方法，其特征在于，按重量比1分硝苯吡啶与2-15分易溶填料，和淀粉，纤维素以及适量的其他惯用的辅助剂一起在成粒机中进行水相粒化。生产的颗粒也加工成惯常的服用型式。
8、按权利要求1的制剂制备方法，其特征在于，结构式Ⅱ
的叉化合物与结构式Ⅲ
的烯胺化合物在有低级醇（1-4个碳原子），最好是异丙醇，作溶剂时，温度在0-40℃之间时进行反应，制得的硝苯吡啶按权利要求6加工成合适的服用型式。
9、按权利要求1的硝苯吡啶制剂，可作为防治血液循环失调的用途。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843419129 DE3419129A1 (de) | 1984-05-23 | 1984-05-23 | Nifedipinpraeparate und verfahren zu ihrer herstellung |
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| CN85101689A true CN85101689A (zh) | 1987-01-24 |
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| CN198585101689A Pending CN85101689A (zh) | 1984-05-23 | 1985-04-01 | 硝苯吡啶制剂及其制备方法 |
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| Country | Link |
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| EP (1) | EP0164587A3 (zh) |
| JP (1) | JPS60255736A (zh) |
| KR (1) | KR850008280A (zh) |
| CN (1) | CN85101689A (zh) |
| AU (1) | AU4280885A (zh) |
| DD (1) | DD236453A5 (zh) |
| DE (1) | DE3419129A1 (zh) |
| DK (1) | DK228185A (zh) |
| ES (1) | ES8607016A1 (zh) |
| GR (1) | GR851246B (zh) |
| HU (1) | HUT38253A (zh) |
| IL (1) | IL75241A0 (zh) |
| PT (1) | PT80499B (zh) |
| ZA (1) | ZA853875B (zh) |
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| DE3419131A1 (de) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Dihydropyridinkombinationspraeparate und verfahren zu ihrer herstellung |
| SE457326B (sv) * | 1986-02-14 | 1988-12-19 | Lejus Medical Ab | Foerfarande foer framstaellning av en snabbt soenderfallande kaerna innehaallande bl a mikrokristallin cellulosa |
| DE3639073A1 (de) * | 1986-11-14 | 1988-05-26 | Klinge Co Chem Pharm Fab | Feste arzneizubereitungen und verfahren zu ihrer herstellung |
| DE627218T1 (de) * | 1992-02-18 | 1995-08-24 | Nippon Shinyaku Co Ltd | Schnelllösliche tablette. |
| US6440457B1 (en) | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
| JPH09208458A (ja) * | 1996-02-02 | 1997-08-12 | Ss Pharmaceut Co Ltd | 不快な味がマスキングされた製剤 |
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| DE1670827C3 (de) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4-(2'-Nitrophenyl)-2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridin |
| SU432703A3 (zh) * | 1971-08-24 | 1974-06-15 | Фридрих Боссерт, Вульф Фатер, Курт Бауер | |
| DE2400819C2 (de) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Verfahren zur Herstellung fester Zubereitungen von schwerlöslichen Arzneimittelwirkstoffen in feinster Verteilung |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
| JPS5785316A (en) * | 1980-11-14 | 1982-05-28 | Kanebo Ltd | Preparation of easily absorbable nifedipine preparation |
| FI72874B (fi) * | 1983-04-12 | 1987-04-30 | Orion Yhtymae Oy | Foerfarande foer framstaellning av laett absorberbar oral doseringsform av laekemedel av nifedipin. |
-
1984
- 1984-05-23 DE DE19843419129 patent/DE3419129A1/de not_active Withdrawn
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1985
- 1985-04-01 CN CN198585101689A patent/CN85101689A/zh active Pending
- 1985-05-11 EP EP85105797A patent/EP0164587A3/de not_active Withdrawn
- 1985-05-20 JP JP60106214A patent/JPS60255736A/ja active Pending
- 1985-05-20 IL IL75241A patent/IL75241A0/xx unknown
- 1985-05-21 ES ES543350A patent/ES8607016A1/es not_active Expired
- 1985-05-21 GR GR851246A patent/GR851246B/el unknown
- 1985-05-21 DD DD85276558A patent/DD236453A5/de unknown
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- 1985-05-22 ZA ZA853875A patent/ZA853875B/xx unknown
- 1985-05-22 KR KR1019850003502A patent/KR850008280A/ko not_active IP Right Cessation
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| Publication number | Publication date |
|---|---|
| DK228185D0 (da) | 1985-05-22 |
| PT80499B (en) | 1987-04-21 |
| AU4280885A (en) | 1985-11-28 |
| ES543350A0 (es) | 1986-06-01 |
| EP0164587A3 (de) | 1986-03-19 |
| IL75241A0 (en) | 1985-09-29 |
| DE3419129A1 (de) | 1985-11-28 |
| GR851246B (zh) | 1985-11-25 |
| DD236453A5 (de) | 1986-06-11 |
| ES8607016A1 (es) | 1986-06-01 |
| ZA853875B (en) | 1986-01-29 |
| PT80499A (en) | 1985-06-01 |
| KR850008280A (ko) | 1985-12-16 |
| HUT38253A (en) | 1986-05-28 |
| JPS60255736A (ja) | 1985-12-17 |
| EP0164587A2 (de) | 1985-12-18 |
| DK228185A (da) | 1985-11-24 |
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