CN114073694A - 丁苯酞制剂及其制备方法 - Google Patents
丁苯酞制剂及其制备方法 Download PDFInfo
- Publication number
- CN114073694A CN114073694A CN202010815865.9A CN202010815865A CN114073694A CN 114073694 A CN114073694 A CN 114073694A CN 202010815865 A CN202010815865 A CN 202010815865A CN 114073694 A CN114073694 A CN 114073694A
- Authority
- CN
- China
- Prior art keywords
- butylphthalide
- preparation
- oil
- formulation
- oleic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 18
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Images
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
本发明提供一种丁苯酞制剂及其制备方法。具体而言,本发明提供了一种丁苯酞制剂,使用油酸作为增溶性辅料,使其口服生物利用度提高,减少个体间差异,降低不良反应的发生。所述制剂具有药物稳定性好,包装,运输,贮藏方便等优点,并且制备工艺简单,易于工业化生产。
Description
技术领域
本发明涉及一种丁苯酞制剂及其制备方法,具体涉及一种丁苯酞口服制剂。
背景技术
丁苯酞是芹菜籽挥发油的主要成分之一,为1.1类国产新药,是抗脑缺血药物,适用于治疗轻、中度急性缺血性脑卒中。丁苯酞可增加缺血区脑灌注、毛细血管的数量、脑血流量,改善全脑缺血的能量代谢,增强蛋白质的合成,保护各种原因导致的神经元损伤;还可减轻脑水肿、保护线粒体功能、增加抗氧化作用,从而发挥抗凋亡作用,保护损伤的脑细胞。
丁苯酞的化学名为(±)-3-丁基-1(3H)-异苯并呋喃酮,结构式如式(I)所示,为淡黄色或无色粘稠的油状物液体。
丁苯酞具有“重构微循环,增加缺血区灌注;保护微粒体,减少细胞死亡”的双重作用机制。在重构微循环方面,丁苯酞可以保护血管结构完整,增加缺血区血流量和周围微血管数量。在保护微粒体方面,可以保护线粒体结构的完整,提高线粒体ATP酶的活性,维持线粒体膜的稳定性。
目前市场上的丁苯酞口服制剂,为石药集团的“恩必普”,即为丁苯酞软胶囊,中国专利CN1623542A是石药集团的丁苯酞软胶囊专利,其中涉及丁苯酞软胶囊及其制备工艺,由丁苯酞、稀释剂植物油和囊材组成,该丁苯酞软胶囊存在口服生物利用度低的问题。
中国专利CN1726909A涉及丁苯酞自乳化释药体系及制备方法和应用,其中加入了乳化剂,例如聚氧乙烯蓖麻油、辛酸癸酸聚乙二醇甘油酯、聚氧乙烯山梨醇油酸酯等表面活性剂,而这些乳化剂均无法达到提高生物利用度的目的。
博士论文“丁苯酞的人体药代动力学研究,中国协和医科大学,叶仲凯”涉及丁苯酞软胶囊,该论文表明丁苯酞软胶囊在个体间变异系数很大,甚至有一名受试者无法测到血药浓度,而个体间的差异很容易造成个体间的有效性差异。
基于现有技术存在的丁苯酞制剂口服生物利用度低,个体间变异系数大的问题,本发明对丁苯酞制剂进行了优化,使用油酸作为增溶性辅料,提高口服给药生物利用度,减少个体间差异,减少给药量,给药次数,充分发挥制剂的药效,降低临床的不良反应。
发明内容
为了解决现有技术中的上述一个或多个问题,本发明在第一方面提供了一种丁苯酞制剂,其特征在于,所述制剂含有丁苯酞和油酸,其中丁苯酞和油酸的重量比为1:0.1-10。
本发明在第二方面提供了一种丁苯酞制剂在制备治疗脑缺血药物中的用途。
相对于现有技术,本发明至少具有如下技术效果:
(1)本发明的丁苯酞制剂的口服生物利用度有明显的提高。
(2)本发明的丁苯酞制剂能够减少个体间差异,降低不良反应的发生。
(3)本发明的丁苯酞制剂具有药物稳定性好,包装,运输,贮藏方便等优点。
(4)本发明的丁苯酞制剂制备工艺简单,易于工业化生产。
附图说明
图1为对比例4的参比制剂与本发明实施例1受试制剂药-时曲线图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合本发明实施例,对本发明的技术方案进行清楚、完整地描述。显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。
为了解决现有技术中的上述一个或多个问题,本发明在第一方面提供了一种丁苯酞制剂,其特征在于,所述制剂含有丁苯酞和油酸,其中丁苯酞和油酸的重量比为1:0.1-10。
本发明使用油酸作为增溶性辅料,使丁苯酞制剂的口服生物利用度提高,减少个体间差异。
在一些优选的实施方式中,丁苯酞和油酸的重量比为1:1-10。
在一些优选的实施方式中,丁苯酞和油酸的重量比为1:1-6。
在一些优选的实施方式中,丁苯酞和油酸的重量比为1:2-4。
本发明的丁苯酞制剂还含有与药学上可接受的载体或辅料,可以以单位剂量形式给药,给药途径为口服,给药剂型可以是液体剂型或固体剂型。
本发明所述的药学上可接受的载体或辅料为口服制剂辅料,所用辅料包括,赋形剂如乳糖、碳酸钙、磷酸钙、磷酸钠;稀释剂与吸收剂如淀粉、环糊精、乳糖、蔗糖、甘露醇、微晶纤维素钠、硫酸钙等;湿润剂与粘合剂如水、乙醇、丙醇、甘油、丙二醇、异丙醇、糖浆、蜂蜜、葡萄糖、明胶浆、羧甲基纤维素钠、磷酸钾等;崩解剂如干燥淀粉、琼脂粉、碳酸钙、碳酸氢钠、十二烷基磺酸钠、甲基纤维素等;崩解抑制剂如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂如季铵盐、十二烷基硫酸钠等;润滑剂如滑石粉、三乙胺硬脂酸镁、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡等。
在一些优选的实施方式中,所述制剂还含有填充剂、防腐剂中的一种或多种。
在一些优选的实施方式中,所述填充剂为植物油。
在一些优选的实施方式中,所述植物油选自豆油、花生油、玉米油、麻油、杏仁油、桃仁油、棉籽油、葵花籽油或橄榄油中一种或多种。
在一些优选的实施方式中,所述防腐剂选自尼泊金甲酯或尼泊金乙酯。
本发明在第二方面提供了一种丁苯酞制剂在制备治疗脑缺血药物中的用途。
在一些优选的实施方式中,所述治疗脑缺血是治疗轻度或中度急性缺血性脑卒中。
具体实施例
下文将通过实施例对本发明进行进一步的说明,但是应当理解的是,本发明的保护范围不限于这些实施例。
实施例1
丁苯酞含量100mg/粒的软胶囊
制备方法:
a.胶囊壳备料:称取明胶2kg、甘油0.8kg、水2kg;
b.化胶:先将水和甘油搅拌混匀,65℃加热,加入明胶,并不断搅拌至完全溶解,然后保持真空进行灭泡,至气泡完全消失,最后,置于保温桶55℃保温。
c.将丁苯酞和油酸于50℃加热溶解搅拌均匀,临用前加热至50℃。
d.将搅拌均匀的胶囊内容物装入自动软胶囊压制机,压制出软胶囊,具体条件为:内容物保温桶温度50℃,空气压力0.5MPa,胶液加热温度65℃,采用直喷方式,喷洗温度44℃,胶皮厚度0.8mm。
实施例2
丁苯酞含量100mg/片
制备方法:
a.将磷酸氢钙和β-环糊精混合均匀为固体混合物;
b.将丁苯酞和油酸混合均匀为液体混合物;
c.将步骤b的液体混合物加入至步骤a的固体混合物中,搅拌,对油进行吸附,制粒;
d.加入硬脂酸镁,进行总混合。
e.压片,制备丁苯酞含量为100mg/片的片剂。
实施例3
丁苯酞含量100mg/粒的软胶囊
制备方法参照实施例1。
实施例4
丁苯酞含量100mg/粒的软胶囊
制备方法参照实施例1。
对比例1
丁苯酞含量100mg/粒的软胶囊
a.按处方量称取相应的原辅料:丁苯酞、丙二醇;
b.混合均匀;
c.按照每粒含100mg丁苯酞灌入胶囊中。
对比例2
丁苯酞含量100mg/粒的软胶囊
增溶剂:吐温80
a.按处方量称取相应的原辅料:丁苯酞、吐温80、大豆油;
b.80℃加热溶解;
c.按照每粒含100mg丁苯酞灌入胶囊中。
对比例3
丁苯酞含量100mg/粒的软胶囊
共聚维酮制备固体分散体
a.按处方量称取相应的原辅料:丁苯酞、共聚维酮、甘露醇;
b.150℃加热熔融;
c.粉碎,按照每粒含100mg丁苯酞灌入胶囊中。
对比例4(市售制剂恩必普,参比制剂)
标示含量:丁苯酞含量100mg/粒的软胶囊
实施例4:比格犬口服生物利用度试验
健康家犬6只,实验前将家犬随机进行编号,采用三制剂双平行试验设计。受试犬禁食12h后,于试验当日清晨统一进食后服用参比制剂,给药前取空白血,给药后15min、30min、45min、1h、1.25h、1.5h、2h、3h、4h、6h、8h、12h、24h静脉取血,离心分离血浆样本。经前肢静脉丛取静脉血至少300μL,置加入带有肝素钠的烘干离心管中,采集的血样离心(离心温度:4℃,离心时间:5min,离心转速:8000rpm)分离血浆,血浆样品于-80℃冻存。待测。采用液质联用法测定血浆中参比制剂的浓度。试验后进行清洗,时间一周。然后进行受试制剂的药代试验。为更加精确的测定受试制剂的血药浓度变化,增加0.75h、1.75h取样点,其余操作与参比制剂一致。
实施例1的受试制剂与对比例4的参比制剂在家犬体内的血药浓度-时间曲线见图1,血药浓度数据见表1和表2,药动学参数对比见表3。
表1 Beagle犬体内对比例4的参比制剂的个体血药浓度(ng/mL)
注:BLOQ低于定量下限。
表2 Beagle犬体内实施例1的受试制剂个体血药浓度(ng/mL)
表3药代参数对比数据
结论:由图1结果可见,本发明实施例1的受试制剂Cmax与对比例4的参比制剂相比,明显增加。因此,实施例1的受试制剂相对生物利用度提高效果明显。相对生物利用度F=AUC0-t(受试制剂)/AUC0-t(参比制剂)。经体重校正后的数据计算,F受试制剂188%,生物利用度可提高至两倍左右。Tmax和Cmax的RSD大幅度低于参比制剂,说明受试制剂的血药浓度波动小,达峰时间稳定。
按照相同的实验方法对实施例2-4,对比例1-3进行比格犬口服生物利用度试验,药代参数对比见表4。
表4实施例2-4,对比例1-3的药代参数对比数据
结论:由表3和表4的结果可见,本发明实施例1-4的受试制剂Cmax与对比例1-4的制剂相比,明显增加。因此,本发明实施例1-4的受试制剂相对生物利用度提高效果明显。由于使用油酸作为增溶性辅料,使其口服生物利用度提高,而其余的表面活性剂吐温80、共聚维酮均无法提高口服生物利用度。
最后应说明的是:以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (9)
1.一种丁苯酞制剂,其特征在于,所述制剂含有丁苯酞和油酸,其中丁苯酞和油酸的重量比为1:0.1-10。
2.根据权利要求1所述的丁苯酞制剂,其特征在于,丁苯酞和油酸的重量比为1:1-10,优选为1:1-6。
3.根据权利要求1或2所述的丁苯酞制剂,其特征在于,丁苯酞和油酸的重量比为1:2-4。
4.根据权利要求1-3所述的丁苯酞制剂,其特征在于,所述制剂还含有与药学上可接受的载体或辅料,剂型是液体剂型或固体剂型。
5.根据权利要求1所述的丁苯酞制剂,其特征在于,所述制剂还含有填充剂、防腐剂中的一种或多种。
6.根据权利要求5所述的丁苯酞制剂,其特征在于,所述填充剂为植物油,优选为豆油、花生油、玉米油、麻油、杏仁油、桃仁油、棉籽油、葵花籽油或橄榄油中一种或多种。
7.根据权利要求5所述的丁苯酞制剂,其特征在于,所述防腐剂选自尼泊金甲酯或尼泊金乙酯。
8.权利要求1-7的丁苯酞制剂在制备治疗脑缺血药物中的用途。
9.根据权利要求8所述的用途,其特征在于,所述治疗脑缺血是治疗轻度或中度急性缺血性脑卒中。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1623542A (zh) * | 2003-12-05 | 2005-06-08 | 中奇制药技术(石家庄)有限公司 | 丁苯酞软胶囊及其制备工艺 |
CN1726909A (zh) * | 2004-08-27 | 2006-02-01 | 石药集团中奇制药技术(石家庄)有限公司 | 丁苯酞自乳化释药体系及其制备方法和应用 |
CN1823729A (zh) * | 2005-12-16 | 2006-08-30 | 中山大学 | 丁苯酞静脉乳剂及其应用 |
CN1839824A (zh) * | 2006-01-18 | 2006-10-04 | 高春平 | 含n-丁基苯酞的注射乳剂药物及其制备方法 |
CN104721166A (zh) * | 2013-12-21 | 2015-06-24 | 石药集团恩必普药业有限公司 | 一种丁基苯酞液体硬胶囊制剂及其制备方法 |
CN105380908A (zh) * | 2015-12-09 | 2016-03-09 | 河北大学 | 一种丁苯酞药物复合物及其制备方法和缓释制剂 |
CN107216298A (zh) * | 2017-07-24 | 2017-09-29 | 北京科莱博医药开发有限责任公司 | 一种丁苯酞的制备方法 |
CN109419800A (zh) * | 2017-08-30 | 2019-03-05 | 石药集团恩必普药业有限公司 | 药物组合物及其应用 |
-
2020
- 2020-08-14 CN CN202010815865.9A patent/CN114073694B/zh active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1623542A (zh) * | 2003-12-05 | 2005-06-08 | 中奇制药技术(石家庄)有限公司 | 丁苯酞软胶囊及其制备工艺 |
CN1726909A (zh) * | 2004-08-27 | 2006-02-01 | 石药集团中奇制药技术(石家庄)有限公司 | 丁苯酞自乳化释药体系及其制备方法和应用 |
CN1823729A (zh) * | 2005-12-16 | 2006-08-30 | 中山大学 | 丁苯酞静脉乳剂及其应用 |
WO2007068212A1 (fr) * | 2005-12-16 | 2007-06-21 | Shijiazhuang Pharma Group Nbp Pharmaceutical Co., Ltd. | Emulsion intraveineuse de butylbenzene phtaleine et son application |
CN1839824A (zh) * | 2006-01-18 | 2006-10-04 | 高春平 | 含n-丁基苯酞的注射乳剂药物及其制备方法 |
CN104721166A (zh) * | 2013-12-21 | 2015-06-24 | 石药集团恩必普药业有限公司 | 一种丁基苯酞液体硬胶囊制剂及其制备方法 |
CN105380908A (zh) * | 2015-12-09 | 2016-03-09 | 河北大学 | 一种丁苯酞药物复合物及其制备方法和缓释制剂 |
CN107216298A (zh) * | 2017-07-24 | 2017-09-29 | 北京科莱博医药开发有限责任公司 | 一种丁苯酞的制备方法 |
CN109419800A (zh) * | 2017-08-30 | 2019-03-05 | 石药集团恩必普药业有限公司 | 药物组合物及其应用 |
Non-Patent Citations (1)
Title |
---|
冯明芳,等: ""3-正丁基苯酞静脉注射亚微乳的制备和稳定性考察"", 《沈阳药科大学学报》, vol. 1985, no. 04, pages 262 - 268 * |
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