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CN100579525C - Sustained release preparation of licardipine hydrochloride and its preparing process - Google Patents

Sustained release preparation of licardipine hydrochloride and its preparing process Download PDF

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CN100579525C
CN100579525C CN 200710019925 CN200710019925A CN100579525C CN 100579525 C CN100579525 C CN 100579525C CN 200710019925 CN200710019925 CN 200710019925 CN 200710019925 A CN200710019925 A CN 200710019925A CN 100579525 C CN100579525 C CN 100579525C
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release
slow
micro
soluble
drop
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CN 200710019925
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CN101011395A (en )
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丁利军
刘付英
姜新东
孙柏旺
张美苏
戴建方
琳 杜
钱燕燕
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东南大学
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Abstract

The invention relates to a method for preparing Licardipine Hydrochloride slow-release agent, which can be used to treat hypertension, coronary disease or the like. The inventive slow-release agent is formed by quick-release stomach-soluble micro drop and slow-release enteric-soluble micro drop at 1:0.5-5 ratios in the hollow capsule. The inventive capsule has slow-release effect in 12 hours. The slow-release enteric-soluble micro drop comprises Licardipine Hydrochloride, medical macromolecule materials, drug release adjusting agent and some medical finding. The micro drops are prepared by extruding-rolling technique. The invention can quickly approach the blood drug density to treatment object and hold the density stably, with low side effect.

Description

盐酸尼卡地平缓释制剂及其制备方法 Nicardipine hydrochloride sustained-release preparation and preparation method

技术领域 FIELD

本发明具体地说是一种主治原发性高血压、冠心病及各种类型心绞痛的盐酸尼卡地平缓释制剂,涉及药物制剂技术领域。 More specifically the present invention is a treating hypertension, coronary heart disease nicardipine hydrochloride sustained-release preparations and various types of angina pectoris, relates to the field of pharmaceutical preparations.

背景技术 Background technique

高血压是心脑血管疾病的重要危险因素。 Hypertension is an important risk factor for cardiovascular disease. 在任何年龄、性别的人群中,心脑血管疾病的危险均与血压升高呈正相关,因而对高血压应加强防治,从而降低心、 脑血管疾病的发生率和死亡率。 At any age, gender groups, the risk of cardiovascular disease and high blood pressure are positively correlated, and thus to hypertension prevention should be strengthened, thereby reducing the incidence and mortality of cardiovascular and cerebrovascular diseases. 老年高血压患者的靶器官损坏较多,多伴有冠心病、心绞痛、肾功能不全等现象。 Elderly patients with hypertensive target organ damage are more and more associated with coronary heart disease, angina, renal insufficiency and so on. 因此,许多国家开展了临床抗高血压、心绞痛、 冠心病等疾病药物的研究。 Therefore, many countries have carried out a clinical study of anti-hypertension, angina, coronary heart disease drugs. 目前,现有用来治疗高血压等心脑血管疾病的药物品种有很多,如利尿剂、肾上腺素能神经抑制剂、血管扩张剂、血管紧张素转化酶抑制剂、5-羟色胺受体掊抗剂、神经节和节后交感神经抑制剂、P-受体阻滞剂和钙离子拮抗剂等,多数只能达到50%〜60%的降压效果,且长期应用还可能产生一些不良反应。 Presently, the variety of drugs used to treat hypertension and other cardiovascular diseases are many, such as diuretics, adrenergic nerve inhibitors, vasodilators, angiotensin converting enzyme inhibitors, serotonin receptor antagonist break up , and postganglionic sympathetic ganglia inhibitors, P- blockers and calcium antagonists, most only 50% ~ 60% of the antihypertensive effect, and also may have some long-term adverse effects.

盐酸尼卡地平(Nicardipine Hydrochloride)为新型二氣吡啶类钙拮抗剂,其化学名称为:2,6-二甲基4-(3-硝基苯基)-1, 4-二氢吡啶-3, 5-二羟酸,3- [> (N- Nicardipine hydrochloride (Nicardipine Hydrochloride) is a novel two gas pyridines calcium antagonists, and its chemical name: 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydro-pyridin-3 , 5-dicarboxylic acid, 3- [> (N-

苄基-N-甲氨基)]乙酯-5-甲酯盐酸盐;分子式为:C26H29N306*HC1;分子量为: Benzyl -N- methylamino)] -5-carbomethoxy ethyl ester hydrochloride; the formula: C26H29N306 * HC1; molecular weight:

515.99。 515.99. 盐酸尼卡地平具有作用广泛、疗效显著、对心功能影响小、副作用少等优点。 Nicardipine hydrochloride has a broad action, a significant effect, little effect on cardiac function, fewer side effects and other advantages. 在临床上被广泛用于治疗原发性高血压、冠心病、心绞痛等疾病,其主要作用机制是抑制心肌与血管平滑肌的跨膜钙离子内流而不改变血钙浓度;对血管具有髙度的选择性,对血管平滑肌的钙离子拮抗作用强于对心肌的作用;无抗心律失常作用,亦无致心律失常作用:可改善动脉的顺应性,延迟动脉粥样硬化的发生;盐酸尼卡地平既有心肌氧供,又有减少心肌氧耗的作用,故可增加慢性稳定型心绞痛患者的运动耐受量,减少心绞痛发作频率。 It is widely used in clinical treatment of hypertension, angina pectoris and other diseases, and its main mechanism of action is inhibition of transmembrane calcium vascular smooth muscle and myocardium without changing the calcium concentration in blood flow; having a degree of vascular Gao selectivity on vascular smooth muscle calcium antagonism stronger action on the myocardium; no antiarrhythmic effect, nor proarrhythmic effects: improving the compliance of the artery can delay the occurrence of atherosclerosis; nicardipine hydrochloride horizon both myocardial oxygen supply, but also to reduce myocardial oxygen consumption, increased exercise tolerance and therefore the amount of chronic stable angina patients, to reduce the frequency of anginal attacks. 盐酸尼卡地平的降压作用是扩张小动脉、降低总外周血管阻力,且不影响交感神经活性。 Nicardipine hydrochloride antihypertensive effect is expansion of small arteries, reducing the total peripheral vascular resistance without affecting sympathetic activity. 盐酸尼卡地平在用于治疗原发性髙血压等心脑血管疾病过程中,其对各期高血压患者的有效率为:I期92.7%, 11期卯.8%, 111期81.1%,长期应用降压效果可达80%以上,且对心肺肾无不良影响,是当前较为理想的降压药物,临床上常作为降压的首选药物。 Nicardipine hydrochloride in a process for the treatment of primary Gao blood pressure and other cardiovascular diseases, hypertension effective rate for each period: I of 92.7%, 11 d .8%, 111 81.1%, long-term antihypertensive effect of up to 80%, and no adverse effects on the heart, lung and kidney, is currently the ideal antihypertensive drugs, often clinically as an antihypertensive drug of choice. 但是该药的生物半衰期短,为了保持较好的疗效,稳定患者的血压,需要按时服药,致使病人频繁服药(每天给药3〜4次)。 But the drug's biological half-life is short, in order to maintain a good effect, stable blood pressure, you need to take medication, often causing the patient medication (administered 3 to 4 times a day). 由于心、脑血管疾病容易猝发,且在某些不能按时服药的病人中出现"停药反跳",往往会严重危害患者的生命安全。 Since heart disease, cerebrovascular disease is easy to burst, and a "withdrawal rebound" can not take medication in some patients, often seriously endanger patient safety. 并且常规制剂,血药浓度波动大,易发生一些不良副作用,不利于患者用药。 And conventional formulations, the blood concentration fluctuations, prone to a number of adverse side effects, is not conducive to patient medication.

目前上市销售盐酸尼卡地平口服制剂既有快速释放的普通片剂,又有维持较长时间疗效的缓释制剂。 Currently marketed tablet ordinary nicardipine hydrochloride immediate release oral formulations of existing, but also to maintain the efficacy of sustained-release formulation for a long time. 由于普通片剂在使用时每天要服药3〜4次,且服药后血药浓度波动较大,因此服药的依从性较差,不良反应也明显偏多。 Since ordinary tablets to be used when taking 3 to 4 times a day, and after taking the blood concentration fluctuations, so poor medication compliance, adverse reactions obviously more. 盐酸尼卡地平缓释制剂在临床上使用较为广泛。 Nicardipine hydrochloride sustained-release formulation of the more widely used in clinical practice. 最早研制盐酸尼卡地平缓释制剂的日本山之内制药株式会社,在中国上市的商品为:佩尔地平缓释胶囊剂。 First developed nicardipine hydrochloride sustained-release formulation in Japan Yamanouchi Pharmaceutical Co., Ltd., in China-listed commodities: nicardipine slow-release capsules. 该产品是通过在空白丸芯上药粉,再包pH依赖型控释膜的方法制得缓释微丸。 The product powder is obtained by in-pareil seeds, then wrapped pH dependent controlled release method to obtain sustained-release pellets film. 中国专利03110949.7 公开了一种在胃肠道环境中控释的盐酸尼卡地平的缓释制剂,使用激光打孔技术在片剂包衣膜上打一释药孔,能达到24小时连续释药的效果。 Chinese Patent No. 03110949.7 discloses a controlled release in the gastrointestinal tract in a sustained release formulation of nicardipine hydrochloride, using laser perforation techniques to play a hole in the release film coated tablets, can reach 24 hours of continuous drug release Effect.

空白丸芯上药粉法制备盐酸尼卡地平缓释微丸能获得外观规整、易于包衣的小球,但生产过程需要价格昂贵的流化床上粉包衣设备,为了确定上药量,还必须进行严格管理的中间过程控制,且生产的成品率不高。 On pareil nicardipine hydrochloride Preparation Method amlodipine powder to obtain sustained-release pellets neat appearance, easily coated pellets, but the production process requires the expensive fluid bed powder coating apparatus, in order to determine the dose, further intermediate management process must be strictly controlled, and the production yield is not high. 本发明克服了上述缺点。 The present invention overcomes the above disadvantages.

发明内容 SUMMARY

技术问题:本发明的目的是提供一种盐酸尼卡地平缓释制剂及其制备方法, 缓释制剂能够有效地控制药物释放速度,降低不良反应,减少给药次数,服药依从性好。 Technical problem: The purpose of the present invention is to provide a nicardipine hydrochloride sustained-release preparation and preparation method, sustained release formulations can be effectively controlled drug release rate, decrease adverse effects, reducing the frequency of administration, drug compliance and good. 该盐酸尼卡地平缓释制剂的生产工艺应相对比较简单,生产过程易于控制,成品率高。 The nicardipine hydrochloride sustained-release preparation of the production process to be relatively simple, easy to control the production process, high yield.

技术方案:本发明的盐酸尼卡地平缓释制剂是由快速释放的胃溶微丸和缓释肠溶微丸组成;胃溶微丸和肠溶微丸按l: 0.5〜5混合装入空心胶囊,制得含盐酸尼卡地平的i^释胶囊,该胶鍵在12小时内有缓释效果。 Technical Solution: nicardipine hydrochloride sustained-release preparation of the present invention is a quick release and a sustained release gastroresistant pellets composed of enteric-coated pellets; enteric gastric pellets and pellets according to l: 0.5~5 charged mixing hollow capsules, containing nicardipine hydrochloride prepared in i ^ release capsules, sustained-release effect of the adhesive bond within 12 hours.

盐酸尼卡地平快速释放的冓溶徼丸的组成为:盐酸尼卡地平占5〜30%;填充剂占60〜卯%;崩解剂占3~10%;其它辅料占5~32%。 Jiao ten billions composition pellet was dissolved nicardipine hydrochloride in the fast release is: nicardipine hydrochloride accounting 5~30%; the filler comprises 60~ d%; disintegrant will comprise from 3 to 10%; Other adjuvants accounts for 5 to 32%. 所述填充剂为:乳糖、甘露醇、蔗糖、葡萄糖、山梨醇等可溶性填充剂中的任意一种或多种与微晶纤维素的混合物;所述崩解剂为:交联聚乙烯吡咯烷酮、 羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠等中的任意一种或多种组合。 The filler is: any one of lactose, mannitol, sucrose, glucose, sorbitol and the like or more of soluble filler mixture of microcrystalline cellulose; the disintegrant is: cross-linked polyvinyl pyrrolidone, the sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethyl cellulose and the like in any one or more combinations.

盐酸尼卡地平缓释肠溶微丸的组成为:盐酸尼卡地平占5〜30%;药用高分子材料占5~20%;药物溶出调节剂占0.1~5.0%;其它辅料占45~90%。 Nicardipine hydrochloride sustained-release composition of enteric pellets of: accounting 5~30% nicardipine hydrochloride; pharmaceutically acceptable polymer material accounts for 5 to 20%; drug dissolution modifier comprises 0.1% to 5.0%; Other adjuvants accounts for 45 ~ 90%.

药用髙分子材料为肠道PH环境下能溶解而在胃液中难溶解的高分子材料。 Gao molecular material is a pharmaceutically acceptable lower intestinal environment can PH polymer material dissolving poorly soluble in gastric fluid.

所述的高分子材料是甲基丙烯酸-甲基丙烯酸甲酯共聚物、纤维素衍生物。 The polymeric material is a methacrylic acid - methyl methacrylate copolymer, cellulose derivative.

甲基丙烯酸-甲基丙烯酸甲酯共聚物是指EUDRAGIT L100-55、 EUDRAGIT L100 、 EUDRAGIT S100和EUDRAGIT L30D0-55。 Methacrylic acid - methyl methacrylate copolymer refers EUDRAGIT L100-55, EUDRAGIT L100, EUDRAGIT S100 and EUDRAGIT L30D0-55.

纤维素衍生物是指邻苯二甲酸羟丙基甲基纤维素(HPMCP)、邻苯二甲酸醋酸纤维素(CAP)和羟丙基甲基纤维素醋酸琥珀酸酯(HPMCAS)。 Refers to a cellulose derivative is hydroxypropyl methyl cellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS).

药物溶出调节剂是指水溶液显酸性的盐类物质,具体是指氯化铵、磷酸二氢钾、磷酸二氢钠、二乙胺盐酸盐和三乙胺盐酸盐。 It refers to a drug dissolution modifiers the acidic aqueous solution of salts, specifically refers to ammonium chloride, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diethylamine hydrochloride and triethylamine hydrochloride.

该制剂由胃溶微丸和肠溶微丸按1: 0.5〜5的比例混合后灌装在胶囊中制成, 1 according to the formulation of gastric and enteric-coated pellets pellets: 0.5~5 mixing ratio after filling in a capsule made,

其中:盐酸尼卡地平缓释肠溶微丸的制备方法是:除药物溶出调节剂外,将各原 Wherein: nicardipine hydrochloride sustained-release preparation of enteric pellets are: In addition to the drug dissolution adjusting agents, each of the original

料干混,将溶有药物溶出调节剂的水溶液作润湿剂制得软材,经孔径为0.5-1.5mm Dry-blended material, the solution of drug dissolution control agent solution as a wetting agent to produce a flexible material, the pore size of 0.5-1.5mm

网板挤出,转速为250-600r/min滚圆5-20min, 40'C干燥;所述的盐酸尼卡地平 Extruded screen, speed 250-600r / min spheronization 5-20min, 40'C drying; the nicardipine hydrochloride

快速释放的胃溶微丸的制备方法是:将各物料干混后,用水作润湿剂制得软材, The method of preparing quick-release gastroresistant pellets is: After dry blending each material, water as a wetting agent to produce a flexible material,

经孔径为0.5-1.5ram网板挤出,转速为250-600r/min滚圆,40°C干燥。 It was extruded from a pore size of 0.5-1.5ram network, speed 250-600r / min spheronization, 40 ° C and dried.

有益效果:由分析试验结果可知:本盐酸尼卡地平缓释胶襄有良好的缓释效 Advantageous Effects: The results can be seen from the analysis: The release of nicardipine hydrochloride sustained-release effect with good Jiaoxiang

果,且在盐酸溶液中能在较短的时间内释放出有效量的盐酸尼卡地平,确保起效 Fruit, and can be released in the hydrochloric acid solution in a short period of time effective amount of nicardipine hydrochloride, ensuring onset

快。 fast. 在肠溶液中,本盐酸尼卡地平缓释胶囊能确保12小时平稳释放盐酸尼卡地平, In parenteral solutions, the nicardipine hydrochloride sustained release capsules 12 hours to ensure a smooth release of nicardipine hydrochloride,

起到平稳降血压效果。 Functions smoothly hypotensive effect.

具体实維方式 Specific dimensionally

采用挤出-滚圆技术制备盐酸尼卡地平胃溶微丸和肠溶微丸。 Extrusion - spheronization technique nicardipine hydrochloride prepared amlodipine gastric and enteric-coated pellets pellets. 胃溶微丸在酸性溶液能快速释放盐酸尼卡地平,肠溶微丸在肠溶液中具有缓释作用。 Pellets in gastric acidic solution quickly release nicardipine hydrochloride, enteric-coated pellets with slow release in the intestine solution. 将盐酸尼卡地平胄溶微丸和肠溶微丸按1: 0.5〜5的比例混合, The helmet dissolved nicardipine hydrochloride pellets and enteric-coated pellets of 1: 0.5~5 mixing ratio,

再将该混合微丸灌入胶囊。 The pellets were then poured into the mixing capsule. 缓释肠溶微丸的处方如下,按质量百分比计。 Release enteric pellets the following prescription, in percentage by mass.

主药:盐酸尼卡地平5〜30% 辅料: The main drug: nicardipine hydrochloride 5~30% Accessories:

药用高分子材料5〜20% 药物溶出调节剂0.1~5.0% 其它辅料余量 Pharmaceutically acceptable polymeric materials 5~20% drug dissolution modifier 0.1% to 5.0% balance other materials

上述处方中的药用高分子材料是指肠道ra环境下能溶解而在胃液中难溶解的髙分子材料,如甲基丙烯酸-甲基丙烯酸甲酯共聚物、纤维素衍生物。 Pharmaceutically acceptable polymeric materials in the above formulation refers to a dissolution of the intestinal environment can ra Gao molecular materials sparingly soluble in gastric juice, such as methacrylic acid - methyl methacrylate copolymer, cellulose derivative. 这里指的甲 Herein refers to A

基丙烯酸-甲基丙烯酸甲酯共聚物可以是EUDRAGIT L100-55、EUDRAGIT L100 、 EUDRAGIT S100和EUDRAGIT L30D0-55;这里指的纤维素衍生物可以是邻苯二甲酸羟丙基甲基纤维素(HPMCP)、邻苯二甲酸醋酸纤维素(CAP)和羟丙基甲基纤维素醋酸琥珀酸酯(HPMCAS)。 Methacrylic acid - methyl methacrylate copolymer may be EUDRAGIT L100-55, EUDRAGIT L100, EUDRAGIT S100 and EUDRAGIT L30D0-55; herein refers to cellulose derivative may be hydroxypropyl methyl cellulose phthalate (HPMCP ), cellulose acetate phthalate (CAP), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS).

上述处方中的药物溶出调节剂是指通过pH值的调整而影响药物溶出速度,如水溶液显酸性的盐类物质:氯化铵、磷酸二氢钾、磷酸二氢钠、二乙胺盐酸盐、 三乙胺盐酸盐。 Above prescription drug dissolution modifier refers to affect the dissolution rate of the drug by adjusting the pH value, such as the acidic aqueous solution of salts: ammonium chloride, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diethylamine hydrochloride , triethylamine hydrochloride.

上述处方中的其它辅料是指药物制剂中常用的填充剂:乳糖、甘露醇、蔗糖、 葡萄糖、山梨醇、淀粉、改性淀粉和微晶纤维素等中的任意一种或多种组合。 The above formulation means the pharmaceutical formulation Other adjuvants commonly used filler: combination of any one or more of lactose, mannitol, sucrose, glucose, sorbitol, starch, modified starches and microcrystalline cellulose, and the like.

上述处方中的其它辅料还指药物制剂中常用的粘合剂:聚乙烯吡咯垸酮、羟丙基甲基纤维素等中的任意一种或多种组合。 The above formulation also refers to other excipients commonly used in pharmaceutical formulations adhesive: any one or more combinations of one embankment polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like.

上述处方中的其它辅料还指药物制剂中常用的崩解剂:交联聚乙烯吡咯烷酮、 The above formulation also refers to other excipients commonly used in pharmaceutical formulations disintegrant: cross-linked polyvinyl pyrrolidone,

羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠等中的任意一种或多种组合。 The sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethyl cellulose and the like in any one or more combinations.

上述处方中的其它辅料还指润滑剂:PEG4000、 PEG4000、硬脂酸镁、滑石粉中的任意一种或多种组合,微粉硅胶等。 Other adjuvants The above formulation also refers to lubricant: PEG4000, PEG4000, magnesium stearate, talc or any one of a variety of combinations, and the like aerosil.

除药物溶出调节剂外,将上述各原料按处方配比进行充分混合。 Addition to the drug dissolution modifying agent, the formulation ratio of the respective raw materials by mixing sufficiently. 将溶有药物溶出调节剂的水溶液作润湿剂制得软材,采用挤出-滚圆技术制备盐酸尼卡地平肠溶缓释微丸。 A solution of drug dissolution control agent solution as a wetting agent to produce a flexible material, by extrusion - spheronization techniques for preparing an enteric nicardipine hydrochloride sustained release pellets. 挤出用网板的孔径为0.5-1.5111111。 Extruded 0.5-1.5111111 pore size of the screen. 滚圆转速为250-600r/min。 Spheronization speed of 250-600r / min. 滚圆时间5-20min。 Spheronization time 5-20min. 最佳挤出用网板孔径为0.8-1.2mm。 Best extruded stencil aperture is 0.8-1.2mm. 最佳滚圆转速为400-500r/min。 Best spheronization speed is 400-500r / min. 滚圆时间10-12min。 Spheronization time 10-12min. 经滚画制得的盐酸尼卡地平肠溶微丸在4(TC热风干燥, 烘干至含水量在3%以下。按中国药典2005年版二部附录XD第一法测定该盐酸尼卡地平肠溶微丸的药物释放情况。释放介质为磷酸盐缓冲液(取磷酸二氢钾6.8g及lg聚山梨酯80,加水900ml使溶解,用氢氧化钠试液调pH值至6.5 土O.05,加水至1000ml) 卯Oml,转速为150r/min,在l、 2、 4、 6、 IO小时取样分析。结果显示,该肠溶微丸有良好的缓释效果,10小时的总释放量大于80%。 Videos by rolling of nicardipine hydrochloride prepared in enteric pellets 4 (TC hot air drying, drying to a moisture content below 3%. The determination of nicardipine hydrochloride intestine by Chinese Pharmacopoeia 2005 Appendix XD first method where dissolved drug release pellets. the release medium was phosphate buffer (potassium dihydrogen phosphate 6.8g taking lg and polysorbate 80, 900ml water was added to dissolve, the pH was adjusted with sodium hydroxide solution to 6.5 soil O.05 , adding water to 1000ml) d Oml, speed of 150r / min, the l, 2, 4, 6, sampling of IO hours. the results show that the enteric-coated pellets with good release effect, the total release is greater than 10 hours 80%.

药物溶出调节剂对药物释放情况有十分明显的影响,选用pH较低的盐类制得的微丸,药物释放加快。 The drug-eluting drug release modifier has a very significant impact on the situation, the selection of a low pH salts obtained pellets, to accelerate drug release. 药用高分子材料的型号及用量对药物释放也有较大的影响。 Pharmaceutically acceptable polymeric materials and the amount of the model has a greater influence on the drug release. 通过选择药用高分子材料和药物溶出调节剂的种类及用量可得到所需要的缓释微丸。 By selecting release pellets of Polymers and drug dissolution type and amount of modifier required is obtained. 此外,滚圆时的转速及滚圆时间对药物释放也有较大的影响。 Further, when the rotational speed and the spheronization time spheronization have a greater influence on the drug release.

胃溶微丸的处方如下,按质量百分比计。 Gastric pellets following prescription, in percentage by mass.

主药:盐酸尼卡地平5〜30% 辅料: The main drug: nicardipine hydrochloride 5~30% Accessories:

填充剂60〜90% 崩解剂3~10% 其它辅料余量上述处方中的填充剂:乳糖、甘露醇、蔗糖、葡萄糖、山梨醇等可溶性填充剂中的任意一种或多种组合和微晶纤维素。 60~90% filler, 3-10% disintegrant Other adjuvants balance above formulation fillers: lactose, mannitol, sucrose, glucose, sorbitol and the like of the soluble filler, and combinations of any one or more micro microcrystalline cellulose.

上述处方中的崩解剂:交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠等中的任意一种或多种组合。 The above formulation disintegrant: cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethyl cellulose and the like in any one or more combinations.

上述处方中的其它辅料是指:固体口服制剂中常用的粘合剂、润滑剂等辅料。 The above formulation refers Other adjuvants: solid oral formulations commonly used binders, lubricants and other accessories. 胃溶微丸的制备过程同上述的肠溶微丸制备过程,采用挤出-滚圆技术,以水作润湿剂。 Preparation of gastroresistant pellets with enteric-coated pellets of the above-described preparation process, extrusion - spheronization technique, using water as a wetting agent. 工艺参数也同肠溶微丸制备。 Process parameters are also prepared with enteric pellets.

按中国药典2005年版二部附录XD第一法测定该盐酸尼卡地平胃溶微丸的药物释放。 As determined by the Chinese Pharmacopoeia 2005 Appendix XD the first method nicardipine hydrochloride horizon gastric drug release pellets. 释放介质为O.lmol/L的盐酸900mi,转速为150r/min,在0.25、 0.5、 1、 2小时取样分析。 The release medium was O.lmol / L of hydrochloric acid 900mi, speed of 150r / min, at 0.25, 0.5, 1, 2 hr sample analysis. 结果显示,该胃溶微丸在0.25小时即有80%的药物释放,1小时药物释放达到95%以上。 The results show that the pellets in gastric i.e., 0.25 hours, 80% of drug release, drug release 1 hour more than 95%.

该制剂由胃瘠微丸和肠溶微丸按1: 0.5〜5的比例混合后灌装在胶囊中制成, 其中:盐酸尼卡地平缓释肠溶徼丸的制备方法是:除药物溶出调节剂外,将各原料干混,将溶有药^T溶出调节剂的水溶液作润湿剂制得软材,经孔径为0.5-1.5mm网板挤出,转速为250-600r/min滚圆5-20min, 40'C干燥;所述的盐酸尼卡地平快速释放的胃溶微丸的制备方法是:将各物料干混后,用水作润湿剂制得软材, 经孔径为0.5-1.5mm网板挤出,转速为250-600r/min滚圆,40°C干燥。 The preparation from the stomach by an enteric-coated pellets and pellets barren: 0.5~5 mixing ratio after filling in a capsule made, wherein: nicardipine hydrochloride sustained-release preparation of enteric pellets Jiao: except the drug dissolution regulator external agent, the dry blending the raw materials, the aqueous solution of the drug as ^ wetting agent to produce a flexible sheet T dissolution modifying agent, is extruded through a screen aperture 0.5-1.5mm, speed 250-600r / min spheronization 5 -20min, 40'C drying; preparation method of nicardipine hydrochloride in the fast release gastroresistant pellets is: after dry blending each material, water as a wetting agent to produce a flexible material, a pore size of 0.5-1.5 mm extrusion screen, speed 250-600r / min spheronization, 40 ° C and dried.

实施例1: 盐酸尼卡地平胃溶微丸的制备 Example 1: Preparation of gastric nicardipine hydrochloride pellets

处方 prescription

<table>table see original document page 8</column></row> <table> <Table> table see original document page 8 </ column> </ row> <table>

制备过程 Preparation Process

将12g聚乙烯吡咯烷酮K-30溶于80ml纯化水中制得润湿剂。 12g of polyvinylpyrrolidone K-30 was dissolved in 80ml purified water to prepare a wetting agent. 将盐酸尼卡地平20g、乳糖130g、微晶纤维素20g、羧甲基淀粉钠12g充分混合,过60目筛。 The nicardipine hydrochloride 20g, lactose 130g, microcrystalline cellulose 20g, 12g sodium carboxymethyl starch, mixed well, passed through a 60 mesh sieve. 将润湿剂加到混合好的干粉中,高速搅拌5分钟,得软材。 The wetting agent is added to the mixed powder, the high speed stirring for 5 minutes to give a soft material. 将软材经1.0mm孔网挤出,在滚圆机上处理10分钟,转速为500转/分。 The soft material extruded through 1.0mm holes network, processed on a spheronizer for 10 minutes, 500 rpm / min. 得到的湿微丸在40'C下鼓风干燥4小时,筛取24-40目的微丸,成品率92%。 The obtained wet pellets in the blast dried for 4 hours at 40'C, 24-40 mesh object taken pellets, yield 92%.

实施例2: 盐酸尼卡地平胃溶微丸的制备 Preparation of gastroresistant pellets of nicardipine hydrochloride: Example 2

处方 prescription

<table>table see original document page 8</column></row> <table>制备过程与实施例1相同,仅是将乳糖替换成甘露醇、羧甲基淀粉钠换成低取代羟丙基纤维素。 <Table> table see original document page 8 </ column> </ row> <table> prepared in the same procedure as in Example 1, is to replace only as mannitol, lactose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose into Su. 成品率88%。 Yield 88%.

实施例3: 盐酸尼卡地平缓释肠溶微丸的制备 Preparation of nicardipine hydrochloride sustained-release enteric-coated pellets: Example 3

处方 prescription

主药及辅料名称 重量(克) The main drug and excipients Name Weight (g)

盐酸尼卡地平 40 Nicardipine hydrochloride 40

EUDRAGITL100-55 25 EUDRAGITL100-55 25

磷酸二氢钾 5 Potassium dihydrogen phosphate 5

微晶纤维素 26 Microcrystalline cellulose 26

乳糖 89 Lactose 89

羧甲基淀粉钠 5 Sodium carboxymethyl starch 5

聚乙烯吡咯烷翻K-30 6 Polyvinylpyrrolidine K-30 6 Total

PEG4000 4 PEG4000 4

纯化水 80 80 Purified water

制备过程 Preparation Process

将盐酸尼卡地平40g;乳糖89g;微晶纤维素,26g; EUDRAGIT Ll 00-55, 25g;羧甲基淀粉钠5g ; PEG4000, 4g充分混合,过60目筛。 The nicardipine hydrochloride 4Og; 89g lactose; microcrystalline cellulose, 26g; EUDRAGIT Ll 00-55, 25g; sodium carboxymethyl starch 5g; PEG4000, 4g mixed, passed through a 60 mesh sieve. 将5g磷酸二氢钾和6g聚乙烯吡咯烷酮K-30溶于80ml纯化水后,加到混合好的干粉中,髙速搅拌5分钟,制得软材。 6g 5g of potassium dihydrogen phosphate and polyvinylpyrrolidone K-30 was dissolved in 80ml purified water, was added to the mixed powder, the speed Gao stirred for 5 minutes to prepare a soft material. 经1.0mm孔网挤出,在滚圆机上处理10分钟,转速为400转/分。 Extruded through 1.0mm holes network, for 10 minutes on a spheronizer speed of 400 rev / min. 得到的湿微丸在40。 The obtained wet pellets at 40. C下鼓风干燥4小时。 C under blowing dry for 4 hours. 筛取24目-40目的微丸。 Take 24 mesh -40 mesh object pellets. 盐酸尼卡地平缓释肠溶徼丸得率85%。 Jiao nicardipine hydrochloride sustained-release enteric-coated pellets 85% yield.

实施例4盐酸尼卡地平缓释肠溶微丸的制备处方 Preparation Prescription 4 nicardipine hydrochloride sustained-release enteric pellets Example

主药及辅料名称 重量(克) The main drug and excipients Name Weight (g)

盐酸尼卡地平 40 Nicardipine hydrochloride 40

EUDRAGIT SIOO 22 EUDRAGIT SIOO 22

氯化铵 8 Ammonium chloride 8

微晶纤维素 25 Microcrystalline cellulose 25

乳糖 卯 Lactose d

羧甲基淀粉钠 5 Sodium carboxymethyl starch 5

聚乙烯吡咯烷酮K-30 6 Polyvinylpyrrolidone K-30 6

PEG4000 4 PEG4000 4

纯化水 80 80 Purified water

制备过程 Preparation Process

制备过程与实施例3相同,仅是将EUDRAGIT L100-55替换成EUDRAGIT SIOO、磷酸二氢钾替换成氯化铵。 Prepared in the same procedure as in Example 3, the only alternative to the EUDRAGIT L100-55 EUDRAGIT SIOO, potassium dihydrogen phosphate to replace ammonium chloride. 盐酸尼卡地平缓释肠溶微丸成品率83%。 Nicardipine hydrochloride sustained-release enteric-coated pellets 83% yield.

实施例5盐酸尼卡地平缓释肠溶微丸的制备 Preparation of enteric pellets release nicardipine hydrochloride embodiment Example 5

处方 prescription

主药及辅料名称 重量(克) The main drug and excipients Name Weight (g)

盐酸尼卡地平 40 Nicardipine hydrochloride 40

邻苯二甲酸羟丙基甲基纤维素(HPMCP) 20 Hydroxypropyl methyl cellulose phthalate (HPMCP) 20

二乙胺盐酸盐 6 Diethylamine hydrochloride 6

微晶纤维素 25 Microcrystalline cellulose 25

乳糖 60 Lactose 60

甘露醇 34 Mannitol 34

交联聚乙烯吡咯烷酮 5 Crosslinked polyvinylpyrrolidone 5

聚乙烯吡n^酮K-30 10 Polyvinyl pyridine n ^ K-30 10-one

纯化水 80 80 Purified water

制备过程 Preparation Process

将盐黢尼卡地平40g;乳糖60g;乳糖34g;微晶纤维素,25g;邻苯二甲酸羟丙基甲基纤维素(HPMCP) 20g;交联聚乙烯吡咯烷酮5g充分混合,过60目筛。 Qu nicardipine salt 4Og; lactose 60g; lactose 34g; microcrystalline cellulose, 25g; hydroxypropylmethyl cellulose phthalate (HPMCP) 20g; crosslinked polyvinylpyrrolidone 5g mixed, passed through a 60 mesh sieve . 将6 g 二乙胺盐酸盐和iOg聚乙烯吡咯烷酮K-30溶于80ml纯化水后,加到混合好的干粉中,高速搅拌5分钟,制得软材。 The 6 g of diethylamine hydrochloride and iOg polyvinylpyrrolidone K-30 was dissolved in 80ml purified water, was added to the mixed powder, the high speed stirring for 5 minutes to prepare a soft material. 经0.8mm孔网挤出,在滚圆机上处理10分钟,转速为450转/分。 Extruded through 0.8mm holes network, for 10 minutes on a spheronizer speed of 450 rev / min. 得到的湿微丸在4(TC下鼓风干燥4小时。筛取24目-40目的微丸。盐酸尼卡地平缓释肠溶微丸得率82%。 The wet pellets 4 obtained in pellets Yield 82% (TC dried for 4 hours under blowing sieve pellets taken 24 -40 mesh object. Nicardipine hydrochloride sustained-release enteric.

实施例6盐酸尼卡地平缓释肠溶胶囊的制备 Preparation of sustained-release enteric-coated capsules of nicardipine hydrochloride Example 6

<table>table see original document page 11</column></row> <table> 制备过程 <Table> table see original document page 11 </ column> </ row> <table> preparation

将盐酸尼卡地平胃溶微丸110g、酸尼卡地平肠溶微丸150 g和微粉硅胶2g 进行充分混合。 The pellets of nicardipine hydrochloride gastric 110g, nicardipine acid and 150 g of enteric pellets 2g silica powder mixed well. 分装至2号空心胶襄中,每粒胶囊中装入255mg左右的微丸。 No. 2 to the hollow dispensing Jiaoxiang in about 255mg per capsule charged pellets. 这样制得的盐酸尼卡地平缓释胶囊的规格为:40毫克/粒(以盐酸尼卡地平计)。 Thus obtained nicardipine hydrochloride sustained release capsules specifications: 40 mg / tablets (in terms of nicardipine hydrochloride).

分析对比 Analysis and comparison

按照国家食品药品监督管理局发布的药品标准WS1- (X-316) -2003Z,对所得的盐酸尼卡地平缓释胶囊进行释放度分析 WS1- (X-316) -2003Z, the resulting nicardipine hydrochloride sustained release capsules were analyzed according to pharmaceutical standards the State Food and Drug Administration released

<table>table see original document page 11</column></row> <table> <Table> table see original document page 11 </ column> </ row> <table>

注:在盐酸洛液中释放至1小时,即滤出不溶物,放入磷酸盐缓冲液进行释放试验。 NOTE: hydrochloric acid is released in Los solution to 1 hour, i.e., insoluble matter was filtered off, placed in a phosphate buffer solution for release assay.

由分析试验结果可知:本盐酸尼卡地平缓释胶囊有良好的缓释效果,且在盐酸溶液中能在较短的时间内释放出有效量的盐酸尼卡地平,确保起效快。 Analysis apparent from the test results: The nicardipine hydrochloride sustained release capsules with good release effect, and can be released in a short period of time effective amount of nicardipine hydrochloride in hydrochloric acid solution, to ensure rapid onset. 在肠溶液中,本盐酸尼卡地平缓释胶囊能确保12小时平稳释放盐酸尼卡地平,起到平稳降血压效果。 In parenteral solutions, the nicardipine hydrochloride sustained release capsules 12 hours to ensure a smooth release of nicardipine hydrochloride, a smooth play hypotensive effect.

Claims (4)

  1. 1.一种盐酸尼卡地平缓释制剂,其特征在于该缓释制剂是由快速释放的胃溶微丸和缓释肠溶微丸组成;胃溶微丸和肠溶微丸按1∶0.5~5混合装入空心胶囊,制得含盐酸尼卡地平的缓释胶囊,该胶囊在12小时内有缓释效果; 盐酸尼卡地平快速释放的胃溶微丸的重量百分比组成为:盐酸尼卡地平占5~30%;填充剂占60~90%;崩解剂占3~10%;余量为其它辅料; 盐酸尼卡地平缓释肠溶微丸的重量百分比组成为:盐酸尼卡地平占5~30%;药用高分子材料占5~20%;药物溶出调节剂占0.1~5.0%;余量为其它辅料; 所述的高分子材料是甲基丙烯酸-甲基丙烯酸甲酯共聚物; 药物溶出调节剂是指水溶液显酸性的盐类物质,具体是指氯化铵、磷酸二氢钾、磷酸二氢钠、二乙胺盐酸盐或三乙胺盐酸盐。 A nicardipine hydrochloride sustained-release formulation, wherein the extended release formulation is a quick release and a sustained release gastroresistant pellets composed of enteric-coated pellets; enteric-coated pellets and pellets gastric by 0.5 ~ 5 mix and hollow capsules to prepare capsules containing nicardipine hydrochloride sustained-release of the sustained release capsule within 12 hours; fast release nicardipine hydrochloride gastroresistant pellets percentage weight composition: nicardipine hydrochloride from 5 to 30%; the filler comprises from 60 to 90%; disintegrant will comprise from 3 to 10%; the balance of other materials; wt nicardipine hydrochloride sustained-release enteric pellets percentage composition: nicardipine hydrochloride accounted 5 to 30%; pharmaceutically acceptable polymer material accounts for 5 to 20%; drug dissolution modifier comprises 0.1% to 5.0%; the balance being other excipients; said polymer material is methacrylic acid - methyl methacrylate copolymer ; drug dissolution modifier refers to the acidic aqueous solution of salts, specifically refers to ammonium chloride, potassium dihydrogen phosphate, sodium dihydrogen phosphate, diethylamine hydrochloride or triethylamine hydrochloride.
  2. 2. 根据权利要求1所述的盐酸尼卡地平缓释制剂,其特征在于所述填充剂为:乳糖、甘露醇、蔗糖、葡萄糖、山梨醇中的任意一种或多种与微晶纤维素的混合物;所述崩解剂为:交联聚乙烯吡咯垸酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠中的任意一种或多种组合。 The nicardipine hydrochloride sustained-release preparation according to claim 1, wherein said filler is: any one of lactose, mannitol, sucrose, glucose, sorbitol, and one or more of microcrystalline cellulose mixtures thereof; the disintegrant is: cross-linked polyvinylpyrrolidone embankment -one, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose in any one or more combinations.
  3. 3. 根据权利要求1所述的盐酸尼卡地平缓释制剂,其特征在于甲基丙烯酸-甲基丙烯酸甲酯共聚物是指EUDRAGIT L100-55、 EUDRAGIT L100 、 EUDRAGITS100或EUDRAGIT L30D0-55。 3. nicardipine hydrochloride sustained-release preparation according to claim 1, wherein the methacrylic acid - methyl methacrylate copolymer refers EUDRAGIT L100-55, EUDRAGIT L100, EUDRAGITS100 or EUDRAGIT L30D0-55.
  4. 4. 一种如权利要求1所述的盐酸尼卡地平缓释制剂的制备方法,其特征在于该制剂由胃溶微丸和肠溶微丸按l: 0.5〜5的比例混合后灌装在胶囊中制成,其中:盐酸尼卡地平缓释肠溶微丸的制备方法是:除药物溶出调节剂外,将各原料干混,将溶有药物溶出调节剂的水溶液作润湿剂制得软材,经孔径为0.5-1.5mm网板挤出,转速为250-600r/min滚圆5-20min, 40。 4. A method for the preparation of nicardipine hydrochloride sustained-release preparation according to claim 1, characterized in that the formulation consists of enteric-coated pellets and pellets gastric press l: the mixing ratio of 0.5~5 in a capsule filling prepared in which: nicardipine hydrochloride sustained-release preparation of enteric pellets are: in addition to the drug dissolution adjusting agents, dry-blending the respective raw materials, and a solution of the wetting agent as the drug dissolution control agent to produce a flexible material was extruded from a pore size of 0.5-1.5mm network, speed 250-600r / min spheronization 5-20min, 40. C干燥;所述的盐酸尼卡地平快速释放的胃溶微丸的制备方法是:将各物料干混后,用水作润湿剂制得软材,经孔径为0.5-1.5mm网板挤出,转速为250-600r/min滚圆,40°C干燥。 C drying; Preparation method of nicardipine hydrochloride in the fast release gastroresistant pellets is: After dry blending each material, water as a wetting agent to produce a flexible material, by extruding a pore size 0.5-1.5mm screen , speed 250-600r / min spheronization, 40 ° C and dried.
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