CN102138911A - Divalproex sodium sustained release tablets and preparation method thereof - Google Patents

Divalproex sodium sustained release tablets and preparation method thereof Download PDF

Info

Publication number
CN102138911A
CN102138911A CN2011100756373A CN201110075637A CN102138911A CN 102138911 A CN102138911 A CN 102138911A CN 2011100756373 A CN2011100756373 A CN 2011100756373A CN 201110075637 A CN201110075637 A CN 201110075637A CN 102138911 A CN102138911 A CN 102138911A
Authority
CN
China
Prior art keywords
cellulose
carbomer
tablets
sodium
divalproex sodium
Prior art date
Application number
CN2011100756373A
Other languages
Chinese (zh)
Other versions
CN102138911B (en
Inventor
孙卫东
李学明
Original Assignee
孙卫东
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 孙卫东 filed Critical 孙卫东
Priority to CN2011100756373A priority Critical patent/CN102138911B/en
Publication of CN102138911A publication Critical patent/CN102138911A/en
Application granted granted Critical
Publication of CN102138911B publication Critical patent/CN102138911B/en

Links

Abstract

The invention belongs to the field of medicinal preparations, and particularly relates to divalproex sodium sustained release tablets and a preparation method thereof. The sustained release table comprises divalproex sodium, a retarding agent, a diluent, a disintegrant, a binder, a pH regulating agent, a lubricant, an antiadherent and the like.

Description

一种双丙戊酸钠缓释片及其制备方法 A dual sodium valproate and preparation method

技术领域 FIELD

[0001] 本发明涉及药物制剂领域,具体地说,涉及一种双丙戊酸钠缓释制剂及其制备方法,本发明还公开了其制备工艺的相关参数。 [0001] The present invention relates to the field of pharmaceutical formulation, in particular, relates to a sustained-release formulation of divalproex and its preparation method, the present invention also discloses its preparation process parameters.

技术背景 technical background

[0002] 双丙戊酸钠是中枢神经系统类药物,又称二-(2-丙基戊酸)氢钠,是由一分子丙戊酸和一分子丙戊酸钠形成的离子化合物。 [0002] Divalproex sodium is a central nervous system drugs, also known as two - (2-propyl-pentanoic acid) of sodium hydrogen ionic compound is formed by one molecule one molecule of valproic acid and sodium valproate. 它是分子式为:C16H3102Na。 It is the formula: C16H3102Na. 分子量为310. 41, 结构式为: A molecular weight of 310.41, the formula:

[0003] [0003]

Figure CN102138911AD00051

[0004] 双丙戊酸钠为白色纤维状结晶或粉末,无臭,味微涩;略有引湿性。 [0004] Divalproex sodium is a white powder or whiskers, odorless, slightly astringent; slightly hygroscopic. 本品溶于乙醇、 在水中略溶解,在乙醚中几乎不溶。 This product was dissolved in ethanol, slightly soluble in water and practically insoluble in ether.

[0005] 双丙戊酸钠最早是由Abbot实验室研发上市的抗癫痫药物,系广谱抗癫痫药物, 主要作用于中枢神经系统。 [0005] divalproex sodium was first developed by Abbot laboratories listed antiepileptic drugs, broad-spectrum anti-epileptic drugs, a major role in the central nervous system. 对动物的药理研究发现本品对各种癫痫的实验模型(全身性和部分性)均有抗惊厥作用。 Pharmacological studies in animals found that goods of various experimental models of epilepsy (generalized and partial) are anticonvulsant effect. 同样本品被发现对人的各种类型癫痫发作有抑制作用,其主要作用机理可能与增加Y-氨基丁酸的浓度有关。 Also this product was found various types of human epilepsy seizures inhibit Its main role may be associated with increasing concentrations of GABA Y-.

[0006] 由于双丙戊酸钠普通剂型释药速率过快使血药浓度峰值偏高,易产生副作用,尤其以胃肠道反应最为常见;由于主要用药人群为癫痫患者,病人往往不能很好自我控制按时服药,普通在给药中常常出现漏服等情况从而使得治疗效果下降或不明显。 [0006] Since the common dosage forms release rate divalproex too high peak plasma concentration, easy to produce side effects, particularly in the most common gastrointestinal reactions; since the main population with epilepsy medication, patients are often not well self-control take medication, and other ordinary circumstances often appear in the missed administration or decreased so that the therapeutic effect is not obvious. 本发明中所涉及的处方及其制备方法有效的解决了上述问题。 Prescription and preparation method of the present invention is directed to solve the above problem effectively.

[0007] 文献报道Venkatramana M. Rao等人研究了以尤特奇ElOO和美多秀K4M为复合缓释骨架材料的双丙戊酸钠缓释片,能提高双丙戊酸钠在低PH环境的释放速度使其给药后迅速起效,减小了缓释片释放度的体内外差异,但该环视骨架缓释时间只能达到8个小时, 病患每天仍需要多次给药,癫痫患者容易出现漏服;有两篇与双丙戊酸钠缓释片制备有关的中国专利CN998146^和CN200580005453. 2,和一篇美国专利US2004/0037880,如专利99814629和200580005453. 2中都要求双丙戊酸钠缓释组合物中高粘度羟丙甲基纤维素的用量在20-40%,产生丙戊酸离子的物质占总重的50〜55%。 [0007] reported Venkatramana M. Rao et al studied the bis sodium valproate to show multiple Eudragit ElOO US K4M sustained release matrix composite material can be improved in a low PH divalproex environment after allowing the administration rate of release rapid onset, reducing the difference between the outer sustained release tablets in vivo release, but the release time can only reach skeleton looking around 8 hours, patients still require multiple daily administration, epilepsy missed prone; there was prepared with two double sodium valproate related CN998146 ^ and Chinese patent CN200580005453 2, and a U.S. Patent No. US2004 / 0037880, 99814629 and Patent 200580005453.2 dipropylene are required the amount of sodium in pentyl sustained release compositions of high viscosity hydroxypropyl methylcellulose in the 20-40%, valproate ion generating 50~55% of the total weight of the substance. 其使用的制备工艺涉及到湿法制粒和干法制粒:干法制粒由于其产率较低(通常低于60% ),常出现颗粒均一度不好、 片重差异大、含量差异大、批间释放度差异大等问题,一般不作为首选方法;双丙戊酸钠对酸、湿度等外界环境因素不太敏感,湿法制粒作为最常用的制粒方法,很使用于双丙戊酸钠缓释片的制备,但由于丙戊酸钠和双丙戊酸钠在吸湿以后会出现其物理化学性质变化难以将其干燥进行进一步的压片,本发明中所采用的处方适合湿法制粒,同时采用的制备工艺不会出现前述专利中制备方法可能出现的双丙戊酸钠吸湿的问题,大大提高了制备工艺的产率。 The preparation process involves using wet granulation and dry granulation: dry granulation, due to its low yield (typically below 60%), often poor particle uniformity, large tablet weight variation, content difference large, batch release difference between such problems are generally not the preferred method; divalproex less sensitive to environmental factors acids, humidity and the like, as the most commonly used wet granulation granulation process, it is used in divalproex preparation of sustained release tablets of sodium valproate, and divalproex but due to their physical and chemical properties will change after moisture absorption is difficult to be further dried tableting formulation employed in the present invention is suitable for wet granulation, preparation problems while using the method for preparing the aforementioned patents may occur divalproex sodium absorbent does not occur, greatly improves the yield of the preparation process.

发明内容 SUMMARY

[0008] 本发明的目的是提供一种双丙戊酸钠缓释制剂及其制备方法,提高用药顺应性, 避免癫痫患者漏服重复服用药品的情况发生,减少药物带来的毒副作用。 [0008] The object of the present invention is to provide a sustained-release formulation of divalproex and its preparation method to improve the medication compliance, prevent epileptic patient misses a repetitive occurrence of taking drugs, to reduce drug side effects caused.

[0009] 本发明的另一个目的是解决双丙戊酸钠口服缓释制剂体积过大不易于吞服的问题。 [0009] Another object of the present invention is to solve the oral sustained release formulation of divalproex sodium too large problem is not easy to swallow.

[0010] 本发明是双丙戊酸钠普通制剂的改进,其人体内实验表明每日服用一次双丙戊酸钠缓释制剂可保证M小时体内药浓度处于有效治疗窗内,并能稳定控制血浆药物浓度峰值,减少药物带来的副作用,提高药物的生物利用度以保证疗效。 [0010] The present invention is an improved formulation of divalproex sodium general, experiments show that the human body once daily sustained-release formulation ensures divalproex M-hour in vivo drug concentration is within the therapeutic window for effective and stable control peak plasma concentration, reduce side effects caused by the drug, increase the bioavailability of the drug to ensure efficacy. 按中国药典2010版中对制剂稳定性的要求进行试验考察,其释放性能稳定均一,选取三个批次进行体外释放度实验测定,批间释放度相对标准误差小于3%,体内实验表明体外释放百分数与体内吸收有良好的线性关系。 Carried out in the 2010 edition of Chinese Pharmacopoeia requirements for stability testing investigated the formulation, stable and homogeneous release properties, select three batches experimentally determined in vitro release, release and inter-assay relative standard deviation of less than 3%, in vivo experiments show that the in vitro release in vivo absorption percentage has a good linear relationship.

[0011] 本发明采用的技术方案为: [0011] aspect of the present invention is used are:

[0012] 一种双丙戊酸钠缓释制剂,其特征在于所述制剂具有一定缓释性能,其缓释原理主要为骨架型缓释片。 [0012] A dual Valproate, wherein said formulation has a certain release performance, the main principle matrix type sustained-release tablets. 所选用的辅料与制备方法均易得可行,且方法重现性好,适宜工业化生产。 The choice of materials and preparation methods are readily available and feasible, and reproducible method, suitable for industrial production.

[0013] 为此,本发明提供一种双丙戊酸钠缓释片组合物,其特征在于,由双丙戊酸钠、阻滞剂、粘合剂、稀释剂、崩解剂、润滑剂、抗粘剂、PH调节剂组成。 [0013] To this end, the present invention provides a sustained-release tablet composition of divalproex sodium, which is characterized by the divalproex sodium, retarders, binders, diluents, disintegrants, lubricants , anti-adherents, PH adjusting agent. 本发明的优选组合物,各组分的质量百分比为: Preferred compositions of the present invention, the mass percentage of the components is:

[0014] [0014]

Figure CN102138911AD00061

[0015] 本发明更优选的组成中,其中阻滞剂为两种不同的成分,为阻滞剂1和阻滞剂2,两者在组合物中的质量百分比分别为: [0015] More preferred compositions according to the present invention, wherein two different-blocker component of blockers and beta-blockers 1 2, both the mass percentage in the composition were:

[0016]阻滞剂 1 5% [0016] 15% blocker

[0017]阻滞剂 2 3%-15%。 [0017] 23% -15% blockers.

[0018] 本发明的组成中,其中所述阻滞剂1选用乙基纤维素、羟丙甲纤维素、羧甲基纤维素、甲基纤维素、羟丙基纤维素、聚丙烯酸、硬脂酸、棕榈蜡、壳聚糖中的一种或者几种的混合物。 [0018] The composition of the present invention, wherein the selection of a retarder ethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyacrylic acid, stearyl acid, carnauba wax, chitosan or a mixture of several. 优选羟丙甲基纤维素,其中对其甲基和羟丙基的取代度有要求,甲基取代比在15% -25%,羟丙基取代比在5% -15%,其2%的水溶液粘度应大于10000厘泊。 Preferably hydroxypropyl methylcellulose, and hydroxypropyl methyl substituted wherein its degree is required, methyl substituted 15% -25% ratio, the ratio of hydroxypropyl substitution of 5% -15%, a 2% of aqueous solution viscosity greater than 10,000 centipoise.

[0019] 所述阻滞剂2选用羟丙甲基纤维素、羟丙基纤维素、预胶化淀粉、醋酸纤维素、乙基纤维素、聚谷氨酸、卡波姆。 [0019] The 2 blocker selected hydroxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, cellulose acetate, ethyl cellulose, polyglutamic acid, carbomer. 优选卡波姆,并选用高纯度级别的口服型卡波姆,如卡波姆934P、卡波姆974P。 Preferably the carbomer, and the selection of high purity grade oral carbomer type, such as carbomer 934P, carbomer 974P.

[0020] 所述稀释剂选自以下辅料中选择一种或几种的混合物:乳糖、淀粉、微晶纤维素、 预胶化淀粉、甘露醇、壳聚糖、糊精,优选的稀释剂为预胶化淀粉。 [0020] The selection of one or more materials selected from the diluent mixture: lactose, starch, microcrystalline cellulose, pregelatinized starch, mannitol, chitosan, dextrin, is preferred diluent pregelatinized starch.

[0021] 所选粘合剂选自聚维酮、水、无水乙醇、不同比例的乙醇和水的混合物、淀粉浆、一定比例的羟丙甲纤维素的水溶液分散体;优选乙醇溶液,浓度在80% -99%。 [0021] The selected binder is selected from povidone, a mixture of water, ethanol, different ratios of ethanol and water, starch paste, aqueous hypromellose a proportion of the dispersion; preferably ethanol solution, the concentration of 80% -99%.

[0022] 所述润滑剂选用硬脂酸镁、滑石粉、氢化植物油、硬脂醇中的一种或几种的混合物,优选滑石粉。 [0022] The choice of lubricant magnesium stearate, talc, hydrogenated vegetable oils, mixtures of one or more of stearyl alcohol, preferably talc.

[0023] 所述抗粘剂选用滑石粉、微粉硅胶、硬脂醇、硬脂酸镁,优选微粉硅胶,优选微粉硅胶。 [0023] The choice of anti-adherents as talc, silica powder, stearyl alcohol, magnesium stearate, preferably silica powder, preferably silica powder.

[0024] 所述pH调节剂选用磷酸三钙、磷酸氢钙、磷酸二氢钙、磷酸氢钠、磷酸二氢钠、磷酸氢钾、磷酸二氢钾、碳酸氢钠或类似的磷酸盐、碳酸盐。 [0024] The pH adjusting agent selected tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate, or the like, carbon salt.

[0025] 本发明特别优选的组合物,其特征在于,各组分的质量为:制成1000片双丙戊酸 [0025] A particularly preferred composition of the invention, wherein the mass of each component is: made of 1000 pairs of valproic acid

钠缓释片处方 Sodium Sustained Release Tablets

[0026] [0026]

Figure CN102138911AD00071

[0027] 本发明最优选的组合物,其特征在于,各组分的质量为:制成1000片双丙戊酸钠 [0027] The most preferred composition of the present invention, wherein the mass of each component is: sodium valproate made 1000 pairs

缓释片处方 Sustained Release Tablets

[0028] [0028]

Figure CN102138911AD00081

[0029] 本发明优选的配方是经过筛选获得的,筛选过程如下: [0029] Formulations of the present invention is preferably obtained through the screening, the screening process is as follows:

[0030] 本发明以安博特实验室在美国上市的DEPAKOTE® ER产品作为参比制剂,通过进行释放度测定实验,以相似因子F2为评价指标,通过正交设计和中心-响应面法优化处方设计,用软件拟合了各个影响因素(羟丙甲基纤维素用量、预胶化淀粉用量、卡波姆用量等) 与响应值释放度相似因子(^)的方程。 [0030] In the present invention listed in U.S. laboratory Bote DEPAKOTE® ER formulations as reference product, measured by release experiment, a similar evaluation index factor F2 through the center and orthogonal design - response surface methodology optimized formulation design, software fitting the various factors (the amount of hydroxypropyl methylcellulose, the amount of pregelatinized starch, carbomer dosage) equation factors (^) with a similar release response value. 筛选出多种辅料及其用量配比,包括:淀粉、微晶纤维素、乳糖、磷酸氢钙、磷酸三钙、预胶化淀粉等填充剂;聚维酮K30、5%低粘度羟丙甲基纤维素溶液、无水乙醇、60〜95%乙醇等粘合剂;羟丙甲基纤维素、乙基纤维素、卡波姆934Ρ 等阻滞剂;微粉硅胶、滑石粉、硬脂酸镁等助流剂。 More excipients selected ratio and amounts thereof, comprising: a starch, microcrystalline cellulose, lactose, dibasic calcium phosphate, tribasic calcium phosphate, pregelatinized starch and the like fillers; Povidone K30,5% low viscosity hypromellose cellulose solution, ethanol, 60~95% ethanol binder; hydroxypropylmethyl cellulose, ethyl cellulose, carbomers and other 934Ρ blockers; aerosil, talc, magnesium stearate other glidants.

[0031] 本发明关于填充剂的实验结果(主要是硬度、脆碎度、释放度指标)发现,淀粉和预胶化淀粉对双丙戊酸钠缓释片的崩解速度后期比乳糖和微晶纤维素慢,但片剂硬度和出片力低于微晶纤维素和乳糖,不利于片剂包衣、运输、储藏的要求。 [0031] The present invention relates to a filler results (mainly hardness, friability, release index) found that starch, pregelatinized starch, and the disintegration rate of sustained release tablets of divalproex sodium ratio of lactose and micro-post microcrystalline cellulose slow, but the sheets and the tablet hardness is less than the force of microcrystalline cellulose and lactose, is not conducive to the tablet coatings, transportation and storage requirements.

[0032] 本发明关于润湿剂的实验结果发现,聚维酮、60%乙醇/水溶液、5%低粘度羟丙甲基纤维素用于其制粒将易导致粉体润湿不均勻,难以制粒或是制得的颗粒粒径分布广, 不适合放大生产压片(有片重差异超标的潜在风险);优选出的80%-90%乙醇能很好的使粉末间形成粒子,产率较高(高于70% )制得的颗粒粒径分布窄(主要指标考察D50), 适宜压片。 [0032] The present invention relates to the discovery results wetting agent, povidone, 60% ethanol / water solution, 5% hydroxypropyl methylcellulose low viscosity for granulated powders will easily lead to non-uniform wetting, it is difficult to granulation or particle size distribution obtained widely, not suitable for scale-tablet (tablet weight variation there is potential risk of excessive); preferably 80% -90% of the ethanol can be well formed so that between the powder particles, production higher rates (above 70%) particle size distribution is narrow obtained (main indicators investigation D50), suitable for tabletting.

[0033] 本发明关于阻滞剂的实验结果发现,乙基纤维素对双丙戊酸钠的缓控释效果最为明显,但存在释放终点太迟,或是预定时间内释放度达不到80%以上,有部分药物被包裹在乙基纤维素材料中;单独使用羟丙甲基纤维素作为缓控释材料,常存在突释等风险,且单独用其制成双丙戊酸钠缓释片存在PH依赖性,较低ρΗ药物释放缓慢,ρΗ升高后释放加速,体内外相关性差;卡波姆系列中有934Ρ和974Ρ两种型号适合用于缓释片,由于高粘度的羟丙甲基纤维素在常用的湿法制粒过程中粘性太强不适宜用水或15%聚维酮Κ30溶液等润湿剂制粒,而卡波姆容易被60-95%的乙醇润湿并产生适宜的粘性,适合湿法制粒并放大至工业化生产中。 [0033] The present invention relates to blockers results found, ethylcellulose effect of slow release divalproex most obvious, but there are too late release end, or within a predetermined time of release of less than 80 % or more, with a portion of the drug is encapsulated in ethyl cellulose material; used alone or as hydroxypropyl methylcellulose slow release material, there is often the risk of a burst like, and which is made with a separate release divalproex PH-dependent sheet exists, a lower ρΗ slow drug release, release after ρΗ poor correlation increased by acceleration, in vivo; carbomer series and have 934Ρ 974Ρ two models suitable for sustained release tablets, because of the high viscosity hydroxypropyl methylcellulose in a conventional wet granulation process with water unsuitable or too viscous 15% solution of povidone Κ30 granulation a wetting agent and the like, and the carbomer is easily wetted 60-95% ethanol and generates appropriate viscosity suitable for wet granulation and enlarged to industrial production. 本发明根据缓释时间需求筛选出934Ρ和羟丙甲基纤维素复合凝胶骨架缓释片,辅以微环境PH调节剂降低了本发明所述的缓释片的ρΗ依赖性以及突释风险,使其骨架在肠道环境下崩解更完全,释放终点比羟丙甲基纤维素骨架缓释片更接近100 %,提高了释放度的体内相关性,通过使用数据统计软件,采用中心复合-响应曲面法优化出一最优化处方的用量范围;用过采用优化范围内中最小总重量的处方,可以得到比普通方法更少辅料,更小体积的缓释片,使得大剂量规格的双丙戊酸钠片更适宜吞咽。 According to the present invention is the screening time release needs of the hydroxypropyl methylcellulose and 934Ρ complex gel matrix sustained-release tablets, combined with the microenvironment PH adjusting agents reduce the dependency ρΗ sustained release tablets according to the present invention, and the risk of a burst , so that the skeleton disintegrate in the intestinal environment more complete release closer to the end than 100% hydroxypropylmethyl cellulose backbone sustained-release tablets, to improve the relevance of in vivo release, and by using a statistical software using the central composite - optimization of the response surface optimization in an amount ranging prescription; spent using the minimum total weight prescription in the optimum range, materials can be less than the conventional method, a smaller volume of the sustained-release tablets, such large dosage strengths of bis more suitably sodium valproate tablets swallowed.

[0034] 本发明还包括本发明的组合物的制备方法包括如下步骤: [0034] The method of preparing a composition according to the present invention comprises the present invention further comprises the steps of:

[0035] 颗粒中间体制备:取处方量的药物与辅料,搅拌混合均勻,加入粘合剂,采用流化床制粒法或是摇摆制粒机制粒法制粒。 Preparation of intermediate particles [0035]: the formulation amounts of drugs and excipients, mixing evenly, adding a binder, using the fluidized bed granulation or granulation swing pelletized particles. 将所制得的颗粒干燥,一定时间后,将颗粒过筛,选取粒径大小适宜的颗粒,测定其水分含量,水分含量合格后加入处方量的润滑剂,混合均勻,置入压片机,调试压力使之在适宜范围内,压片,取处方量包衣材料配制成包衣溶液,将包衣液雾化进行包衣。 The resulting granules are dried, after a certain time, the particles are sieved to select the appropriate size of the particle size, moisture content measured, the moisture content prescribed amount of lubricant is added after passing, mixed, placed in a tableting machine, commissioning pressure so that in a suitable range, tabletting, coating material formulation amounts formulated as a coating solution, coating the coating liquid for atomization. 包衣结束后干燥一定时间,即得成品双丙戊酸钠缓释片。 After the coating has dried to a certain time, ie finished divalproex sodium tablets.

[0036] 该方法还包括:直接压片法:取处方量的药物和辅料,分别将其粉碎至一定粒径, 通过80至120目筛网后,混合均勻,置入压片机中,压片。 [0036] The method further comprising: direct compression process: The formulation amount of drug and excipients, are pulverized to a certain particle size, between 80 and 120 through the mesh screen, uniformly mixed, placed in a tablet press, pressure sheet.

[0037] 本发明选用优化的处方,采用流化床制粒法、摇摆制粒机制粒法或湿法制粒机制粒中的一种或几种制粒方法,然后采用压片法制备双丙戊酸钠缓释片,也可采用直接干法压片制备缓释片。 [0037] The present invention selects an optimized prescription, fluidized bed granulation, granulation process one or more swing pelletized granulation or wet granulation in a granulator, and then prepared using bis valproate tablet sodium sustained release tablets, may also be employed a dry direct tableting tablets.

[0038] 本发明由于使用多种阻滞剂形成了复合凝胶骨架,阻滞剂2可以大大减少阻滞剂1的用量;复合阻滞剂比单一阻滞剂具有更好的体内外相关性,符合缓释材料使释放行为更接近零级释放。 [0038] The present invention is the use of a more complex gel matrix formed blockers, blockers can greatly reduce the amount of retarder 2 1; blockers having an outer composite better correlation than a single blocker vivo , in line with the sustained release material behavior closer to zero order release. 本发明由于使用了PH调节剂,减少了pH变化对双丙戊酸钠释放度的影响,从而减少药物释放行为的体内外差异。 The present invention, since a PH adjusting agent, reducing the effects of pH change on the release divalproex sodium, thereby reducing the difference in outer vivo drug release behavior. 本发明的缓释片的缓释原理属于骨架控释,此类型缓释片稳定性优于包衣型缓释片,不易因为外层包衣的变化而引起药物的突释。 Sustained release tablets of the principles of the present invention belongs to the matrix controlled-release, sustained-release tablets of this type is superior to the stability of coated sustained release tablets, is not easy to change because the outer coating causes a burst of drug. 同时薄膜包衣材料能提高缓释片剂的稳定性,保证药品质量稳定,上述薄膜包衣材料可选用欧巴代系类薄膜包衣材料、低粘度羟丙甲基纤维素中的一种或几种。 While the film coatings can improve the stability of the delayed release tablets, to ensure stable quality of the drug coating of the film-based materials can be selected based Opadry film coating material, a low viscosity hydroxypropylmethyl cellulose of one or several. 由于采用优化处方比例的辅料与主药在混合搅拌机混合均勻,采用顶喷式流化床喷入粘合剂即可得到适宜粒径的颗粒,也可将粘合剂加入到粉体中后再采用摇摆式制粒机制备颗粒中间体,选择粒径适宜的颗粒中间体,与润滑剂混合后进行压片,片剂性状可选择圆形、椭圆形或胶囊型,优选胶囊型的片剂,便于病患吞咽。 Since the ratio of the optimized formulation auxiliaries and main drug uniformly mixed in a mixer, the top-spray fluid bed binder is sprayed into a suitable particle diameters can be obtained, can then be added to the powder adhesive using an oscillating granulator granules prepared intermediate, intermediate to select suitable particle diameter, tabletting lubricants after mixing, selectable traits tablet circular, oval or capsule, preferably a capsule-shaped tablet, facilitate patient swallowing.

[0039] 本发明的优点在于: [0039] The advantage of the present invention:

[0040] (1)本发明之双丙戊酸钠缓释片,制备过程工艺简单易行,在实验室规模下,已能完成10000-30000单位的放大生产。 [0040] (1) bis sodium valproate in the present invention, the preparation process is simple, laboratory scale, has been able to produce an enlarged complete 10000-30000 units.

[0041] (2)本发明制备的缓释片,动物体内药代动力学研究,与普通制剂等效,并未产生因缓释作用而减少生物利用度的问题,其释放模型降低了血浆药物浓度峰值,从而减少了毒副作用产生的可能,每日服用一次提高了患者用药的顺应性。 [0041] The sustained-release tablets (2) prepared in the present invention, the drug in vivo pharmacokinetic study animals, the formulation equivalent to normal, did not produce a sustained release effect due to decreased bioavailability problems, which reduces the plasma drug release model the peak concentration, thereby reducing the possibility of side effects generated taken once a day improves patient compliance with medication.

[0042] (3)本发明之缓释制剂,经加速试验考察,在40°C、相对湿度75%的条件下6个月内性状稳定、药物含量、有关物质均在可控范围内,适宜工业化生产。 [0042] (3) sustained-release preparation of the present invention, the accelerated test inspection, at 40 ° C, the relative humidity of 75% for 6 months stable traits, drug content, related substances are within the controllable range, suitably Industrial production.

[0043] 表1批次101105双丙戊酸钠缓释片的稳定性考察 [0043] Table 1 Stability of sodium valproate in a batch of 101,105 pairs

[0044] 表2批次101103双丙戊酸钠缓释片的稳定性考察 [0044] Table 2 Stability of the batch of 101,103 pairs of sodium valproate

[0045] 表3批次101101双丙戊酸钠缓释片的稳定性考察 [0045] Table 3 Stability of the batch of 101,101 pairs of sodium valproate

[0046] 表4不同处方的筛选过程(考察硬度、粒径分布、流动性指数、可压性指数与总片重) [0046] Table 4 different screening process prescriptions (Discussion hardness, particle size distribution, fluidity index, compressibility index and the total tablet weight)

[0047] 表1 [0047] TABLE 1

Figure CN102138911AD00101

轻丙甲基纤维素卡波姆 Light methylcellulose carbomer

善达 Shanda

微晶纤维素硬脂酸镁微粉硅胶磷酸氢钙无水乙醇 Microcrystalline cellulose, calcium hydrogen phosphate magnesium stearate aerosil ethanol

[0062] [0062]

[0063] 制备过程及工艺(摇摆颗粒机制粒法): [0063] and preparation process (granulation mechanism rock particles):

[0064] 取处方量的药物、微晶纤维素、羟丙基纤维素、卡波姆、善达、磷酸氢钙,通过80目蹄网后于搅拌混合机中混合1小时后备用。 [0064] The formulation amount of the drug, microcrystalline cellulose, hydroxypropyl cellulose, carbomer, was good, dicalcium phosphate, mixing after 1 hour backup shoe 80 mesh net after stirring mixer. 取15%聚维酮溶液适量,喷入到备用的粉末中搅拌制成软材。 Take 15% povidone appropriate solution, the powder is injected into the spare stirred obtain a soft material. 打开摇摆制粒机,将软材通过M目筛网,挤出形成长度适宜的颗粒,放置于烘箱中70摄氏度干燥60分钟,进行均勻度和含水量检查,合格后,加入处方量的硬脂酸镁和微粉硅胶,混合1小时后加入到压片机中压片,既得双丙戊酸钠缓释片。 Granulator swing open, the soft material mesh M, the length of extrusion suitable particle form, placed in an oven dried 70 ° C for 60 minutes and water content uniformity inspection, after passing the formulation amounts of added stearyl aerosil and magnesium, was added after 1 hour of mixing to compression tableting machine, acquired divalproex sodium tablets.

[0065] 实施例2 [0065] Example 2

[0066] 1000片双丙戊酸钠缓释片处方 [0066] 1000 pairs of sodium valproate Tablets

[0067] [0067]

150. Og 40. Og 5. Og 5. Og 20g 适量 150. Og 40. Og 5. Og 5. Og 20g amount

附图说明 BRIEF DESCRIPTION

[0055] 图1优选处方所得双丙戊酸钠缓释片的体外释放度 [0055] FIG 1 is preferably obtained in vitro release of sustained-release tablets of divalproex sodium formulation

[0056] 图2复合骨架材料的筛选 [0056] Filter material 2 in FIG composite scaffold

[0057] 图3通过软件拟合的主要缓控释辅料用量优化的过程具体实施方式 [0057] 3 major amounts of slow release excipients optimization process by software fitting DETAILED DESCRIPTION FIG.

[0058] 以下为本发明的具体实施方式,所述的实施例是为了进一步描述本发明而不是限制本发明。 [0058] DETAILED DESCRIPTION The following present invention, according to further embodiments are described in the present invention without limiting the present invention. 凡与本发明等效的技术方案均属于本发明的保护范围。 Where the equivalent aspect of the present invention belong to the scope of the present invention.

[0059] 实施例1 [0059] Example 1

[0060] 1000片双丙戊酸钠缓释片处方 [0060] 1000 pairs of sodium valproate Tablets

[0061] [0061]

Figure CN102138911AD00111
Figure CN102138911AD00121

[0068] 8%低粘度羟丙甲基纤维素水溶液适量 [0068] 8% low viscosity hydroxypropyl methylcellulose solution amount

[0069] 制备过程及工艺: [0069] and preparation process:

[0070] 将药物与取处方量的药物、微晶纤维素、羟丙基纤维素、卡波姆、善达、磷酸氢钙粉碎,通过80目筛网后于搅拌混合机中混合1小时后,将粉体置于流化床床体中。 [0070] The pharmaceutical formulation amounts of the drug, microcrystalline cellulose, hydroxypropyl cellulose, carbomer, was good, calcium hydrogen phosphate pulverized, mixed for 1 hour by a 80 mesh sieve after the stirring mixer , the powder was placed in a fluidized bed. 配置8%低粘度羟丙甲基纤维素水溶液,加入处方量的微粉硅胶并搅拌使之成混悬液,采用流化床进行制粒,流化床制粒工艺为:蠕动泵输液速度为3ml/min、空气压缩机压力为2Bar、流化床进风温度35°C ;流化一段时间后取20-40目粒径的颗粒,70摄氏度干燥Ih后,进行均勻度和含水量检查,合格后,加入处方量的滑石粉,混合机中混合1小时后加入到压片机中进行压片,既得缓释片。 Configuration 8% low viscosity hydroxypropyl methylcellulose aqueous solution, the amount of micronized silica gel was added and the formulation was stirred to make into a suspension, use of fluidized bed granulation, fluidized bed granulation process: a peristaltic pump infusion rate of 3ml / min, air pressure 2Bar compressor, fluid bed inlet air temperature 35 ° C; particle size from 20 to 40 mesh particles were fluidized for some time, after drying Ih is 70 degrees Celsius, and the water content of the uniform inspection, after adding prescribed amount of talc mixed in a mixer is added to one hour tableting machine into tablets, sustained release tablets acquired.

[0071] 实施例3 [0071] Example 3

[0072] 1000片双丙戊酸钠缓释片处方 [0072] 1000 pairs of sodium valproate Tablets

[0073] [0073]

Figure CN102138911AD00122

[0074] 制备工艺: [0074] Preparation process:

[0075] 缓释片片芯的制备工艺:[0076] 将药物与取处方量的药物、微晶纤维素、羟丙基纤维素、乳糖、卡波姆、善达、磷酸氢钙粉碎,通过80目筛网后于搅拌混合机中混合1小时后,加入处方量的硬脂酸镁和滑石粉,混合机中混合0. 5小时后加入到压片机中进行直接压片,既得缓释片。 Preparation [0075] The core pieces release process: [0076] The pharmaceutical formulation amounts of the drug, microcrystalline cellulose, hydroxypropyl cellulose, lactose, Carbopol, was good, calcium hydrogen phosphate pulverized by direct compression after 80 mesh sieve after the stirring mixer for 1 hour, an amount of the formulation added magnesium stearate and talc, 0.5 hours were added to the blender tablet press, release vested sheet.

[0077] 实施例4 [0077] Example 4

[0078] 处方 [0078] Prescription

[0079] [0079]

Figure CN102138911AD00131

[0080] 制备工艺: [0080] Preparation process:

[0081] 缓释片片芯的制备工艺: [0081] The sustained release preparation of the core pieces:

[0082] 将药物与取处方量的药物、微晶纤维素、羟丙基纤维素、卡波姆、善达、磷酸氢钙粉碎,通过80目筛网后于搅拌混合机中混合1小时后,该粉体备用。 [0082] The pharmaceutical formulation amounts of the drug, microcrystalline cellulose, hydroxypropyl cellulose, carbomer, was good, calcium hydrogen phosphate pulverized, mixed for 1 hour by a 80 mesh sieve after the stirring mixer the powder standby. 配置15%适量的聚维酮溶液,像溶液中加入处方量的微粉硅胶并搅拌使之成混悬液,加入到药物粉体中制成软材。 Configuring an appropriate amount of a 15% povidone solution, was added as prescribed amount of micronized silica gel and stirred to make into a suspension, the drug was added to the powder made in soft material. 打开摇摆制粒机,将软材放入通过筛孔,筛孔选择16-20目筛网,形成长度适中的颗粒,放置于烘箱中40摄氏度干燥45分钟,进行均勻度和含水量检查,合格后,加入处方量的滑石粉,混合机中混合1小时后加入到压片机中进行压片,既得缓释片。 Open swing granulator, into the soft material by selecting 16-20 mesh sieve, sieve, forming granules of moderate length, placed in an oven and dried at 45 ° C in 40 minutes, and water content uniformity Inspection, after adding prescribed amount of talc mixed in a mixer is added to one hour tableting machine into tablets, sustained release tablets acquired.

Claims (10)

1. 一种双丙戊酸钠缓释片组合物,其特征在于,由双丙戊酸钠、阻滞剂、粘合剂、稀释剂、崩解剂、润滑剂、抗粘剂、PH调节剂组成。 A sustained-release tablet composition of divalproex sodium, which is characterized by the divalproex sodium, retarders, binders, diluents, disintegrants, lubricants, anti-adherents, PH regulator agent.
2.权利要求1的组合物,其特征在于: 各组分的质量百分比为:双丙戊酸钠 5%-70%阻滞剂 5%-60%粘合剂 0.1%-30%稀释剂 1%-50%崩解剂 1%-50%润滑剂 1%-50%抗粘剂 0.1%-20%pH调节剂 0.1%-20%。 The composition of claim 1, wherein: the mass percentage of the components are: 5% -70% divalproex sodium blockers 5-60% binder 0.1% to 30% diluent 1 % -50% -50% 1% disintegrant 1-50% lubricant 0.1% to 20% anti-tack agent the pH adjusting agent 0.1% to 20%.
3.权利要求2的组合物,其特征在于:其中阻滞剂为两种不同的成分,为阻滞剂1和阻滞剂2,两者在组合物中的质量百分比分别为:阻滞剂1 5%阻滞剂2 3%-15%。 The composition of claim 2, wherein: wherein the retarder of two different components of a blocker blockers and 2, both the mass percentage in the composition are: blockers blocker 15% 23% -15%.
4.权利要求3的组合物,其特征在于:其中所述阻滞剂1选用乙基纤维素、羟丙甲纤维素、羧甲基纤维素、甲基纤维素、羟丙基纤维素、聚丙烯酸、硬脂酸、棕榈蜡、壳聚糖中的一种或者几种的混合物。 The composition of claim 3, wherein: 1 wherein said retarder selected ethylcellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyethylene acid, stearic acid, carnauba wax, chitosan or a mixture of several. 优选羟丙甲基纤维素,其中对其甲基和羟丙基的取代度有要求,甲基取代比在15% _25%,羟丙基取代比在5% _15%,其2%的水溶液粘度应大于10000厘泊。 Preferably hydroxypropyl methylcellulose, and hydroxypropyl methyl substituted wherein its degree is required, a substituted methyl _25% than 15%, 5% hydroxypropyl substitution ratio _15%, a viscosity of a 2% aqueous solution It should be greater than 10,000 centipoise. 所述阻滞剂2选用羟丙甲基纤维素、羟丙基纤维素、预胶化淀粉、醋酸纤维素、乙基纤维素、聚谷氨酸、卡波姆。 2 the blocker selected hydroxypropylmethyl cellulose, hydroxypropyl cellulose, pregelatinized starch, cellulose acetate, ethyl cellulose, polyglutamic acid, carbomer. 优选卡波姆,并选用高纯度级别的口服型卡波姆,如卡波姆934P、 卡波姆974P。 Preferably the carbomer, and the selection of high purity grade oral carbomer type, such as carbomer 934P, carbomer 974P. 所述稀释剂选自以下辅料中选择一种或几种的混合物:乳糖、淀粉、微晶纤维素、预胶化淀粉、甘露醇、壳聚糖、糊精,优选的稀释剂为乳糖。 The diluent excipient selected the following mixture of one or more selected from: lactose, starch, microcrystalline cellulose, pregelatinized starch, mannitol, chitosan, dextrin, preferably the diluent is lactose. 所选粘合剂选自聚维酮、水、无水乙醇、不同比例的乙醇和水的混合物、淀粉浆、一定比例的羟丙甲纤维素的水溶液分散体;优选乙醇溶液,浓度在80% -99%。 The selected binder is selected from povidone, a mixture of water, ethanol, different ratios of ethanol and water, starch, a certain percentage of an aqueous solution of hydroxypropyl methylcellulose dispersion; preferably ethanol solution, at a concentration of 80% -99%. 所述润滑剂选用硬脂酸镁、滑石粉、氢化植物油、硬脂醇中的一种或几种的混合物,优选硬脂酸镁。 The choice of lubricant magnesium stearate, talc, hydrogenated vegetable oils, mixtures of one or more of stearyl alcohol, preferably magnesium stearate. 所述抗粘剂选用滑石粉、微粉硅胶、硬脂醇、硬脂酸镁,优选微粉硅胶,优选微粉硅胶。 The choice of anti-adherents as talc, silica powder, stearyl alcohol, magnesium stearate, preferably silica powder, preferably silica powder. 所述PH调节剂选用磷酸三钙、磷酸氢钙、磷酸二氢钙、磷酸氢钠、磷酸二氢钠、磷酸氢钾、磷酸二氢钾、碳酸氢钠或类似的磷酸盐、碳酸盐。 The PH adjusting agent selected tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium bicarbonate or the like, phosphates, carbonates.
5.权利要求4的组合物,其特征在于,各组分的质量为:制成1000片双丙戊酸钠缓释片处方双丙戊酸钠 125-250mg羟丙甲基纤维素 60-150mg卡波姆 5-70mg乳糖 80-160mg微晶纤维素 20-140mg硬脂酸镁 I-IOmg微粉硅胶 I-IOmg磷酸氢钙 5-50mg无水乙醇 适量 The composition of claim 4, wherein the mass of each component is: made of 1000 pairs of divalproex sodium valproate Tablets 125-250mg hydroxypropylmethyl cellulose 60-150mg carbomer 80-160mg lactose 5-70mg microcrystalline cellulose 20-140mg magnesium stearate aerosil I-IOmg I-IOmg anhydrous dibasic calcium phosphate 5-50mg ethanol q.s.
6.权利要求5的组合物,其特征在于,各组分的质量为:制成1000片双丙戊酸钠缓释片处方双丙戊酸钠 269. Ig羟丙甲基纤维素 llO.Og卡波姆 50.0g乳糖 80.0g微晶纤维素 lOO.Og硬脂酸镁 5.0g微粉硅胶 5.0g磷酸氢钙 20g无水乙醇 适量 The composition of claim 5, wherein the mass of each component is: made of 1000 pairs of divalproex sodium valproate Tablets 269. Ig hydroxypropylmethylcellulose llO.Og microcrystalline cellulose 50.0g lactose 80.0g carbomer lOO.Og silica powder 5.0g magnesium stearate 5.0g ethanol suitable amount of anhydrous calcium hydrogen phosphate 20g
7.权利要求1的组合物的制备方法,其特征在于,包括如下步骤:颗粒中间体制备:取处方量的药物与辅料,搅拌混合均勻,加入粘合剂,采用流化床制粒法、摇摆制粒机制粒法制粒或是剪切法制粒。 The method of preparing a composition according to claim 1, characterized by comprising the steps of: preparing particles of intermediate: the formulation amounts of drugs and excipients, mixing evenly, adding a binder, using a fluidized bed granulation method, swing pelletized grain shear granulation or granulation. 将所制得的颗粒干燥,一定时间后,将颗粒过筛,选取粒径大小适宜的颗粒,测定其水分含量,水分含量合格后加入处方量的润滑剂, 混合均勻,置入压片机,调试压力使之在适宜范围内,将与润滑剂混合均勻的颗粒压制成缓释片:取处方量包衣材料配制成包衣溶液,将包衣液雾化进行包衣。 The resulting granules are dried, after a certain time, the particles are sieved to select the appropriate size of the particle size, moisture content measured, the moisture content prescribed amount of lubricant is added after passing, mixed, placed in a tableting machine, commissioning pressure within an appropriate range so that the particles are mixed with a lubricant compressed into sustained-release tablets: the formulation amount of the coating material formulated as a coating solution, coating the coating liquid for atomization. 包衣结束后干燥一定时间,即得成品双丙戊酸钠缓释片。 After the coating has dried to a certain time, ie finished divalproex sodium tablets.
8.权利要求7的制备方法,其特征在于该方法包括如下步骤:直接压片法:取处方量的药物和辅料,分别将其粉碎至一定粒径,通过80至120目筛网后,混合均勻,置入压片机中,压片。 The method of preparation according to claim 7, characterized in that the method comprises the steps of: direct compression process: The formulation amount of drug and excipients, are pulverized to a certain particle size, between 80 and 120 through the mesh screen, mixed uniformly placed tableting machine, tabletting.
9.权利要求7的制备方法,其特征在于,1000片双丙戊酸钠缓释片处方 9. A production method as claimed in claim 7, wherein, 1,000 pairs of sodium valproate Tablets
Figure CN102138911AC00041
制备方法取处方量的药物、微晶纤维素、羟丙基纤维素、卡波姆、善达、磷酸氢钙,通过80目筛网后于搅拌混合机中混合1小时后备用。 The method of preparing a pharmaceutical formulation amounts, microcrystalline cellulose, hydroxypropyl cellulose, carbomer, was good, dicalcium phosphate, mixing after 1 hour through 80 mesh screen standby after stirring mixer. 取15%聚维酮溶液适量,喷入到备用的粉末中搅拌制成软材。 Take 15% povidone appropriate solution, the powder is injected into the spare stirred obtain a soft material. 打开摇摆制粒机,将软材通过M目筛网,挤出形成长度适宜的颗粒,放置于烘箱中70摄氏度干燥60分钟,进行均勻度和含水量检查,合格后,加入处方量的硬脂酸镁和微粉硅胶,混合1小时后加入到压片机中压片,既得双丙戊酸钠缓释片。 Granulator swing open, the soft material mesh M, the length of extrusion suitable particle form, placed in an oven dried 70 ° C for 60 minutes and water content uniformity inspection, after passing the formulation amounts of added stearyl aerosil and magnesium, was added after 1 hour of mixing to compression tableting machine, acquired divalproex sodium tablets.
10.权利要求7的制备方法,其特征在于,1000片双丙戊酸钠缓释片处方 10. The production method of claim 7, wherein, 1,000 pairs of sodium valproate Tablets
Figure CN102138911AC00042
制备方法取处方量的药物、微晶纤维素、羟丙基纤维素、卡波姆、善达、磷酸氢钙,通过80目筛网后于搅拌混合机中混合1小时后备用。 The method of preparing a pharmaceutical formulation amounts, microcrystalline cellulose, hydroxypropyl cellulose, carbomer, was good, dicalcium phosphate, mixing after 1 hour through 80 mesh screen standby after stirring mixer. 取15%聚维酮溶液适量,喷入到备用的粉末中搅拌制成软材。 Take 15% povidone appropriate solution, the powder is injected into the spare stirred obtain a soft material. 打开摇摆制粒机,将软材通过M目筛网,挤出形成长度适宜的颗粒,放置于烘箱中70摄氏度干燥60分钟,进行均勻度和含水量检查,合格后,加入处方量的硬脂酸镁和微粉硅胶,混合1小时后加入到压片机中压片,既得双丙戊酸钠缓释片。 Granulator swing open, the soft material mesh M, the length of extrusion suitable particle form, placed in an oven dried 70 ° C for 60 minutes and water content uniformity inspection, after passing the formulation amounts of added stearyl aerosil and magnesium, was added after 1 hour of mixing to compression tableting machine, acquired divalproex sodium tablets.
CN2011100756373A 2011-03-28 2011-03-28 Divalproex sodium sustained release tablets and preparation method thereof CN102138911B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2011100756373A CN102138911B (en) 2011-03-28 2011-03-28 Divalproex sodium sustained release tablets and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN2011100756373A CN102138911B (en) 2011-03-28 2011-03-28 Divalproex sodium sustained release tablets and preparation method thereof

Publications (2)

Publication Number Publication Date
CN102138911A true CN102138911A (en) 2011-08-03
CN102138911B CN102138911B (en) 2012-12-12

Family

ID=44406856

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2011100756373A CN102138911B (en) 2011-03-28 2011-03-28 Divalproex sodium sustained release tablets and preparation method thereof

Country Status (1)

Country Link
CN (1) CN102138911B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103230380A (en) * 2013-05-06 2013-08-07 北京四环制药有限公司 Divalproex sodium enteric-coated tablet core as well as preparation method and application thereof
CN104146976A (en) * 2014-08-06 2014-11-19 沈阳药科大学 Heavy-load valproic acid drug sustained release tablet and preparation method thereof
CN106389368A (en) * 2015-07-29 2017-02-15 四川科瑞德制药股份有限公司 Sodium valproate sustained release preparation as well as preparation process and applications thereof
CN107028907A (en) * 2016-02-04 2017-08-11 成都康弘药业集团股份有限公司 A kind of Divalproex sodium sustained-release tablet

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1335769A (en) * 1998-12-18 2002-02-13 艾博特公司 Controlled release formulation of divalproex sodium
WO2003103635A1 (en) * 2002-06-07 2003-12-18 Ranbaxy Laboratories Limited Extended release formulation of divalproex sodium
CN1921838A (en) * 2004-02-19 2007-02-28 兰贝克赛实验室有限公司 Extended release pharmaceutical compositions of divalproex sodium

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1335769A (en) * 1998-12-18 2002-02-13 艾博特公司 Controlled release formulation of divalproex sodium
WO2003103635A1 (en) * 2002-06-07 2003-12-18 Ranbaxy Laboratories Limited Extended release formulation of divalproex sodium
CN1921838A (en) * 2004-02-19 2007-02-28 兰贝克赛实验室有限公司 Extended release pharmaceutical compositions of divalproex sodium

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
《JOURNAL OF PHARMACEUTICAL SCIENCES》 20030630 YIHONG QIU et al Once-a-Day Controlled-Release Dosage Form of Divalproex Sodium I: Formulation Design and In Vitro/In Vivo Investigations 1167页"实验"部分至1172页"结果及讨论"部分 1-4 第92卷, 第6期 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103230380A (en) * 2013-05-06 2013-08-07 北京四环制药有限公司 Divalproex sodium enteric-coated tablet core as well as preparation method and application thereof
CN103230380B (en) * 2013-05-06 2015-02-18 北京四环制药有限公司 Divalproex sodium enteric-coated tablet core as well as preparation method and application thereof
CN104146976A (en) * 2014-08-06 2014-11-19 沈阳药科大学 Heavy-load valproic acid drug sustained release tablet and preparation method thereof
CN104146976B (en) * 2014-08-06 2017-02-15 沈阳药科大学 Heavy-load valproic acid drug sustained release tablet and preparation method thereof
CN106389368A (en) * 2015-07-29 2017-02-15 四川科瑞德制药股份有限公司 Sodium valproate sustained release preparation as well as preparation process and applications thereof
CN107028907A (en) * 2016-02-04 2017-08-11 成都康弘药业集团股份有限公司 A kind of Divalproex sodium sustained-release tablet

Also Published As

Publication number Publication date
CN102138911B (en) 2012-12-12

Similar Documents

Publication Publication Date Title
DK175627B1 (en) Pharmaceutical preparation for oral administration with controlled release and prolonged action
CN100473382C (en) Oral dosage form for propiverine or pharmaceutically acceptable salts thereof with an extended release of the active ingredient
JP4219988B2 (en) Fenofibrate pharmaceutical composition having high bioavailability and method for preparing the same
CN1248690C (en) Oral preparation containing ranolazine hydrochloride for treating cardiovascular disease
KR20110116027A (en) Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix
DK1351668T3 (en) Pharmaceutical dosage forms with delayed release and minimized with pH-dependent solubility profiles
KR940011242B1 (en) Process for preparing sustained-release pharmaceutical preparations
CN1997354B (en) Galenic formulations of organic compounds
CN1170540C (en) Sustained-release theophylline tablet
DE69913197T2 (en) Sodium hydrogen dival program formulations with controlled release
US9387191B2 (en) Ferric citrate dosage forms
JP2638389B2 (en) Slow release matrix tablet indapamide after oral administration
US20070059365A1 (en) Novel formulation of ropinirole
KR20080012306A (en) Pharmaceutical composition
EP2200591A2 (en) Controlled release pharmaceutical dosage forms of trimetazidine
EP1238662B1 (en) Method for manufacturing drug granules, the drug granules and pharmaceutical preparation containing the drug granules
US20040156898A1 (en) Controlled release formulation of divalproex sodium
JP6151727B2 (en) Ulipristal acetate ester tablets
WO2010080580A2 (en) Extended-release pharmaceutical formulations
JP6357687B2 (en) Formulation of lacosamide once a day
AU2007242984A1 (en) Controlled released preparations of oxcarbazepine having sigmoidal release profile
JP5816091B2 (en) Sodium oxybate immediate release dosage form
US20110111027A1 (en) Immediate release formulations and dosage forms of gamma-hydroxybutyrate
CN1168792A (en) Matrix table allowing prolonged release of sodium salt of tianeptine after administration by oral route
FR2819720A1 (en) New tablets of fenofibrate

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
C14 Grant of patent or utility model
ASS Succession or assignment of patent right

Owner name: ZHONGSHUAI PHARMACEUTICAL SCIENCE AND TECHNOLOGY I

Free format text: FORMER OWNER: SUN WEIDONG

Effective date: 20140123

C41 Transfer of patent application or patent right or utility model