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Publication numberCN1189171 C
Publication typeGrant
Application numberCN 01807427
PCT numberPCT/EP2001/003502
Publication date16 Feb 2005
Filing date28 Mar 2001
Priority date3 Apr 2000
Also published asCA2401910A1, CA2401910C, CN1420771A, DE60140662D1, EP1272179A1, EP1272179B1, US20010036959, US20030004205, US20050271721, WO2001074357A1
Publication number01807427.8, CN 01807427, CN 1189171 C, CN 1189171C, CN-C-1189171, CN01807427, CN01807427.8, CN1189171 C, CN1189171C, PCT/2001/3502, PCT/EP/1/003502, PCT/EP/1/03502, PCT/EP/2001/003502, PCT/EP/2001/03502, PCT/EP1/003502, PCT/EP1/03502, PCT/EP1003502, PCT/EP103502, PCT/EP2001/003502, PCT/EP2001/03502, PCT/EP2001003502, PCT/EP200103502
InventorsR-D格贝尔, A维尔, W普雷斯, G诺伊格鲍尔
Applicant弗哈夫曼-拉罗切有限公司
Export CitationBiBTeX, EndNote, RefMan
External Links: SIPO, Espacenet
Hydrophilic molecular disperse solutions of carvedilol
CN 1189171 C
Abstract  translated from Chinese
本发明涉及药学上可接受的组合物,其包含作为一种浓度在5%(重量/重量)以上的分子分散体分布的卡维地洛或其药学上可接受的盐,以及涉及包含这些组合物的给药剂型和它们用于治疗和/或预防疾病如高血压、心机能不全或心绞痛的用途。 Salts of the present invention relates to a pharmaceutically acceptable composition comprising as an acceptable concentration of 5% (w / w) or more of the molecular dispersion of the distribution of carvedilol or a pharmaceutically acceptable, and which comprise these combinations matter of dosage forms and their use for the treatment and / or prevention of diseases such as hypertension, cardiac insufficiency or angina purposes.
Claims(22)  translated from Chinese
1.一种药学上可接受的组合物,包含作为一种浓度在5%重量/重量以上的在一种或多种不具有表面活性的佐剂或一种或多种非离子表面活性剂中作为分子分散体分布的卡维地洛或其药学上可接受的盐。 A pharmaceutically acceptable composition comprising as a concentration of 5% w / w of at least one or more surfactants or adjuvants one or more nonionic surfactants having no in As the molecular dispersion of the distribution of carvedilol or a pharmaceutically acceptable salt thereof.
2.根据权利要求1的组合物,所述组合物为固体或半固体溶液。 The composition according to claim 1, wherein the composition is a solid or semi-solid solution.
3.根据权利要求1的组合物,其中聚乙二醇作为不具有表面活性的佐剂存在。 The composition according to claim 1, wherein the polyethylene glycol as a surfactant adjuvants having no existence.
4.根据权利要求3的组合物,其中所述聚乙二醇的分子量为1,000-20,000。 The composition according to claim 3, wherein the polyethylene glycol has a molecular weight from 1,000 to 20,000.
5.根据权利要求4的组合物,其中所述聚乙二醇的分子量为4,000-10,000。 The composition according to claim 4, wherein said polyethylene glycol has a molecular weight 4,000-10,000.
6.根据权利要求1的组合物,其中一种糖替代物作为不具有表面活性的佐剂存在。 The composition according to claim 1, wherein a sugar substitute as having no adjuvant surfactant present.
7.根据权利要求6的组合物,其中益寿糖作为糖替代物存在。 The composition according to claim 6, wherein isomalt is present as the sugar substitute.
8.根据权利要求1的组合物,其中聚氧乙烯-聚氧丙烯共聚物作为非离子表面活性剂。 The composition according to claim 1, wherein the polyoxyethylene - polyoxypropylene copolymer as the non-ionic surfactant.
9.根据权利要求7或8的组合物,其中不具有表面活性的佐剂与非离子表面活性剂的比率为1000∶1至1∶1。 9. The composition ratio of 7 or claim 8, wherein the adjuvant surfactant having no nonionic surfactant is 1000:1 to 1:1.
10.根据权利要求9的组合物,其中不具有表面活性的佐剂与非离子表面活性剂的比率为100∶1至10∶1。 Ratio of 10. The composition of claim 9, wherein the adjuvant surfactant having no nonionic surfactant is 100 to 1 to 10:1.
11.根据权利要求1的组合物,其中所述卡维地洛的浓度为5%重量/重量-60%重量/重量。 11. The composition of claim 1, wherein the concentration of carvedilol is 5% w / w to 60% w / w.
12.根据权利要求11的组合物,其中所述卡维地洛的浓度为10%重量/重量-40%重量/重量。 12. The composition of claim 11, wherein the concentration of carvedilol was 10% w / w to 40% w / w.
13.根据权利要求1的组合物,其中存在高度分散的二氧化硅。 13. The composition of claim 1, wherein the presence of highly dispersed silica.
14.根据权利要求13的组合物,其包含10-20%重量/重量的卡维地洛、65-85%重量/重量的聚乙二醇、1-10%重量/重量的聚氧乙烯-聚氧丙烯共聚物和0.1-10%重量/重量的高度分散的二氧化硅。 14. The composition of claim 13, comprising 10 to 20% w / w of carvedilol, 65-85% w / w of polyethylene glycol, 1-10% w / w of polyoxyethylene - polyoxypropylene copolymer and 0.1-10% wt / wt highly dispersed silicon dioxide.
15.一种包含权利要求1-14之任一项的组合物的药学上可接受的给药剂型。 15. A composition comprising any one of claims 1 to 14 of a pharmaceutically acceptable dosage forms.
16.根据权利要求15的药学上可接受的给药剂型,所述给药剂型具有改良的活性物质释放,其中95%的活性物质在2-24小时内释放。 According to claim 15 in a pharmaceutically acceptable dosage form, the dosage form having modified release of active substance, 95% of the active substance is released within 2-24 hours.
17.根据权利要求15或权利要求16的药学上可接受的给药剂型,所述给药剂型是固体给药剂型。 17. The claim 15 or claim 16 in a pharmaceutically acceptable dosage form, the dosage form is administered in a solid dosage form.
18.根据权利要求15或权利要求16的药学上可接受的给药剂型,所述给药剂型是口服给药剂型。 As claimed in claim 15 or claim 16, a pharmaceutically acceptable dosage form, the dosage form is a dosage form for oral administration.
19.一种用于生产权利要求1-14之任一项的组合物的方法,所述方法包括将卡维地洛与不具有表面活性的佐剂和/或非离子表面活性剂混合。 19. A method for producing a composition according to claim any one of 1 to 14, said method comprising carvedilol and no adjuvant surface active agent and mixing / or nonionic surfactants.
20.根据权利要求19的方法,其中通过喷雾固化将所得的熔化物固化。 20. The method according to claim 19, wherein the resulting cured by spraying melt solidified.
21.根据权利要求1-14之任一项的组合物用于生产治疗或预防疾病的药物的用途。 21. The process of any one of 1 to 14 for producing a composition according to claim medicament for treatment or prevention of disease uses.
22.根据权利要求21的用途,其中所述疾病是高血压、心机能不足或心绞痛。 22. The use according to claim 21, wherein the disease is hypertension, cardiac insufficiency or angina pectoris.
Description  translated from Chinese
卡维地洛的亲水分子分散液 Carvedilol hydrophilic molecular dispersion

本发明涉及卡维地洛和/或其药学上可接受的盐的浓缩的固体或半固体、亲水分子分散液,包含这些溶液的给药剂型和它们用于治疗或预防疾病的用途。 The present invention relates to carvedilol and / or a pharmaceutically acceptable salt concentrated solid or semi-solid, hydrophilic molecular dispersion dosage forms containing these solutions and their use for the treatment or prevention of disease.

卡维地洛是一种含血管舒张组分的非选择性β-阻断剂,它通过拮抗α-肾上腺素受体而起作用。 Carvedilol is a non-selective β- blocker component comprising a vasodilator, which α- adrenergic receptor by antagonizing effect. 而且,卡维地洛还具有抗氧化性能。 Moreover, carvedilol also has antioxidant properties. 卡维地洛(1-(4-咔唑基氧基)-3-[2-(2-甲氧基苯氧基)乙基-氨基]-2-丙醇)是欧洲专利0 004920的对象,且可以根据其所述的方法制备。 Carvedilol (1- (4-carbazolyl) -3- [2- (2-methoxyphenoxy) ethyl - amino] -2-propanol) is the object of European Patent 0 004 920 and which can be prepared according to the method described in.

在制药技术中,固体分子的分散液是固体分散体的一个小组。 In pharmaceutical technology, solid molecular dispersion liquid is a group of solid dispersions. “固体或半固体分散体”在药学文献中理解为一种或多种固体如卡维地洛和/或其药学上可接受的盐在惰性、固体或半固体状的载体中的细小分散分布。 "Solid or semi-solid dispersion" is understood as one or more solid in the pharmaceutical literature as carvedilol and / or a pharmaceutically acceptable salt small inert, solid or semi-solid carrier dispersed distribution . 活性物质可以分子分散的形式存在,即单分子分布成为一种固体真溶液或在玻璃状非晶相中的细小结晶分散形式。 Active substance may be present in the form of molecular dispersion, i.e. the distribution of a single molecule or a true solution into a solid glassy amorphous phase in fine crystalline dispersed form. 但是,共晶混合物,即特定混合比的极细分布的活性物质和佐剂的结晶结构也在此常规术语的范围内。 However, the eutectic mixture, within the scope of the active substance that is a particular distribution of the mixing ratio of fine crystal structure and an adjuvant would also like conventional terms. 其中,过渡形式是可能的。 Among them, the transitional forms are possible. 这种分散材料的尺寸始于原子或分子,并由它们扩大到若干毫米度量的颗粒。 This size of the dispersed material began atoms or molecules, which expanded by a few millimeters to measure the particles. 因此,平均颗粒直径用作一种对分散体系进行分类的适宜的度量。 Therefore, the average particle diameter of the dispersion system was used as a suitable measure of classification. 一般来说,区分为分子分散(<1.0μm,固体或半固体溶液)、胶体分散(1-100μm)和粗分散(<0.5μm)体系。 In general, divided into molecularly dispersed (<1.0μm, solid or semi-solid solution), colloidal dispersion (1-100μm) and coarse dispersion (<0.5μm) system. 因此,必须考虑到这些分类界限在一定程度上是任意建立的,因为各种体系之间的过渡没有被清楚地定义。 Therefore, we must take into account the boundaries of these categories is arbitrary to some extent established, because the transition between various systems has not been clearly defined. 真固体溶液在其严格的物理学含义上是指通过将混合结晶形式的组分进行普通结晶而得到的仅有的单相体系。 Really solid solution on its strict physics refers to the ordinary meaning of crystallization by mixing the components obtained in crystalline form only a single phase system. 各种可能形式的状态的组合经常导致固体分散体的产生。 Combinations of various possible forms of state frequently result in solid dispersions. 可以通过X-射线衍射光谱或差热分析来确定最为明显的主要特征。 It can be determined by means of the main features of the most significant X- ray diffraction spectra or differential thermal analysis.

卡维地洛的“药学上可接受的盐”包括碱金属盐如Na或K盐,碱土金属盐如Ca或Mg盐,以及与诸如以下有机酸或无机酸的盐:盐酸、氢溴酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸或甲苯磺酸,它们对活生物体无毒。 Carvedilol "pharmaceutically acceptable salts" includes alkali metal salts such as Na or K salts, alkaline earth metal such as Ca or Mg salts, and salts with organic or inorganic acids such as the following: the hydrochloric, hydrobromic, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, mesylate or tosylate, their non-toxic to living organisms.

当pH值在药学相关的1-8范围内时,卡维地洛在含水介质中的溶解度为大约1mg-100mg/100ml(取决于pH值)。 When the pH value in the range of 1-8 in a pharmaceutically relevant, carvedilol solubility in aqueous media is about 1mg-100mg / 100ml (depending on the pH value). 已发现此pH值是有问题的,尤其是在高度浓缩的肠胃外配方如注射液或其它用于生产小体积的眼或口给药剂型的配方的配制中。 This has been found that the pH is problematic, especially in the preparation of highly concentrated parenteral formulations such as injection or other means for the production of small volume administration forms for ocular or oral formulation.

在快速释放的卡维地洛配方如商用配方的经口给药的情况下,达到至多80%的吸收度,其中相当一部分再吸收的卡维地洛被非常快速地代谢。 In the case of oral administration of rapid release carvedilol formulations such as commercial formula, reaching up to 80% of the absorption, of which a considerable part of the resorbed carvedilol being very rapidly metabolized.

关于卡维地洛的胃肠道再吸收的研究,已确定卡维地洛的再吸收在通过胃肠道如在回肠和结肠期间变弱,仅占胃再吸收的一部分。 About gastrointestinal resorption of carvedilol studies have identified carvedilol reabsorption in the gastrointestinal tract, such as during the ileum and colon become weak, only a portion of the stomach resorption. 发现这种情况是非常不利的,特别是在应当在数小时内发生释放的缓释剂型的研制过程中。 It found that the situation is very bad, especially in should occur within a few hours of sustained release dosage form development process of. 据推测较弱的再吸收全部或至少部分归因于卡维地洛的溶解度随pH值的升高而下降。 Presumably weak resorption all or at least part due to the solubility of carvedilol with increasing pH value decreases. 在强酸区(大约pH1-2)也可获得非常低的溶解度。 In the acid region (about pH1-2) can be obtained with very low solubility.

为了改善再吸收度,特别是在较低的肠区的再吸收度,已分别进行关于佐剂和适于增加卡维地洛的溶解度和/或溶解速度的配方的研究。 In order to improve the re-absorption, particularly in the re-absorption of the lower intestinal region, respectively studies on adjuvant and adapted to increase the solubility of carvedilol and / or dissolution rate of the formulation.

因此,本发明的基本目的是使用制药技术中可获得的试剂改善卡维地洛的再吸收,特别是在经口给药情况下,具体在较低的肠区的再吸收。 Therefore, the basic object of the present invention is the use of pharmaceutical agents available technology to improve the resorption of carvedilol, particularly in the case of oral administration, particularly in the lower intestinal reabsorption region.

从以下的事实出发:一方面卡维地洛的pH依赖性溶解度和另一方面卡维地洛的溶解速度代表至少一个卡维地洛再吸收的限制因素,施用溶解形式的卡维地洛应该能够改善再吸收。 From the following facts: on the one hand carvedilol pH-dependent solubility and on the other hand carvedilol dissolution rate limiting factor in at least one representative of carvedilol resorption, administration dissolved form of carvedilol should re-absorption can be improved. 但是因为如上所述,在药学相关范围内的含水介质中卡维地洛的溶解度非常低,所以由于实际的原因排除使用水溶液形式的最终药物。 But because, as mentioned in the relevant range of pharmacy aqueous medium carvedilol solubility is very low, so for practical reasons to exclude the use of an aqueous solution of the final drug.

已具体尝试提供浓缩的固体经口配方,其中,活性物质作为一种分子分散体分布,并因此而可以被更快速地再吸收。 Specific attempts have been concentrated to provide a solid oral formulation, wherein the active substance distributed as a molecular dispersion, and can thus be resorbed more quickly.

这种难溶性药物的“固体”分子分散液的一些实例,所谓的“固体溶液”根据文献是已知的。 Some examples of "solid" elements such dispersions of poorly soluble drugs, the so-called "solid solution" is known in the literature. 因此,可以通过从有机溶剂生产皮质类固醇和聚乙烯吡咯烷酮(PVP)的共沉淀物而短暂地产生澄清的过饱和溶液。 Therefore, the production from the organic solvent by corticosteroids and polyvinylpyrrolidone (PVP) and co-precipitate briefly produce a supersaturated solution clarification.

研究已确定卡维地洛可以溶于处在有机溶剂如二氯甲烷中的聚乙烯吡咯烷酮(PVP)或羟丙基甲基纤维素(HPMC)的溶液。 Research has determined that carvedilol may be dissolved in an organic solvent such as dichloromethane polyvinylpyrrolidone (PVP) or hydroxypropyl methyl cellulose (HPMC) was added. 在除去溶剂之后,由此分别获得在PVP或HMPC中的固体溶液。 After the solvent was removed, thereby obtaining a solid solution in PVP or, respectively, HMPC. 未交联的并具有8000-630000、优选25000分子量的聚乙烯吡咯烷酮可以用于配方中。 Uncrosslinked and have 8000-630000, preferably 25,000 molecular weight polyvinylpyrrolidone may be used in the formulation.

但是,对于工业化应用,优选在避开使用有机溶剂的情况下制得的药学上可接受的配方。 However, for the industrial applications, it is preferable to avoid the use of organic solvents in the case to obtain a pharmaceutically acceptable formulation.

作为对上述共沉淀物的一种可替代的选择,还考虑所谓“固化的熔化物”形式的固体溶液。 As one of the above coprecipitate alternative choices, but also to consider the so-called solid solutions "solidified melt" form. 但是作为考虑这些熔化物的基础的一些佐剂的实验表明,如果将卡维地洛“埋入”这些佐剂,则也得不到非结晶形态,即在此溶液固化之后得不到作为分子分散体的分布;因而全部或部分得到的非结晶形态仅可保持短时间,或者熔化物的足够快速的固化不再占主导地位。 But as a basis for considering some of these melt adjuvant experiments show that if the carvedilol "buried" These adjuvants, it is also not a non-crystalline form, that is, after curing this solution can not be used as molecular Distribution dispersion; fast enough so that all of the cured or partially non-crystalline form can be maintained only a short time, or melt no longer dominant.

令人惊奇的是,现已发现卡维地洛可以在特定的条件下溶于某些选择的佐剂中,且其中的活性物质即使在室温下也保持分子分布。 Surprisingly, it has been found that carvedilol can be dissolved in certain selected adjuvants under certain conditions, and in which the active substance is maintained even at room temperature molecular distribution. 由此,获得固体或蜡状配方(所谓的固体溶液),其中卡维地洛以分子分散形式,即非晶形式存在。 Thus, a solid or waxy formula (so-called solid solution), which carvedilol in molecular dispersed form, which amorphous form.

关于这些佐剂的实例,可以列举具体的不具有表面活性的佐剂,如聚乙二醇(PEG)或糖替代物以及非离子表面活性剂,例如聚氧乙烯硬脂酸酯如Myrj52,或聚氧乙烯-聚氧丙烯共聚物如PluronicF 68。 Examples of these adjuvants include surfactants having no specific adjuvants, such as polyethylene glycol (PEG) or sugar substitutes as well as non-ionic surfactants, such as polyoxyethylene stearates e.g. Myrj52 , or polyoxyethylene - polyoxypropylene copolymers e.g. PluronicF 68.

上述聚氧乙烯-聚氧丙烯共聚物中的亲水聚氧乙烯基的含量优选为70%-90%。 Said polyoxyethylene - polyoxypropylene copolymer content of hydrophilic polyoxyethylene is preferably 70% to 90%. 在一个特别优选的实施方案中,亲水聚氧乙烯基与亲水聚氧丙烯基的比率为大约80∶20,平均分子量优选为大约8750。 In a particularly preferred embodiment, the ratio of hydrophilic polyoxyethylene polyoxypropylene and hydrophilic groups is about 80:20, preferably an average molecular weight of about 8750.

上述的聚氧乙烯硬脂酸酯优选具有亲水亲油平衡(HLB)值为10-20,优选14-20,特别是16-18。 Said polyoxyethylene stearates preferably have a hydrophilic-lipophilic balance (HLB) value of 10-20, preferably 14-20, especially 16-18.

在糖替代物,尤其是益寿糖(isomalt)(氢化的异麦芽酮糖醇)系列中,发现Palatinit特别合适。 Sugar substitutes, especially isomalt (isomalt) (hydrogenated isomaltulose alcohol) series, found Palatinit particularly suitable. Palatinit是一种氢化的异麦芽酮糖醇,它由大约等份的1-O-α-D-吡喃葡萄糖基-D-山梨醇和1-O-α-D-吡喃葡萄糖基-D-甘露糖醇二水合物组成。 Palatinit is a hydrogenated isomaltulose alcohols, which consists of approximately equal parts of 1-O-α-D- glucopyranosyl -D- sorbitol and 1-O-α-D- glucopyranosyl -D - mannitol dihydrate composition.

而且,关于本发明,发现分子量为1,000-20,000,优选4,000-10,000,尤其是6,000-8,000的聚乙二醇特别合适。 Furthermore, with the present invention, a molecular weight of 1,000 to 20,000 was found, preferably 4,000-10,000, especially 6,000-8,000 polyethylene glycol are particularly suitable.

在本发明的一个优选的实施方案中,将卡维地洛溶于非离子表面活性剂,优选Pluronic68,或者溶于不具有表面活性的佐剂,优选聚乙二醇6,000。 In a preferred embodiment of the present invention, the carvedilol is dissolved in a non-ionic surfactant, preferably Pluronic68, or dissolved without a surface active adjuvants, preferably polyethylene glycol 6,000.

因此,可以将卡维地洛溶于在约70℃下熔化的聚乙二醇6,000。 Therefore, carvedilol is dissolved at about 70 ℃ molten polyethylene glycol 6,000. 以这种方式获得高度浓缩的卡维地洛溶液(最大500mg/ml),其中的卡维地洛作为一种分子分散体分布在溶液中。 In this manner a highly concentrated solution of carvedilol (up to 500mg / ml), which carvedilol distributed as a molecular dispersion in solution. 而且,可以将其它添加剂,例如纤维素衍生物如羟丙基甲基纤维素或羟丙基纤维素混合以控制活性物质的释放。 Furthermore, other additives may be, e.g., cellulose derivatives such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose were mixed to control the release of the active substance. 而且,本发明的组合物可以包含高度分散的二氧化硅作为抗结块剂。 Furthermore, the compositions of the present invention can contain highly dispersed silicon dioxide as an anti-caking agent.

可以用上述的佐剂生产其中卡维地洛作为分子分散体分布的浓缩的药学上可接受的固体溶液。 You can use the above adjuvant production which carvedilol as a concentrated dispersion of the distribution of molecular pharmaceutically acceptable solid solution.

因此,本发明涉及药学上可接受的组合物,所述组合物包含作为一种浓度在5%(重量/重量)以上的分子分散体分布的卡维地洛或其药学上可接受的盐。 Accordingly, the present invention relates to pharmaceutically acceptable compositions, the composition comprises, as a concentration of 5% (w / w) or more of the molecular dispersion of the distribution of carvedilol or a pharmaceutically acceptable salt of the combination.

作为一种分子分散体分布,应理解为活性物质单分子分布在适宜的载体中。 Distributed as a molecular dispersion, it should be understood a monomolecular distribution of the active substance in a suitable carrier.

在优选的实施方案变型中,本发明组合物中的卡维地洛含量为5%(重量/重量)-60%(重量/重量),优选5%(重量/重量)-50%(重量/重量),特别是10%(重量/重量)-40%(重量/重量),其中的重量%具体与组合物(活性物质和佐剂)的总重量有关。 In a preferred embodiment variant, the compositions of the present invention carvedilol content of 5% (w / w) to 60% (w / w), preferably 5% (w / w) to 50% (w / by weight), in particular a 10% (wt / wt) -40% (wt / wt), and wherein the weight% of specific composition (active substance and adjuvant) is related to the total weight.

包含本发明这些固体溶液的卡维地洛配方具有较好的活性物质再吸收度,并因此与含有结晶卡维地洛的配方相比改善了生物利用度,因为活性物质的溶解形式比结晶状态更快速地被再吸收。 These solid solutions of the present invention contain carvedilol formulations with good resorption of the active substance, and as compared with formulations containing crystalline carvedilol improves the bioavailability, since the active substance in the form of soluble than the crystalline state more quickly reabsorbed.

可以通过例如X-射线衍射法和/或差示扫描量热法(DSC)分别检测和控制卡维地洛作为一种在基质中的分子分散体,即所谓的非结晶形态(与通常的结晶形态相比)的分布。 For example, by X- ray diffraction method and / or differential scanning calorimetry (DSC) were used to detect and control carvedilol as a molecular dispersion in the matrix, the so-called non-crystalline form (with the usual crystalline or Compared form) distribution.

特别优选室温下为固体的溶液。 The solid solution is particularly preferably at room temperature. 在一个优选的实施方案中,本发明的佐剂的熔点小于120℃,特别是熔点为30-80℃。 In a preferred embodiment, the adjuvant of the present invention is less than the melting point of 120 ℃, especially a melting point of 30-80 ℃.

上述的佐剂可以单独或与两种或更多种佐剂组合使用。 The above-mentioned adjuvants may be used alone or in combination with two or more adjuvants in combination. 特别优选不具有表面活性的佐剂(优选聚乙二醇)与非离子表面活性剂(优选聚氧乙烯-聚氧丙烯共聚物如PluronicF68)的组合。 Particularly preferably not a surface active adjuvants (preferably polyethylene glycol) and nonionic surfactant (preferably polyoxyethylene - polyoxypropylene copolymers e.g. PluronicF68) combination. 使用这些佐剂混合物,一方面可以生产稳定的卡维地洛固体溶液,另一方面表面活性物质的加入可以加快活性物质从固体溶液中释放。 Using these adjuvant mixture, one can produce a stable carvedilol solid solution, on the other surface-active substances can be added to accelerate the release of active substance from the solid solution.

发现含有佐剂聚乙二醇(优选聚乙二醇6,000)以及0.1%-50%、优选0.1%-10%的聚氧乙烯-聚氧丙烯共聚物如PluronicF68的卡维地洛的固体溶液特别合适。 Found to contain adjuvants polyethylene glycol (preferably polyethylene glycol 6,000) and 0.1% to 50%, preferably 0.1% to 10% of polyoxyethylene - polyoxypropylene copolymers such as PluronicF68 carvedilol solid Particularly suitable solution.

在本发明的一个具体的实施方案中,上述不具有表面活性的佐剂如聚乙二醇6,000与表面活性佐剂如PluronicF68的比率为1000∶1至1∶1,优选100∶1至10∶1。 In one specific embodiment of the present invention, not having the above-described surface active adjuvants such as polyethylene glycol 6,000 with a surfactant adjuvants such PluronicF68 ratio of 1000:1 to 1, preferably to 100:1 10:1.

本发明的卡维地洛的固体溶液和由其生产的药物还可以包含其它添加剂,如粘合剂、增塑剂、稀释剂、载体物质、润滑剂、抗静电剂、抗氧剂、吸附剂、分离剂、分散剂、糖衣喷漆(drageeing lacquer)、消泡剂、成膜剂、乳化剂、膨胀剂和填充剂。 Carvedilol solid solution and its production of agents of the invention may also contain other additives, such as binders, plasticizers, diluents, carrier materials, lubricants, antistatic agents, antioxidants, adsorbents separating agents, dispersing agents, sugar-coated paint (drageeing lacquer), defoamers, film forming agents, emulsifiers, extenders and fillers.

上述的添加剂可以是有机或无机物质,如水、糖、盐、酸、碱、醇、有机聚合物等等。 The above-described additives may be organic or inorganic substances, water, sugar, salts, acids, bases, alcohols, organic polymers and the like. 优选的添加剂为乳糖、蔗糖、α-乳糖-水合物的聚合物(tablettose)、羧甲基淀粉钠、硬脂酸镁、各种纤维素和取代的纤维素如甲基羟丙基纤维素、聚合纤维素化合物、高度分散的二氧化硅、玉米淀粉、滑石、各种聚合聚乙烯吡咯烷酮化合物以及聚乙烯醇及其衍生物。 Preferred additives are lactose, saccharose, α- lactose - monohydrate polymer (tablettose), sodium carboxymethyl starch, magnesium stearate, various celluloses and substituted celluloses such as hydroxypropyl methyl cellulose, polymeric cellulose compounds, highly dispersed silicon dioxide, maize starch, talc, various polymeric polyvinylpyrrolidone compounds as well as polyvinyl alcohols and derivatives thereof. 先决条件是在生产中所用的所有添加剂是无毒的,且有利地不改变活性物质的生物利用度。 Prerequisite that all additives used in production are non-toxic and advantageously do not change the bioavailability of the active substance.

在优选的实施方案中,本发明的组合物包含卡维地洛、聚乙二醇、聚氧乙烯-聚氧丙烯共聚物以及高度分散的二氧化硅。 In a preferred embodiment, the compositions of the present invention comprises carvedilol, polyethylene glycol, polyoxyethylene - polyoxypropylene copolymers, and highly dispersed silica. 在特别优选的实施方案中,本发明的组合物包含10-20%(重量/重量)卡维地洛、65-85%(重量/重量)聚乙二醇、1-10%(重量/重量)聚氧乙烯-聚氧丙烯共聚物和0.1-10%(重量/重量)高度分散的二氧化硅,其中的百分比涉及四种指定物质的总重量,而不管组合物中是否存在附加的佐剂。 In a particularly preferred embodiment, the compositions of the present invention comprises 10-20% (w / w) carvedilol, 65-85% (wt / wt) polyethylene glycol, 1-10% (w / w ) Polyoxyethylene - polyoxypropylene copolymer and 0.1-10% (wt. / wt.) highly dispersed silicon dioxide, which is directed to the percentage of the total weight of the four specified substance, and regardless of whether the composition is the presence of additional adjuvants .

当使上述佐剂中的卡维地洛的熔化物在室温下固化时,此熔化物中存在的任何结晶组分可以导致加快从无定形卡维地洛中结晶。 When the above-mentioned adjuvant carvedilol melt cured at room temperature, any crystalline components present in this melt can lead to accelerate from an amorphous crystalline carvedilol.

令人惊奇的是,现在已发现佐剂和溶解的活性物质的熔化物尽可能快地固化(优选通过喷雾固化)得到特别稳定的固体溶液。 Surprisingly, it has been found that the melt adjuvant and dissolved active substance cured as soon as possible (preferably by spray solidification) to give a particularly stable solid solution. 总之,卡维地洛分散体的分子分散状态的迅速“冻结”似乎特别有助于保持非结晶形态。 In short, rapid "freeze" of carvedilol dispersion of molecular dispersion state it seems to be particularly helpful to keep a non-crystalline form. 这种情况也适用于在已用喷雾干燥法生产固体溶液时,由还包括除卡维地洛以外的纤维素衍生物、特别是羟丙基甲基纤维素或羟丙基纤维作为“固体溶液”的基质的溶液生产固体溶液。 This also applies when you are using the spray drying method for producing a solid solution by further comprising a cellulose derivative other than carvedilol, especially hydroxypropyl methyl cellulose or hydroxypropyl cellulose as a "solid solution "The solution producing solid solution matrix.

在喷雾干燥的情况下,在宽大的圆柱形容器上端通过一种喷雾器设备将欲干燥的材料作为溶液或悬浮液喷雾,得到一种滴雾。 In the case of spray drying, the upper end of the large cylindrical container through an atomizer device For dried material as a solution or suspension was sprayed to give a droplet mist. 将所得的滴雾与热空气(优选>100℃)或被导入喷雾区附近的干燥器的惰性气体混合。 The resulting drop fog and hot air (preferably> 100 ℃) or import mixed zone near the spray dryer inert gas. 所得的溶剂蒸汽被干燥空气吸收并被送走,通过分离器从此容器中移出分离的粉末。 The resulting solvent vapor is absorbed by the dry air away, from separate powder container is removed through the separator.

在喷雾固化的情况下,在宽大的圆柱形容器上端通过一种可加热的喷雾器设备将欲固化的材料作为熔化物喷雾,得到一种滴雾。 In the case of spray cured at the upper end of the large cylindrical container through a heated nebulizer device will want to melt solidified material as a spray, to obtain a drop of fog. 将所得的滴雾与冷却的空气(优选<25℃)混合,然后将其导入喷雾区附近的干燥器。 The drop mist and cooling air (preferably <25 ℃) resulting mixed, and then import the spray area near the dryer. 释放出的固化热由空气吸收并被送走,通过分离器从此容器中移出分离的固化粉末。 Release of heat absorption by the cured away by the air, separated from curable powder container is removed through the separator. 关于喷雾器的设置,要将(可加热的)旋转压力喷嘴、气动喷嘴(二元/四元喷嘴)或离心喷雾器考虑在内。 Set on the sprayer, to (heatable) rotary pressure nozzles, pneumatic nozzles (yuan / quaternary nozzles) or centrifugal atomizer into account.

卡维地洛的固体溶液可以有利地进行多种形式的药用。 Carvedilol solid solution can be advantageously carried out various forms of medicine. 因此,这种作为分子分散体分布的埋入的卡维地洛可以被进一步加工成快速释放的给药剂型,如具有改善的再吸收度的片剂、薄膜片剂、胶囊、颗粒剂、丸剂等。 Therefore, this distribution as a molecular dispersion embedded carvedilol may be further processed into rapid release administration forms, such as tablets having improved degree of resorption, film tablets, capsules, granules, pills and so on. 这与已采用结晶卡维地洛生产的常规的快速释放经口药物相比,使某些情况下的剂量减小。 This is compared with already using crystalline carvedilol production of conventional quick release oral medication, so in some cases, reduce the dose.

卡维地洛固体溶液还可以特别有利地用于生产具有改良的释放特征的药物。 Carvedilol solid solution can be particularly advantageous for the production of drugs with an improved release characteristics. 改良的释放特征,应理解为例如在大于2小时、优选2-24小时以后释放95%,或者是其释放按时延迟的pH依赖性释放。 Modified release profile, to be understood as e.g. after more than 2 hours, preferably 2-24 hours to release 95%, or time delayed release pH dependent release. 为此目的,可以将所述的卡维地洛固体溶液加工成具有改良释放的常规口服药物,或与具有改良释放的常规口服药物一起加工。 For this purpose, the carvedilol solid solution is processed according to conventional oral modified release drugs, or processed with conventional oral modified release drugs.

具有改良释放特征的药物的实例为抗胃液的薄膜片剂或缓释制剂,如水胶体基质或其中的活性物质通过腐蚀或扩散过程而释放的类似药物。 Examples of drugs with improved release characteristics of the film is resistant to gastric juices or sustained release tablet formulations, such as water or gel matrix wherein the active substance diffusion process by etching or the like to release the medicament. 可以通过加入进一步的佐剂或薄膜包衣,或者通过加入常规药学释放体系,将本发明的配方加工成具有改良的活性物质释放的配方。 By the addition of further adjuvants or film coatings or by adding conventional pharmaceutical delivery system, the formulation of the present invention is processed into formulations with improved release of the active substance. 因此,可以将本发明的配方加到例如水胶体基质体系,特别是基于纤维素衍生物如羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素或聚丙烯酸酯衍生物如EudragitRL的那些。 Accordingly, the formulations of the present invention may be added, for example a hydrocolloid matrix systems, especially those based on cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose or polyacrylate derivatives such as EudragitRL those. 上述的基质可以另外或任选地包含依赖pH而膨胀的水胶体基质形成剂,例如藻酸钠或羧甲基纤维素钠。 The above-described substrate may additionally or optionally comprise pH-dependent swellable hydrocolloid and matrix-forming agent, e.g., sodium alginate or sodium carboxymethylcellulose. 通过加入这种佐剂,可以实现单独确定的目标释放。 By adding such adjuvants can achieve the goals alone release. 因此,与结晶的活性物质相比,本发明的固体溶液导致明显的再吸收改善。 Thus, as compared with the crystalline active substance, a solid solution of the present invention results in significantly improved resorption.

因此,可以将本发明的卡维地洛的喷雾固化的固体溶液,优选含PluronicF 68、聚乙二醇6000、高度分散的二氧化硅和卡维地洛的那些(优选根据实施例4)加工成片剂,加工方法例如为直接压片法、制粒法或与如下控制释放的亲水基质形成剂共同压制:平均粘度为大约100mPa.s的羟丙基甲基纤维素2208(MethocelK100 LV-Premium)和平均粘度为大约4000mPa.s的羟丙基甲基纤维素2208(MethocelK4M-Premium),以及与润滑剂或抗结块剂如硬脂酸镁和微晶纤维素(AvicelPH102)共同压制。 Thus, the present invention carvedilol spray cured solid solution, preferably it can contain PluronicF 68, polyethylene glycol 6000, highly dispersed silica and those of carvedilol (preferably according to Example 4 ) processed into a tablet, processing methods, for example, direct compression, granulation, or a hydrophilic matrix forming agent together with the controlled release following repression: an average viscosity of about 100mPa.s hydroxypropyl methyl cellulose 2208 (Methocel K100 LV-Premium) and an average viscosity of about 4000mPa.s hydroxypropyl methylcellulose 2208 (MethocelK4M-Premium), and with a lubricant or anti-caking agents such as magnesium stearate and microcrystalline cellulose (AvicelPH102) co-pressed. 此外,可以用常规的喷漆如OpadrylII White Y-30-18037和OpadrylClearYS-1-7006将片剂包衣。 In addition, you can use a conventional painting as OpadrylII White Y-30-18037 and OpadrylClearYS-1-7006 coated tablets.

本发明的药物配方适于生产常规的给药剂型,优选口服给药剂型,以用于治疗和/或预防心脏和循环疾病,如高血压、心机能不足和心绞痛。 Pharmaceutical formulations of the present invention are suitable for the production of conventional dosage forms, preferably oral dosage forms, for the treatment and / or prevention of heart and circulatory diseases, such as hypertension, cardiac insufficiency and angina.

本发明药物配方的给药剂量取决于患者的年龄、患者的需求和给药途径。 Dose pharmaceutical formulations of the present invention depends on the age, the patient's needs and route of administration of the patient. 一般考虑大约1mg-50mg卡维地洛/天的剂量。 General considerations dose of about 1mg-50mg carvedilol / day. 为此,使用卡维地洛活性物质含量大约为1mg-50mg的配方。 For this reason, the use of carvedilol active substance content of about 1mg-50mg formulation is.

本发明还涉及一种生产卡维地洛的浓缩的固体或半固体分子分散液的方法,包括卡维地洛和亲水佐剂如聚乙二醇、和/或表面活性物质如PluronicF 68的掺混物。 The present invention also relates to a method for producing concentrated carvedilol solid or semi-solid molecular dispersion, including carvedilol and a hydrophilic adjuvants such as polyethylene glycol, and / or surface-active substances such as PluronicF 68 blends. 在优选的实施方案中,所得的配方然后进行喷雾固化。 In a preferred embodiment, the formulation obtained is then sprayed cured.

而且,本发明涉及一种用于治疗疾病如高血压、心机能不足或心绞痛的方法,所述方法包括施用包含上述药物配方的药物。 Further, the present invention relates to a medicament for the treatment of diseases such as hypertension, cardiac insufficiency or angina pectoris, said method comprising administering said pharmaceutical formulation comprising a.

以下的实施例意在描述本发明的优选实施方案,而不是对其进行限定。 The following examples are intended to describe the preferred embodiment of the present invention, rather than be limited.

实施例1卡维地洛固体溶液:卡维地洛 50.0g聚乙二醇6,000 250.0g总重: 300.0g Example 1 Carvedilol solid solution: Carvedilol polyethylene glycol 6,000 250.0g 50.0g total weight: 300.0g

70℃下熔化聚乙二醇6,000。 At 70 ℃ melted polyethylene glycol 6,000. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt.

实施例2卡维地洛固体溶液:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 250.0g总重: 300.0g70℃下熔化聚氧乙烯-聚氧丙烯共聚物。 Example 2 Carvedilol solid solution: Carvedilol 50.0g polyoxyethylene - polyoxypropylene copolymer 250.0g Gross weight: at 300.0g70 ℃ melting polyoxyethylene - polyoxypropylene copolymers. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt.

实施例3卡维地洛固体溶液:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 15.0g聚乙二醇6,000 235.0g总重: 300.0g70℃下熔化聚乙二醇6,000。 EXAMPLE 3 Carvedilol solid solution: Carvedilol 50.0g polyoxyethylene - polyoxypropylene copolymer of polyethylene glycol 6,000 235.0g 15.0g total weight: at 300.0g70 ℃ melting polyethylene glycol 6,000. 然后将聚氧乙烯-聚氧丙烯共聚物搅拌加到上述熔化物中,同样地熔化并将熔化物均化。 Then a polyoxyethylene - polyoxypropylene copolymer is stirred added to the melt, and the melt was similarly melt homogenized. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt.

如果需要,可以通过进一步加入佐剂改善固体溶液的技术加工性能如流动性,参见实施例4。 If desired, an adjuvant can be improved by further adding a solid solution of the technical processing properties such as fluidity, see Example 4.

实施例4卡维地洛固体溶液:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 15.0g聚乙二醇6,000 232.0g高度分散的二氧化硅 3.0g总重: 300.0g EXAMPLE 4 Carvedilol solid solution: Carvedilol 50.0g polyoxyethylene - polyoxypropylene copolymer silica 3.0g of polyethylene glycol 6,000 232.0g 15.0g total weight of highly dispersed: 300.0g

70℃下熔化聚乙二醇6,000。 At 70 ℃ melted polyethylene glycol 6,000. 然后将聚氧乙烯-聚氧丙烯共聚物搅拌加到上述熔化物中,同样地熔化并将熔化物均化。 Then a polyoxyethylene - polyoxypropylene copolymer is stirred added to the melt, and the melt was similarly melt homogenized. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt. 用高度分散的二氧化硅处理卡维地洛固体溶液并均匀混合。 Highly dispersed silica treated with carvedilol solid solution and uniformly mixed.

而且,更高含量的表面活性佐剂提供稳定的非结晶埋入。 Moreover, higher levels of surfactant adjuvants provide a stable amorphous buried.

实施例5卡维地洛固体溶液:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 125.0g聚乙二醇6,000 125.0g总重: 300.0g70℃下熔化聚乙二醇6,000。 EXAMPLE 5 Carvedilol solid solution: Carvedilol 50.0g polyoxyethylene - polyoxypropylene copolymer of polyethylene glycol 6,000 125.0g 125.0g Total weight: at 300.0g70 ℃ melting polyethylene glycol 6,000. 然后将聚氧乙烯-聚氧丙烯共聚物搅拌加到上述熔化物中,同样地熔化并将熔化物均化。 Then a polyoxyethylene - polyoxypropylene copolymer is stirred added to the melt, and the melt was similarly melt homogenized. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt.

实施例6卡维地洛固体溶液:卡维地洛 50.0g益寿糖 450.0g总重: 500.0g将益寿糖在其熔点以上熔化。 EXAMPLE 6 Carvedilol solid solution: Carvedilol isomalt 450.0g 50.0g total weight: 500.0g will isomalt melt above its melting point. 然后,将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Then, and uniformly stirred to dissolve carvedilol added to the resulting melt. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt.

实施例7快速释放卡维地洛片剂使用固体溶液:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 15.0g聚乙二醇6,000 232.0g Example 7 Quick release carvedilol tablets using a solid solution: Carvedilol 50.0g polyoxyethylene - polyoxypropylene copolymer of polyethylene glycol 6,000 232.0g 15.0g

高度分散的二氧化硅 3.0gα-乳糖-水合物的聚合物 146.0g羧甲基淀粉钠 15.0g高度分散的二氧化硅 4.0g硬脂酸镁 10.0g总重: 475.0g70℃下熔化聚乙二醇6,000。 Highly dispersed silica 3.0gα- lactose - monohydrate sodium carboxymethyl starch polymer 146.0g 15.0g highly dispersed silicon dioxide Magnesium stearate 4.0g 10.0g Total weight: 475.0g70 ℃ molten polyethylene Alcohol 6,000. 然后将聚氧乙烯-聚氧丙烯共聚物搅拌加到上述熔化物中,同样地熔化并将熔化物均化。 Then a polyoxyethylene - polyoxypropylene copolymer is stirred added to the melt, and the melt was similarly melt homogenized. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt. 随后用高度分散的二氧化硅处理卡维地洛固体溶液并均匀混合。 Followed by highly disperse silica processing carvedilol solid solution and uniformly mixed. 用α-乳糖-水合物的聚合物处理所得的混合物并混合。 With α- Lactose - treating the resulting polymer mixture was added and mixed hydrates. 将由羧甲基淀粉钠、高度分散的二氧化硅和硬脂酸镁组成的外相(润滑剂、流动剂、分离剂和增量剂)加到以上混合物中并均匀混合。 By sodium carboxymethyl starch, external phase highly dispersed silicon dioxide and magnesium stearate composition (lubricant, flow agent, separating agent and extender) was added to the above mixture and uniformly mixed. 然后以常规方式,考虑目标活性物质的含量,将所得的混合物压成药剂或填充至胶囊。 Then in a conventional manner, considering the content of the target active substance, the resulting mixture was pressed into or filled into pharmaceutical capsules.

实施例8卡维地洛缓释片:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 15.0g聚乙二醇6,000 232.0g高度分散的二氧化硅 3.0gα-乳糖-水合物的聚合物 146.0g羟丙基甲基纤维素2208 240.0g高度分散的二氧化硅 4.0g硬脂酸镁 10.0g总重: 700.0g70℃下熔化聚乙二醇6,000。 Polymerization hydrates - polyoxypropylene copolymer of polyethylene glycol 6,000 232.0g 15.0g highly dispersible silica 3.0gα- lactose - carvedilol 50.0g polyoxyethylene: 8 carvedilol sustained-release tablets EXAMPLE was hydroxypropyl methylcellulose 2208 240.0g 146.0g highly dispersible silica Magnesium stearate 4.0g 10.0g total weight: at 700.0g70 ℃ melting polyethylene glycol 6,000. 然后将聚氧乙烯-聚氧丙烯共聚物搅拌加到上述熔化物中,同样地熔化并将熔化物均化。 Then a polyoxyethylene - polyoxypropylene copolymer is stirred added to the melt, and the melt was similarly melt homogenized. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt. 随后用高度分散的二氧化硅处理卡维地洛固体溶液并均匀混合。 Followed by highly disperse silica processing carvedilol solid solution and uniformly mixed. 用α-乳糖-水合物的聚合物处理所得的混合物并混合。 With α- Lactose - treating the resulting polymer mixture was added and mixed hydrates. 将由羟丙基甲基纤维素2208、高度分散的二氧化硅和硬脂酸镁组成的外相(润滑剂、流动剂、分离剂和增量剂)加到以上混合物中并均匀混合。 2208, the external phase highly dispersed silicon dioxide and magnesium stearate composition (lubricant, flow agent, separating agent and extender) was added to the above mixture and uniformly mixed by hydroxypropylmethyl cellulose. 然后以常规方式,考虑目标活性物质的含量,将所得的混合物压成药剂或填充至胶囊。 Then in a conventional manner, considering the content of the target active substance, the resulting mixture was pressed into or filled into pharmaceutical capsules.

实施例9卡维地洛缓释片:卡维地洛 50.0g聚氧乙烯-聚氧丙烯共聚物 15.0g聚乙二醇6,000 232.0g高度分散的二氧化硅 3.0gα-乳糖-水合物的聚合物 96.0g羟丙基甲基纤维素2208 240.0g藻酸钠 50.0g高度分散的二氧化硅 4.0g硬脂酸镁 10.0g总重: 700.0g70℃下熔化聚乙二醇6,000。 Polymerization hydrates - polyoxypropylene copolymer of polyethylene glycol 6,000 232.0g 15.0g highly dispersible silica 3.0gα- lactose - carvedilol 50.0g polyoxyethylene: 9 carvedilol sustained-release tablets EXAMPLE was 96.0g hydroxypropyl methyl cellulose, sodium alginate 2208 240.0g 50.0g highly dispersible silica Magnesium stearate 4.0g 10.0g total weight: at 700.0g70 ℃ melting polyethylene glycol 6,000. 然后将聚氧乙烯-聚氧丙烯共聚物搅拌加到上述熔化物中,同样地熔化并将熔化物均化。 Then a polyoxyethylene - polyoxypropylene copolymer is stirred added to the melt, and the melt was similarly melt homogenized. 将卡维地洛搅拌加到所得的熔化物中并均匀地溶解。 Carvedilol added to the resulting melt is stirred and uniformly dissolved. 然后将熔化物喷雾固化成卡维地洛固体溶液。 The melt is then solidified into a spray of carvedilol solid solution. 或者,如果固化迅速发生的话,可以通过其它方法将熔化物固化。 Alternatively, if rapid solidification occurs, it can be cured by other methods melt. 随后用高度分散的二氧化硅处理卡维地洛固体溶液并均匀混合。 Followed by highly disperse silica processing carvedilol solid solution and uniformly mixed. 用α-乳糖-水合物的聚合物处理所得的混合物并混合。 With α- Lactose - treating the resulting polymer mixture was added and mixed hydrates. 将由藻酸钠、高度分散的二氧化硅和硬脂酸镁组成的外相(润滑剂、流动剂、分离剂和增量剂)加到以上混合物中并均匀混合。 By sodium alginate, highly dispersed silicon dioxide and the external phase magnesium stearate composition (lubricant, flow agent, separating agent and extender) was added to the above mixture and uniformly mixed. 然后以常规方式,考虑目标活性物质的含量,将所得的混合物压成药剂或填充至胶囊。 Then in a conventional manner, considering the content of the target active substance, the resulting mixture was pressed into or filled into pharmaceutical capsules.

Classifications
International ClassificationA61K9/14, A61K31/403, A61K47/04, A61P9/10, A61K47/30, A61P9/12, A61K9/16, A61K47/34, A61P9/04, A61K9/22, A61K9/20, A61P9/00
Cooperative ClassificationA61K9/146, A61K31/403, A61K9/145, A61K9/1635, A61K9/205, A61K9/2054, A61K9/2027
European ClassificationA61K9/16H6B, A61K9/20H6F, A61K9/20H6F2, A61K9/20H6B, A61K9/14H4, A61K9/14H6, A61K31/403
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