WO2004026291A1 - Formulations orales d'ibuprofene et de tramadol, methodes de preparation de ces dernieres - Google Patents

Formulations orales d'ibuprofene et de tramadol, methodes de preparation de ces dernieres Download PDF

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WO2004026291A1
WO2004026291A1 PCT/CN2003/000713 CN0300713W WO2004026291A1 WO 2004026291 A1 WO2004026291 A1 WO 2004026291A1 CN 0300713 W CN0300713 W CN 0300713W WO 2004026291 A1 WO2004026291 A1 WO 2004026291A1
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ibuprofen
tramadol
pharmaceutically acceptable
oral preparation
acceptable salt
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PCT/CN2003/000713
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English (en)
French (fr)
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Shuyi Zhang
Jin Wang
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Shuyi Zhang
Jin Wang
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Publication of WO2004026291A1 publication Critical patent/WO2004026291A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention is a compound oral analgesic preparation composed of ibuprofen and tramadol. Background technique
  • Opioid alkaloids have been used as analgesics for severe pain for many years. However, because opioid alkaloids can cause a series of adverse reactions, they cannot be given repeatedly or in large doses. Relevant literature has described these side effects in detail, see "The Pharmacological Principles of Therapeutics", 1975, 5th edition, page 245, Chapter 15, by J. Jaffe and W. Martin, L. Goodman and Edited by A. Gilman. The document states that morphine and its analogues, such as codeine, heroin, and hydroxycodeinone, are opioid analgesics and can cause side effects such as respiratory failure, constipation, tolerance, and addiction.
  • non-opioids such as acetaminophen, aspirin and ibuprofen can also be used for analgesic treatment.
  • acetaminophen, aspirin and ibuprofen do not cause opioid analgesics tolerance, addiction, and side effects.
  • acetaminophen, aspirin, and ibuprofen can only reduce moderate pain, while opioid analgesics can effectively relieve more severe severe pain. See Pharmacological Principles of Therapeutics, 1975, p. 5 Edition, p. 325, chapter 15, by Woodbury, D. and Fingl, E., edited by L. Goodman and A. Gilman.
  • opioid alkaloids In order to reduce the side effects of opioid alkaloids, the combined use of opioids and other drugs containing non-opioid analgesic components can reduce the amount of opioids while achieving the analgesic effect of the original opioid dose. It has been reported that some compound preparations can also produce synergistic analgesic effects. For example, A. Takemori in the Annual Report of the New York Academy of Sciences, 1976, No. 262, p. 281 states that the combination of opioid alkaloids and other non-analgesics can produce a variety of different analgesic effects. , followeded by sub-additive (inhibitory), enhanced or super-enhanced effects. Taber et al., J. Pharra. Expt.
  • Ibuprofen is an anti-inflammatory drug that has been used to relieve pain in humans and animals.
  • Hydrocodone, 7, 8-dihydrocodienone mainly contains an analgesic and analgesic component, and its effect is similar to that of codeine.
  • the analgesic effect of the compound formulation of ibuprofen and hydrocodone, Vi CO prof en s is far better than the analgesic effect of increasing any one of the single medicine amount, US Patent No. 4,587,252.
  • the complex is compared with two single drugs at the same analgesic dose, and the former is considered to have less side effects than the latter two.
  • the invention proposes for the first time a new preparation for treating pain in mammals, especially humans, and a preparation method thereof.
  • This method is mainly used for mammals, especially humans, to take a compound formulation composed of tramadol or its pharmaceutically acceptable salt and ibuprofen or its pharmaceutically acceptable salt by the oral route.
  • the technical solution adopted by the present invention to solve the above problems is: the ibuprofen-tramadol compound oral preparation is characterized in that the compound oral preparation contains tramadol or its pharmaceutically acceptable salts and ibuprofen or its pharmacology Compound analgesic pharmaceutical preparations of salts.
  • the formula according to the present invention comprises a tramadol or a pharmaceutically acceptable salt thereof and ibuprofen or a pharmaceutically acceptable salt thereof.
  • the mass ratio of tramadol and ibuprofen may be between 1: 1 and 1:50.
  • the formula according to the present invention comprises a tramadol or a pharmaceutically acceptable salt thereof and ibuprofen or a pharmaceutically acceptable salt thereof, and an ideal mass ratio range is between 1: 1 m and 1:20, and the range is 1: 2 The effect is better to 1. ⁇ 15.
  • the formula according to the present invention contains (1) 80mg-800mg ibuprofen or a pharmaceutically acceptable salt thereof, (2) 12.5mg-200mg tramadol or a pharmaceutically acceptable salt thereof, and (3) a tablet or capsule is prepared Commonly used medicinal excipients.
  • the medicinal auxiliary materials according to the present invention may be microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, colloidal silicon dihydrate, and magnesium stearate.
  • the technical solution used by the present invention to solve the above problems is as follows:
  • the method for preparing the ibuprofen-tramadol compound oral preparation is characterized in that: an appropriate amount of tramadol or its pharmaceutically acceptable salts and ibuprofen or its
  • the medicinal salts and necessary medicinal auxiliary materials are mixed in a granulator, and then granulated in water or other liquids, and dried, and the dried granules are ground, and other medicines are added. It is mixed with auxiliary materials, and the lubricated particles can be made into different preparations according to requirements.
  • the different preparations described in the present invention may be tablets, as long as the lubricated granules are compressed into tablets with a tablet extruder and then coated.
  • the different preparations according to the present invention may also be compound capsules, as long as the lubricated particles are filled into the capsules.
  • the present invention proposes for the first time a compound preparation of an anti-inflammatory and analgesic drug ibuprofen and a central analgesic drug tramadol.
  • the analgesic effect of the compound preparation is far better than the analgesic effect of increasing any one of the single medicines. And this compound rarely shows the side effects of opioid analgesics such as addiction, tolerance, constipation, and respiratory failure. It can greatly improve the effectiveness of treating pain. Best practice
  • this new formulation can be demonstrated by a variety of pharmacological methods.
  • one of the methods is to use the mouse acetic acid writhing method (H. Collier et al., Br. J. Pharmacol., 32, 295 (1968)) to compare ibuprofen, tramadol, and The efficacy of the compound.
  • the results of this method are usually very close to the results of experiments on humans.
  • tramadol hydrochloride was completely dissolved in distilled water, and ibuprofen was completely dissolved.
  • mice Dissolved in distilled water or completely dissolved in distilled water containing 2% by volume of Tween 80 (containing 100% polysorbate 80), formulated into various doses of tramadol hydrochloride, ibuprofen, tramadol And ibuprofen mixture solution.
  • Select female mice weighing 15-22 g.
  • each group of mice was injected with different doses of tramadol hydrochloride, ibuprofen, tramadol and ibuprofen mixture solutions, and another group of mice was injected with distilled water or a volume percentage of 2 in the same way.
  • Tween 80% distilled water was used as a control group.
  • Each group of mice was administered at 0.4ml / 10g.
  • mice 30 minutes later, each group of mice was injected with a volume ratio of 0.6% acetic acid 0.2ml 0 and the number of writhing in 15 minutes was continuously observed.
  • abdominal muscle tissue of the mouse contracts with back arching and limb extension, it is considered a "twisted body" symptom.
  • Tramadol and ibuprofen are mixed in different proportions, and multiple doses of the compound in each group are taken (generally 4 to 6 groups of doses). Based on the above experimental design, the analgesia of each group can be measured after 30 minutes. effect. This experimental design also allows for completely random testing of the effects of various single-dose doses. When 10, 20, 30 mg / kg tramadol was used in combination with 50 or 100 mg / kg ibuprofen, the number of writhing induced by acetic acid in test mice was significantly lower than that of tramadol 30mg / kg and ibuprofen 100 mg / kg The number of twists observed when used alone.
  • Tramadol and ibuprofen show a synergistic analgesic effect, and the amount of these two components in the compound is less than Tramadol, which can produce the same analgesic effect, respectively. And ibuprofen dosage.
  • the mass ratio of tramadol and ibuprofen can generally be in the range of 1: 1 to 1. ⁇ 50.
  • the compounds mixed in certain proportions show a synergistic analgesic effect.
  • the more accurate ratio is from 1: 2 to
  • the ideal ratio is from 1: 2 to 1:15.
  • the tramadol-ibuprofen complex in this quality range has been shown to work synergistically for analgesia.
  • the mass ratios of tramadol hydrochloride and ibuprofen in samples A and B were 1: 5.33 and 1: 4, respectively.
  • appropriate amounts of components 1 to 4 should be placed in a high-efficiency granulator or an ordinary granulator and mixed. It is then granulated in water or other suitable liquid and dried in a dryer. Grind the dried granules and add components 5-7 to mix them. The lubricated granules were compressed into tablets of 400 mg and 300 mg with a tablet extruder, respectively.
  • the above steps are performed according to the traditional tablet manufacturing process.
  • the final product can be wrapped with a traditional coating.
  • the above formula can also be made into compound capsules.
  • An appropriate amount of components 1 to 4 should be placed in an efficient granulator or an ordinary granulator and mixed. Water or other suitable liquid is then added to form granules and dried in a dryer. The dried granules are then mixed and added with components 5-7. The lubricated granules were filled into capsules and made into capsules with masses of 400 mg and 300 mg, respectively. The above steps are all performed according to the traditional capsule making process.
  • the novelty of this invention lies in a compound drug made of ibuprofen and tramadol to improve and enhance the analgesic effect.
  • each dosage unit contains (1) 80mg-800mg ibuprofen or a pharmaceutically acceptable salt thereof, (2) 12.5mg-200mg tramadol or a pharmaceutically acceptable salt thereof, and (3) Pharmaceutical excipients commonly used in tablets and capsules.

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Description

布洛芬一曲马朵复方口服制剂及其制备方法 技术领域
本发明为由布洛芬和曲马朵组成的复方口服镇痛制剂。 背景技术
阿片类生物碱多年以来一直是作为治疗重度疼痛的镇痛药物。但 因为阿片类生物碱会产生一系列不良反应，因此不能重复或大剂量给 药。 相关文献曾对这些副作用作了详细的阐述， 参见《治疗学的药理 学原理》， 1975年，第 5版，第 245页，第 15章， J. Jaffe和 W. Martin 著， L. Goodman和 A. Gilman编。 该文献指出， 吗啡及其同类药物， 如可待因、 海洛因、羟二氢可待因酮， 均属于阿片类镇痛药， 能引起 呼吸衰竭、 便秘、 耐受和成瘾等副作用。
作为与阿片类生物碱不同的另一种选择非阿片类物质如对乙酰 氨基酚、 阿司匹林和布洛芬也可用于镇痛治疗。和阿司匹林一样， 布 洛芬和对乙酰氨基酚均不会引起阿片类镇痛药的耐受、上瘾和毒副作 用。 但是， 对乙酰氨基酚、 阿司匹林和布洛芬只能减轻中度疼痛， 而 阿片类镇痛药则能有效缓解更为剧烈的重度疼痛，参见《治疗学的药 理学原理》， 1975年，第 5版， 第 325页，第 15章， Woodbury, D. 和 Fingl, E.著， L. Goodman禾口 A. Gilman编。
为减少阿片类生物碱副作用，将阿片和其他含有非阿片类镇痛成 分的药物复合使用，可以实现在减少阿片用量的同时又能达到原阿片 剂量的镇痛效果。 己有报道指出一些复方制剂还能产生协同镇痛效 应。 例如， A. Takemori在 《纽约科学学会年报》， 1976年， 第 262 期，第 281页中指出， 阿片类生物碱和其他非镇痛类药物混合后的复 合成分能产生多种不同的止痛效果， 依次为次加性 （抑制性）、 增强 性或超增强性效果。 . Taber 等在《J. Pharra. Expt. Thera.》 , 1969 年， 第 29期， 第 169章， 第 1节中指出， 吗啡和另一种阿片类镇痛 药美沙酮的复方制剂可增强镇痛效果。 美国专利第 4571400 号已公 开，阿片类镇痛药布洛二氢和非阿片类镇痛药双氢可待因两种成分在 一定比例内复合具有超强镇痛效果。 A. Pircio 等在 《Arch. Int. Pharmacodyn.》 , 1978年， 第 116期， 第 235页中称， 阿片镇痛药布 托非洛和非阿片镇痛药对乙酰氨基酚即 ΑΡΑΡ若按 1: 125比例 混合， 可超强镇痛， 而若按 1: 10比例混合， 则没有明显的超强镇痛 效果。
布洛芬是一种消炎药， 一直以来用于缓解人体和动物体内的疼 痛。 氢可酮即 7， 8-dihydrocodienone主要含一种麻醉镇痛成分， 其效果与可待因类似。 布洛芬和氢可酮复方制剂即 ViCOprofen s的镇 痛效果要远远好于增加其中任何一种单药用量的镇痛效果，美国专利 第 4587252号。 同时，将该复合物分别与两种单药在相同镇痛剂量的 条件下作比较， 前者的副作用被认为要小于后两者的副作用。
. 含有曲马朵和对乙酰氨基成分的普通片剂及其使用方法已被授 予专利， 美国专利第 5336691号。 通常成人剂量为每 4-6小时服用 1-2片片剂即 Ultracet™。 该复方片剂具有镇痛和止咳作用。 发明内容
本发明首次提出了一种治疗哺乳动物尤其是人体体内疼痛的新 制剂及其制备方法。此方法主要是对哺乳动物， 特别是人体， 通过口 服途径服用由曲马朵或其药用盐和布洛芬或其药用盐组成的复方制 剂。 本发明解决上述问题所采用的技术方案是：该布洛芬一曲马朵复 方口服制剂，其特点是： 该复方口服制剂为含有曲马朵或其药用盐类 和布洛芬或其药用盐类的复方镇痛药物制剂。
本发明所述的配方包含一种曲马朵或其药用盐类和布洛芬或其 药用盐类， 曲马朵和布洛芬的质量比可以在 1: 1到 1: 50之间。
本发明所述的配方包含一种曲马朵或其药用盐类和布洛芬或其 药用盐类， 理想的质量比范围在 1 : 1 m 1： 20之间， 且范围在 1: 2 到 1.· 15之间效果更佳。 本发明所述的配方含有 （1 ) 80mg-800mg 布洛芬或其药用盐 类，（2) 12. 5mg- 200mg曲马朵或其药用盐类， 和 (3)制备片剂或胶囊常 用的药用辅料。
本发明所述的药用辅料可以是微晶纤维素、预胶化淀粉、淀粉羟 乙酸钠、 胶态二态化硅及硬脂酸镁。
本发明解决上述问题所釆用的技术方案还有：该布洛芬一曲马朵 复方口服制剂的制备方法， 其特点是： 将适量的曲马朵或其药用盐类 和布洛芬或其药用盐类加上必要的药用辅料置于制粒机中混匀，然后 在清水或其它液体中制成颗粒，并烘干，再将烘干后的颗粒进行碾磨， 并加入其它药用辅料与之混合，经润滑后的颗粒物可根据需要做成不 同的制剂。
本发明所述的不同的制剂可以是片剂，只要将润滑后的颗粒物用 片剂挤压机压缩成片剂， 再包裹包衣即可。
本发明所述的不同的制剂也可以是复方胶囊，它只要将润滑后的 颗粒物装入胶囊中即可。
本发明首次提出了将消炎镇痛药布洛芬和中枢镇痛药曲马朵制 成复方制剂。该复方制剂的镇痛效果远好于增加其中任何一种单药用 量的镇痛效果。且这种复合物也很少出现成瘾、耐受、 便秘和呼吸衰 竭等阿片类镇痛药的副作用。它能够在很大程度上提高治疗疼痛的效 果。 最佳实施方式
该新配方的效果可经多种药理学方法进行证明。 例如， 其中方法 之一是采用小鼠乙酸扭体法 （H. Collier 等， Br. J. Pharmacol. , 32, 295 (1968) )来比较布洛芬、曲马朵和含这两种成分的复方的药效。 通常本方法的结果与在人体上进行试验的结果非常接近。 在检测曲马朵、布洛芬以及这两种成分混合物镇痛效果的实验中， 按上述实验方法，将曲马朵盐酸盐完全溶于蒸馏水中， 将布洛芬完全 溶于蒸馏水或完全溶于含体积百分比为 2 %的吐温 80 (含 100 %聚 山梨酯 80) 的蒸馏水中， 配成多种剂量的曲马朵盐酸盐、 布洛芬、 曲马朵和布洛芬混合物溶液。 选体重为 15- 22g的雌鼠。 通过口服途 径， 对各组小鼠注入不同剂量的曲马朵盐酸盐、布洛芬、 曲马朵和布 洛芬混合物溶液，另外选择一组小鼠按相同方法注入蒸馏水或含体积 百分比为 2 %的吐温 80 的蒸馏水， 作为对照组。 每一组小鼠均按 0. 4ml/10g给药。
30分钟后， 对每组小鼠分别注入体积比为 0. 6%乙酸 0. 2ml 0 并 持续观察 15分钟内的扭体次数。 当小鼠腹部肌肉组织出现收缩并伴 有背部拱起以及四肢伸展， 即被认为是 "扭体"症状。
曲马朵和布洛芬按不同比例混合， 对每一组比例的复合物取多种 剂量 （一般为 4~6组剂量）， 通过上述实验设计， 30分钟后即可测 定各组剂量的镇痛效果。这种实验设计同时也允许完全随机测试各种 单药剂量的效果。 当 10， 20， 30 mg/kg 曲马朵分别与 50 或 100 mg/kg布洛芬合用时， 被试小鼠因醋酸诱发的扭体次数大大低于曲 马朵 30mg/kg和布洛芬 100 mg/kg 单独使用所观察到的扭体次数。
在该实验中， 本发明产生的效果非常明显： 曲马朵和布洛芬表现 出协同镇痛效应，且复合物中这两种成分的用量都分别少于可产生相 同镇痛效果的曲马朵和布洛芬单药的用量。
曲马朵和布洛芬质量比一般可以在 1: 1到 1.· 50的范围内。 中 以某些比例混合的复合物表现出协同镇痛效果。例如按曲马朵和布洛 芬质量比为 1 : 1 1： 20混合的复合物， 更准确的比例是从 1: 2到 最理想的比例是从 1 : 2到 1 : 15。 在这一质量范围的曲马朵一布 洛芬复合物已被证明能协同镇痛。
以下实验样本更精确的描述了这种新配方， 且这两组实验样本仅 旨在阐明本发明， 而不是对本发明进行限定。
Figure imgf000006_0001
在样本 A和 B中曲马朵盐酸盐和布洛芬的质量比分别为 1 : 5. 33 和 1 : 4。 要制得这两种剂型， 应将适量的组分 1一 4置于高效制粒机 或普通制粒机中混匀。然后在清水或其他适宜的液体中制成颗粒， 并 在烘干机中烘千。 再将烘干后的颗粒进行研磨并加入组分 5— 7与之 混合。经润滑后的颗粒物用片剂挤压机分别压缩成 400mg和 300mg的 片剂。上述步骤都是按照传统的片剂制作工艺迸行。最终产物可以包 裹传统的包衣。 同时，上述配方也可制成复方胶囊， 应将适量的组分 1一 4置于高 效制粒机或普通制粒机中混匀。然后加入水或其他适宜的液体制成颗 粒， 并在烘干机中烘干。 再将烘干后的颗粒进行并加入组分 5— 7与 之混合。 润滑后的颗粒物装入胶囊， 制成质量分别为 400mg和 300mg 的胶囊。 上述步骤都是按照传统的胶囊制作工艺进行。
此项发明的新颖性在于布洛芬和曲马朵制成的复合药物， 以改善 及提高镇痛疗效。
该发明的理想配方是， 每个剂量单位含由 （1 ) 80mg-800mg 布洛 芬或其药用盐，（2) 12. 5mg-200mg曲马朵或其药用盐， 和（3)制备片剂 和胶囊常用的药物辅料。

Claims

权 利 要 求 书 一种布洛芬一曲马朵复方口服制剂， 其特征在于： 该复方口 服制剂为含有曲马朵或其药用盐类和布洛芬或其药用盐类的复方镇 痛药物制剂。
2、 根据权利要求 1所述的一种布洛芬一曲马朵复方口服制剂， 其特征在于：所述的配方包含一种曲马朵或其药用盐类和布洛芬或其 药用盐类， 曲马朵和布洛芬的质量比可以在 1: 1到 1: 50之间。
3、 根据权利要求 1所述的一种布洛芬一曲马朵复方口服制剂， 其特征在于：所述的配方包含一种曲马朵或其药用盐类和布洛芬或其 药用盐类， 理想的质量比范围在 1 : 1 1： 20之间， 且范围在 1 : 2 到 1: 15之间效果更佳。
4、 根据权利翠求 1所述的一种布洛芬一曲马朵复方口服制剂， 其特征在于： 所述的配方含有 （1 ) 80mg-800mg 布洛芬或其药用盐 类， (2) 12. 5mg-200mg曲马朵或其药用盐类， 和 (3)制备片剂或胶囊常 用的药用辅料。
5、 根据权利要求 4所述的一种布洛芬一曲马朵复方口服制剂， 其特征在于： 所述的药用辅料可以是微晶纤维素、预胶化淀粉、 淀粉 羟乙酸钠、 胶态二态化硅及硬脂酸镁。
6、一种布洛芬一曲马朵复方口服制剂的制备方法，其特征在于： 将适量的曲马朵或其药用盐类和布洛芬或其药用盐类再加上必要的 药用辅料置于制粒机中混匀， 然后在清水或其它液体中制成颗粒， 并 烘干，再将烘干后的颗粒进行碾磨，并加入其它的药用辅料与之混合， 经润滑后的颗粒物可根据需要做成不同的制剂。
7、 根据权利要求 6所述的一种布洛芬一曲马朵复方口服制剂， 其特征在于：所述的不同的制剂可以是片剂， 只要将润滑后的颗粒物 用片剂挤压机压缩成片剂， 再包裹包衣即可。
8、 根据权利要求 6所述的一种布洛芬一曲马朵复方口服制剂， 其特征在于： 所述的不同的制剂也可以是复方胶囊， 它只要将润滑后 的颗粒物装入胶囊中即可。
PCT/CN2003/000713 2002-08-28 2003-08-25 Formulations orales d'ibuprofene et de tramadol, methodes de preparation de ces dernieres WO2004026291A1 (fr)

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EP2149546A1 (en) 2008-07-31 2010-02-03 Laboratorios Del. Dr. Esteve, S.A. Salts of tramadol and ibuprofen and their crystal form in the treatment of pain
WO2010025934A1 (en) * 2008-09-05 2010-03-11 Grünenthal GmbH Pharmaceutical combination comprising 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol and an nsaid
WO2011027009A1 (es) * 2009-09-04 2011-03-10 Farmalider, S.A. Composición farmacéutica de ibuprofeno, tramadol y un aminoácido básico, procedimiento para su preparación y utilización de la misma

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CN1073095A (zh) * 1991-10-30 1993-06-16 麦克尼拉布公司 含有一种曲马多成分和一种非甾体抗炎药物的组合物
WO2000027799A1 (es) * 1998-11-06 2000-05-18 Vita-Invest, S.A. Nuevos esteres derivados de compuestos fenil-ciclohexil sustituidos

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CN1073095A (zh) * 1991-10-30 1993-06-16 麦克尼拉布公司 含有一种曲马多成分和一种非甾体抗炎药物的组合物
WO2000027799A1 (es) * 1998-11-06 2000-05-18 Vita-Invest, S.A. Nuevos esteres derivados de compuestos fenil-ciclohexil sustituidos

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2149546A1 (en) 2008-07-31 2010-02-03 Laboratorios Del. Dr. Esteve, S.A. Salts of tramadol and ibuprofen and their crystal form in the treatment of pain
WO2010025934A1 (en) * 2008-09-05 2010-03-11 Grünenthal GmbH Pharmaceutical combination comprising 6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol and an nsaid
WO2011027009A1 (es) * 2009-09-04 2011-03-10 Farmalider, S.A. Composición farmacéutica de ibuprofeno, tramadol y un aminoácido básico, procedimiento para su preparación y utilización de la misma
ES2356762A1 (es) * 2009-09-04 2011-04-13 Farmalider S.A. Composicion farmaceutica de ibuprofeno, tramadol y un aminoacido basico, procedimiento para su preparacion y utilizacion de la misma.

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