WO2005123052A1 - Drug composition containing ambroxol and erdosteine or acetylcysteine - Google Patents

Abstract

The present invention relates to the composition comprising ambroxol and erdosteine, or their pharmaceutically acceptable salts, in addition, relates to the composition comprising ambroxol and acetylcysteine, or their pharmaceutically acceptable salts. The present invention also relates to the kits containing the compositions mentioned above, and the utilization of the products. These compositors may be used in treating sputamentum ropiness, difficulty in stethocatharsis, which are caused by chronic bronchitis, bronchial asthma, and also may be used in preventing difficulty in stethocatharsis and pulmonitis complication after surgery.

Description

含有氨溴索和厄多司坦或乙酰半胱氨酸的药物组合物及其应用 技术领域 Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof

本发明涉及一种药物组合物及其应用， 所述的药物组合物含有氨 溴索和厄多司坦或其二者的可药用盐， 所述的药物组合物还可以含有 氨溴索和乙酰半胱氨酸或者二者的可药用盐， 以及该类药物组合用于 制备防治呼吸道充血及感染的各种炎症和祛痰等相关疾病的药物中的 应用， 特别是祛痰方面的应用。 背景技术 The invention relates to a pharmaceutical composition and an application thereof. The pharmaceutical composition contains ambroxol and erdosteine or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may further include ambroxol and Application of acetylcysteine or a pharmaceutically acceptable salt of the two, and the combination of such drugs for the preparation of drugs for the prevention and treatment of various diseases such as respiratory congestion and infection, inflammation and expectoration, especially for expectoration . Background technique

氨溴索是溴己新的活性代谢产物， 其毒性低， 疗效确切， 祛痰作 用比溴己新强， 该药在 1984年以盐酸盐的形式用于临床。 盐酸氨溴索 已居许多国家如美国、 英国、 德国日本等国广泛用于治疗呼吸系统疾 病， 临床效果优良， 几乎无毒副作用。 盐酸氨溴索临床上广泛用于伴 有痰液分泌异常及排痰功能不良的急性、 慢性呼吸道疾病， 例如急慢 性支气管炎、 哮喘型支气管炎、 支气管扩张及气管哮喘、 肺部手术病 人的术后肺交响曲并发症的预防治疗和辅助治疗， 肺结构等引起的痰 液粘稠， 咳痰困难以及早产儿及新生儿婴儿呼吸窘迫综合症 （IRDS) 的治疗。 Ambroxol is the active metabolite of bromhexine. It has low toxicity and accurate curative effect. Its expectorant effect is stronger than that of bromhexine. In 1984, the drug was used as a hydrochloride in the clinic. Ambroxol hydrochloride has been widely used in many countries such as the United States, Britain, Germany, Japan and other countries for the treatment of respiratory diseases with excellent clinical effects and almost no toxic side effects. Ambroxol hydrochloride is widely used clinically for acute and chronic respiratory diseases with abnormal sputum secretion and poor sputum excretion, such as acute and chronic bronchitis, asthma-type bronchitis, bronchiectasis and tracheal asthma, and lung surgery. Preventive and adjuvant treatment of complications of posterior lung symphony, sticky sputum caused by lung structure, difficulty in expectoration, and treatment of respiratory distress syndrome (IRDS) in premature and newborn infants.

盐酸氨溴索口服吸收迅速， 消除半衰期 2~3 小时， 其制剂形式主 要有片剂， 缓释微丸胶囊， 溶液剂， 糖浆， 水针剂及其它复方制剂， 但由于盐酸氨溴索的水溶性不太理想， 使其制剂应用和临床应用都受 到一定限制。 Ambroxol hydrochloride is quickly absorbed orally and its elimination half-life is 2 to 3 hours. Its main preparations are tablets, sustained-release pellets, solutions, syrups, water injections and other compound preparations. However, due to the water solubility of ambroxol hydrochloride, It is not ideal, and its application and clinical application are limited.

厄多司坦是一种前体药物， 其结构中带有非游离的封闭的巯基， 对局部粘蛋白无活性作用， 口服后经代谢产生三个含有游离巯基的代 谢产物而发挥药理作用， 因而口服后无明显胃肠道副作用。 实验证明， 厄多司坦体内代谢物能使支气管分泌物中粘蛋白的二硫键断裂， 并改 变分泌物组成和流变学性质， 降低痰粘度， 改善受抑制的呼吸功能， 本品能清除自由基， 有效保护 al-抗胰蛋白本科免受烟、 尘诱发的氧化 灭活作用， 防止对肺弹性蛋白及中性粒细胞的损伤。 本品还能明显增 加 IgA/白蛋白、 乳铁蛋白 /白蛋白的比值， 减弱局部炎症， 增加和改善 抗生素对支气管粘膜的渗透作用， 有利于呼吸道各种炎症的治疗。Erdosteine is a prodrug with a non-free blocked thiol group in its structure and has no active effect on local mucin. After oral administration, three metabolites containing free thiol groups are metabolized to exert pharmacological effects. No obvious gastrointestinal side effects after oral administration. Experiments prove that Erdosteine metabolites can break the disulfide bonds of mucin in bronchial secretions, and change the composition and rheological properties of secretions, reduce the viscosity of sputum and improve the inhibited respiratory function. This product can remove free radicals, Effectively protect al-antitrypsin from smoke and dust-induced oxidative inactivation and prevent damage to lung elastin and neutrophils. This product can also significantly increase the ratio of IgA / albumin, lactoferrin / albumin, reduce local inflammation, increase and improve the penetration of antibiotics into the bronchial mucosa, and is beneficial to the treatment of various inflammations of the respiratory tract.

乙酰半胱氨酸最常用的粘痰溶解性祛痰药， 临床用以喷雾吸入为 主。 Acetylcysteine is the most commonly used phlegm-soluble sputum expectorant. It is mainly used for spray inhalation.

我们惊喜地发现， 把氨溴索和厄多司坦或氨溴索和乙酰半胱氨酸 复方联合使用， 疗效显著增加， 副作用减少。 发明内容 We were pleasantly surprised to find that the combination of ambroxol and erdosteine or ambroxol and acetylcysteine combined significantly increased the efficacy and reduced the side effects. Summary of the invention

本申请发明人存在令人惊奇的发现， 氨溴索与厄多司坦， 氨溴索 和乙酰半胱氨酸的药物组合可提供特别有益的祛痰作用， 而没有观察 到副作用。 而且这类药物组合特别适合用于治疗呼吸道充血及感染的 各种炎症如慢性支气管炎、 哮喘等痰粘不易咳出患者。 The inventors of the present application have surprisingly found that the drug combination of ambroxol with erdosteine, ambroxol and acetylcysteine can provide a particularly beneficial expectorant effect without observing side effects. In addition, this kind of drug combination is particularly suitable for treating various inflammations such as chronic bronchitis, asthma, etc., which are difficult to cough in patients with respiratory tract congestion and infection.

本发明的一个目的是提供两种用于预治祛痰的新的药物组合， 所 述的药物组合包括顺序给予或同时给予药学上可接受量的氨溴索和厄 多司坦， 氨溴索和乙酰半胱氨酸或其二者的药物可接受形式， 其中， 氨溴索的每天用量为 l-2000mg， 厄多司坦的每天用量为 l-2000mg， 乙 酰半胱氨酸的每天用量为 l-2000mg。 It is an object of the present invention to provide two new drug combinations for pre-treating expectorants, said drug combination including sequential or simultaneous administration of a pharmaceutically acceptable amount of ambroxol and erdosteine, ambroxol And acetylcysteine or a pharmaceutically acceptable form thereof, wherein the daily dosage of ambroxol is 1-2000mg, the daily dosage of erdosteine is 1-2000mg, and the daily dosage of acetylcysteine is l-2000mg.

同时给药包括给予氨溴索和厄多司坦或氨溴索和乙酰半胱氨酸， 或者将每种活性剂的单独制剂基本上同时给药。 Simultaneous administration includes administration of ambroxol and erdosteine or ambroxol and acetylcysteine, or separate formulations of each active agent are administered substantially simultaneously.

应当理解， 氨溴索和厄多司坦， 氨溴索和乙酰半胱氨酸是分别以 其药学上可接受的形式作为药物活性剂给药的， 其药学上可接受的形 式包括药学上可接受的盐、 酯和溶剂化物。 本发明的 "药学上可接受的"包括人和兽医用途。It should be understood that ambroxol and erdosteine, ambroxol and acetylcysteine are administered as pharmaceutically active agents in their pharmaceutically acceptable forms, respectively, and their pharmaceutically acceptable forms include pharmaceutically acceptable Accepted salts, esters and solvates. "Pharmaceutically acceptable" for the present invention includes human and veterinary use.

为了避免疑问， 本发明给出的药学上可接受形式的氨溴索或厄多 司坦或乙酰半胱氨酸的标量，包括 mg量时， 该标量是关于化合物本身 给出的： 例如 50mg盐酸盐形式的氨溴索是指含有 50mg氨溴索的盐酸 盐的量； 例如 200mg盐酸盐形式的厄多司坦是指含有 200mg的厄多司 坦的盐酸盐的量。 For the avoidance of doubt, the scalar amounts of ambroxol or erdosteine or acetylcysteine in the pharmaceutically acceptable form given in the present invention, including the amount in mg, are given for the compound itself: for example 50 mg of salt Ambroxol in the acid salt form refers to the amount of the hydrochloride salt containing 50 mg of ambroxol; for example, Erdosteine in the form of 200 mg hydrochloride means the amount of the hydrochloride salt containing 200 mg of Erdosteine.

在一个特定方面， 该药物组合包含每天给予 l-2000mg的氨溴索。 特别是， 该药物组合包含每天给予 l-500mg、 500-1000mg 或 1000-2000mg 的氨溴索。 优选的是， 该药物组合包含每天给予 100-lOOOmg的氨溴索。 In a specific aspect, the pharmaceutical combination comprises 1-2000 mg of ambroxol administered daily. In particular, the pharmaceutical combination contains 1-500 mg, 500-1000 mg, or 1000-2000 mg of ambroxol administered daily. Preferably, the pharmaceutical combination comprises 100-1000 mg of ambroxol administered daily.

在一个特定方面，该药物组合包含每天给予 l-2000mg的厄多司坦。 特别是， 该药物组合包含每天给予 l-500mg、 500-1000mg 或 1000-2000mg 的厄多司坦。 优选的是， 该药物组合包含每天给予 l-1000mg的厄多司坦。 In a specific aspect, the pharmaceutical combination comprises 1-2000 mg of erdosteine administered daily. In particular, the pharmaceutical combination comprises erdosteine administered at 1-500 mg, 500-1000 mg, or 1000-2000 mg per day. Preferably, the pharmaceutical combination comprises 1-1000 mg of erdosteine administered daily.

在一个特定方面，该药物组合包含每天给予 l-2000mg的乙酰半胱 氨酸。 特别是， 该药物组合包含每天绔予 l-500mg、 500-1000mg 或 1000-2000mg 的乙酰半胱胺酸。 优选的是， 该药物组合包含每天给予 l-1000mg的乙酰半胱氨酸。 In a specific aspect, the pharmaceutical combination comprises 1-2000 mg of acetylcysteine administered daily. In particular, the pharmaceutical combination contains 1-500 mg, 500-1000 mg, or 1000-2000 mg of acetylcysteine per day. Preferably, the pharmaceutical combination comprises 1-1000 mg of acetylcysteine administered daily.

本发明通过实验证明， 氨溴索与厄多司坦， 氨溴索和乙酰半胱氨 酸的药物组合可提供的特别有益的防治呼吸道充血及感染的炎症如慢 性支气管炎、 哮喘等咳痰困难作用， 并表现相对于对照的协同作用， 所述对照预期为单独的活性药剂的作用总和。 The invention proves through experiments that the combination of ambroxol and erdosteine, ambroxol and acetylcysteine can provide particularly beneficial prevention and treatment of respiratory congestion and inflammation of infections such as chronic bronchitis, asthma, and sputum. Effect and exhibit a synergistic effect relative to a control that is expected to be the sum of the effects of the individual active agents.

祛痰作用可以利用常规方法来描述其特征， 例如通过测定咳痰量 的增加。 The expectorant effect can be characterized by conventional methods, for example by measuring an increase in the amount of expectorant.

在一个优选的方面， 本发明的药物组合的两种活性剂的剂量水平 将小于达到单纯加和的祛痰作用所需要的剂量。 在本发明中， 活性药物优选以药物组合物的形式给药， 如上所示， 两种组合物可包括多种药物或仅一种药物。 因此， 本发明的另一目的 是提供一种药物组合物，该组合物含有 l-2000mg的氨溴索和 l-2000mg 的厄多司坦或者含有 l-2000mg的氨溴索和 l-2000mg的乙酰半胱氨酸 或其二者药学上可接受的盐， 以及药学上可接受的载体。In a preferred aspect, the dose level of the two active agents of the pharmaceutical combination of the invention will be less than the dose required to achieve the expectorant effect of pure addition. In the present invention, the active drug is preferably administered in the form of a pharmaceutical composition. As shown above, the two compositions may include multiple drugs or only one drug. Therefore, another object of the present invention is to provide a pharmaceutical composition containing 1-2000 mg of ambroxol and 1-2000 mg of erdosteine or 1-2000 mg of ambroxol and 1-2000 mg of Acetylcysteine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

换言之， 本发明涉及一种用于防治呼吸道充血及感染的各种炎症， 用于祛痰的药物组合物， 所述的药物组合物包括顺序给予或同时给予 药学上可接受形式的氨溴索和选自厄多司坦、 乙酰半胱氨酸， 其中， 氨溴索的含量为 l-2000mg， 厄多司坦的含量为 l-2000mg， 乙酰半胱氨 酸的含量为 l-2000mg。 In other words, the present invention relates to a pharmaceutical composition for preventing and treating various inflammations of respiratory tract congestion and infection, and for expectoration. The pharmaceutical composition comprises sequential or simultaneous administration of ambroxol in a pharmaceutically acceptable form and It is selected from Erdostein and acetylcysteine, wherein the content of ambroxol is 1-2000mg, the content of Erdostein is 1-2000mg, and the content of acetylcysteine is 1-2000mg.

所述的氨溴索为碱或其可药用盐。 本发明药物组合物的制剂形式 为注射剂、 粉针剂、 喷雾剂、 片剂、 缓释剂、 滴丸、 冲剂、 胶囊剂或 缓释微丸。 The ambroxol is a base or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention is in the form of injections, powder injections, sprays, tablets, sustained-release agents, dripping pills, granules, capsules or sustained-release pellets.

由此可见， 本发明还提供一种本发明药物组合物在制备祛痰的药 物中的应用。 It can be seen that the present invention also provides an application of the pharmaceutical composition of the present invention in the preparation of an expectorant.

本发明组合物可以通过将 l-2000mg氨溴索和 l-2000mg厄多司坦 或者含有 l-2000mg的氨溴索和 l-2000mg的乙酰半胱氨酸或其二者药 学上可接受的盐与药学上可接受的载体混合后， 按照常规的制备方法 加以制备。 The composition of the present invention can be obtained by mixing 1-2000 mg of ambroxol and 1-2000 mg of erdostan After mixing with a pharmaceutically acceptable carrier, it is prepared according to a conventional preparation method.

通常该类组合物适合于口服给药和注射给药， 也适合其他的给药 方法， 例如经皮给药。 Such compositions are generally suitable for oral and injection administration, as well as other methods of administration, such as transdermal administration.

该组合物可以是片剂、 胶囊、 粉剂、 喷雾剂、 颗粒、 锭剂、 栓剂， 或口服液或无菌胃肠外溶液或悬液等液体制剂形式。 The composition can be in the form of tablets, capsules, powders, sprays, granules, dragees, suppositories, or liquid preparations such as oral solutions or sterile parenteral solutions or suspensions.

该组合物可以是大或小容量注射剂、 冻干粉针、 无菌粉分装等制 剂形式。 The composition may be in the form of a large or small volume injection, a lyophilized powder injection, a sterile powder portion, and the like.

为了达到给药的一致性， 本发明组合物优选为单剂形式。 用于口服给药的单剂表示形式可以是片剂和胶囊， 并可含有常规 赋形剂诸如粘合剂， 例如糖浆、 阿拉伯胶、 明胶、 山梨醇、 黄芪胶或 聚乙烯吡咯烷酮； 填充剂， 例如乳糖、 糖、 玉米淀粉、 磷酸钙、 山梨 醇或甘氨酸； 压片润滑剂， 例如硬脂酸镁； 崩解剂， 例如淀粉、 聚乙 烯吡咯垸酮、 淀粉乙醇酸钠或微晶纤维素； 或药学上可接受的湿润剂， 诸如十二烷基硫酸钠。In order to achieve uniform administration, the composition of the present invention is preferably in a single-dose form. Single-dose representations for oral administration may be tablets and capsules, and may contain conventional excipients such as binders such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, For example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants such as magnesium stearate; disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; Or a pharmaceutically acceptable wetting agent, such as sodium lauryl sulfate.

这些组合物优选以与相关日剂量适宜的量制成单位剂量。 合适的 氨溴索的单位剂量包含 l-2000mg的各种剂量。 可以每天给药 1-6次， 但最优选每天给药 1次 （注射给药） 或 3次 （口服给药）。 These compositions are preferably made into unit doses in an amount appropriate to the relevant daily dose. Suitable unit doses of ambroxol include various doses ranging from 1 to 2000 mg. It can be administered 1-6 times a day, but most preferably it is administered once (injection) or three times (orally).

厄多司坦的合适剂量包括每天给予 l-2000mg的各种剂量，但最优 选每天给药 1次 （注射给药） 或 3次 （口服给药）。 Suitable doses of Erdostan include various doses of 1-2000 mg per day, but optimally it is administered once a day (injection) or three times (orally).

乙酰半胱氨酸的合适剂量包括每天给予 l-2000mg的各种剂量，但 最优选每天给药 1次 （注射给药） 或 3次 （口服给药）。 Suitable doses of acetylcysteine include various doses of 1-2000 mg per day, but most preferably are administered once (injection) or 3 times (orally) per day.

固体口服组合物可以用常规的混合、 填充或压片法制备。 重复混 合操作可以用于将活性剂充分分布到使用大量填充剂量的组合物中。 这样的操作当然是本领域中常规的。 片剂可以按照常规制备方法制得 包衣片或素片。 Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. Repeated blending operations can be used to distribute the active agent sufficiently into a composition using a large amount of filler. Such operations are of course routine in the art. The tablets can be made into coated or plain tablets according to a conventional method.

口服液体制剂可以是例如乳剂、 糖浆或酏剂的形式， 或者可以作 为干燥产品存在， 使用前再用水或其他合适的载体重新构成。 这种液 体制剂可以含有常规添加剂， 诸如悬浮剂， 例如山梨醇、 糖浆、 甲基 纤维素、 明胶、 羟乙基纤维素、 羧甲基纤维素、 硬脂酸铝凝胶或氢化 食用脂； 乳化剂， 例如卵磷脂、 脱水山梨醇一油酸酯、 或阿拉伯胶； 无水载体（可包括食用油）， 例如杏仁油、 馏化椰子油或油性酯， 所述 的油性酯包括甘油酯、 丙二醇或乙醇； 防腐剂， 例如对羟基苯甲酸甲 酯或丙酯或山梨酸； 如果需要， 还可加入常规调味剂或着色剂。 Oral liquid preparations can be in the form of, for example, emulsions, syrups or elixirs, or they can be present as dry products and reconstituted with water or other suitable carriers before use. This liquid formulation may contain conventional additives such as suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated food fat; emulsification; Agents, such as lecithin, sorbitan monooleate, or gum arabic; anhydrous carriers (which can include edible oils), such as almond oil, distilled coconut oil, or oily esters, where the oily esters include glycerides, propylene glycol Or ethanol; preservatives, such as methyl or propyl parabens, or sorbic acid; if desired, conventional flavoring or coloring agents can also be added.

对于胃肠外给药， 特别是注射剂， 可利用两种活性组分分别与无 菌载体制备单位液体剂型， 并且根据所用的浓度将其悬浮或溶解于载 体中。 在制备溶液时， 可以将活性成分溶解于注射用水并过滤灭菌， 之后灌注到小瓶或安瓿中并密封。 有利的是， 可以将辅助剂诸如局部 麻醉剂、 防腐剂和缓冲剂溶解于该载体中。 为了增强稳定性， 可以将 该组合物冷冻后再填充到小瓶中， 并在真空下除去水分。 胃肠外悬液 是用实质上相同的方式制备而得， 只是活性组分不是溶解于载体中， 而是悬浮于载体中， 且灭菌不是通过过滤完成。 该活性组分可以通过 与环氧乙垸接触后， 再悬浮于无菌载体中而进行灭菌。 有利的是， 在 该组合物中包含表面活性剂或湿润剂以促进该化合物均匀分布。For parenteral administration, especially injections, two active ingredients can be used separately from Bacterial carriers are prepared in unit liquid dosage form and are suspended or dissolved in the carrier depending on the concentration used. When preparing a solution, the active ingredient can be dissolved in water for injection and filtered for sterilization, then poured into a vial or ampoule and sealed. Advantageously, adjuvants such as a local anesthetic, preservatives and buffering agents can be dissolved in the carrier. To enhance stability, the composition can be frozen and filled into vials, and the water can be removed under vacuum. Parenteral suspensions are prepared in substantially the same way, except that the active ingredients are not dissolved in the carrier, but are suspended in the carrier, and sterilization is not accomplished by filtration. The active ingredient can be sterilized by contacting with ethylene oxide and resuspending it in a sterile carrier. Advantageously, a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.

另外， 还可按照常规方法将药物组合中的单味活性制剂或药物组 合物制成缓控释制剂， 如缓释微丸或控释微丸。 In addition, a single-taste active preparation or a pharmaceutical composition in a pharmaceutical combination can also be made into a sustained-release preparation according to a conventional method, such as a sustained-release pellet or a controlled-release pellet.

根据不同的给药方法，组合物可以含有 0.1%-99%重量，优选 1-60% 重量的活性物质。 Depending on the method of administration, the composition may contain from 0.1% to 99% by weight, preferably from 1 to 60% by weight of active substance.

因此， 本发明还涉及氨溴索和厄多司坦、 氨溴索和乙酰半胱氨酸 的加和或协同组合物， 这些协同组合物用于慢性支气管炎、 支气管哮 喘等疾病引起的痰液粘稠、 咯痰困难和痰阻气管等， 亦可用于防治手 术后咯痰困难和肺炎合并症。 Therefore, the present invention also relates to the addition or synergistic composition of ambroxol and erdosteine, ambroxol and acetylcysteine. These synergistic compositions are used for sputum caused by diseases such as chronic bronchitis and bronchial asthma. Viscosity, difficulty in expectoration, and sputum obstruction can also be used to prevent complications such as difficulty in expectoration and pneumonia after surgery.

本发明还可以涉及一种药盒， 其特征在于其含有氨溴索、 厄多司 坦、 乙酰半胱氨酸， 或它们的药学上可接受的盐， 其中， 氨溴索的含 量为 l-2000mg， 厄多司坦的含量为 l-2000mg。本发明还涉及另一种药 盒， 氨溴索的含量为 l-2000mg， 乙酰半胱氨酸的含量为 l-2000mg。 患 者按顺序和 /或同时使用药盒内的所述药物以达到使用本发明组合物的 目的。 以下实施例用以进一步阐述本发明， 而不起任何限制作用 具体实施方式The present invention may also relate to a kit, which is characterized in that it contains ambroxol, erdosteine, acetylcysteine, or a pharmaceutically acceptable salt thereof, wherein the content of ambroxol is 1- 2000mg, Erdosteine content is 1-2000mg. The invention also relates to another kit, the content of ambroxol is 1-2000 mg, and the content of acetylcysteine is 1-2000 mg. The patient uses the drugs in the kit sequentially and / or simultaneously to achieve the purpose of using the composition of the present invention. The following examples are provided to further illustrate the present invention without any limitation. detailed description

实施例 1:Example 1:

氨溴索和厄多司坦盐氨溴索和乙酰半胱氨酸盐和的药理研究结果。 Results of Pharmacological Studies of Ambroxol and Erdosteine Salt Ambroxol and Acetylcysteine

1 )、 试验方法1) Test method

将 160只雄性小鼠随机分成 15组， 分别为阴性对照组， 盐酸氨溴索 低、 中、 高剂量组， 乙酰半胱氨酸低、 中、 高剂量组， 厄多司坦低、 中、 高剂量组， 氨溴索和乙酰半胱氨酸盐 （1： 1 ) 低、 中、 高剂量组， 氨溴索和厄多司坦盐 （1： 1 )低、 中、 高剂量组， 每日口服试验样品 1 次， 连续口服 3天， 给药体积为 0.4ml， 阴性对照组口服同体积生理盐 水。 末次给药前 1天禁食， 于末次给药后 0.5小时腹腔注射 5%酚红溶 液 500mg/kg，0.2ml/只。再 0.5小时后给予过量麻醉药处死动物，分离气 管， 插入注射针， 用 2ml生理盐水冲洗， 冲洗液加 IM NaOH O. lml显 色， 用 722型分光光度计于 546nm波长比色， 计算出酚红含量。 160 male mice were randomly divided into 15 groups, which were negative control groups, low, medium and high dose groups of ambroxol hydrochloride, low, medium and high dose groups of acetylcysteine, low, medium and high doses of erdosteine High-dose group, ambroxol and acetylcysteine (1: 1) low, medium, and high-dose groups, ambroxol and erdosteine salt (1: 1), low, medium, and high-dose groups, each The oral test sample was taken once a day for 3 consecutive days, with a dose volume of 0.4 ml. The negative control group received the same volume of saline. Fasting one day before the last administration, and intraperitoneally injecting a 5% phenol red solution 500mg / kg, 0.2ml / head 0.5 hours after the last administration. After another 0.5 hours, the animals were sacrificed by giving an excessive amount of anesthesia, the trachea was separated, the injection needle was inserted, and the solution was rinsed with 2 ml of physiological saline. The rinse solution was added with IM NaOH O. 1 ml to develop a color, and the 722 spectrophotometer was used at 546 nm to determine the colorimetry. Red content.

2)、 试验结果 2), test results

试验结果见表 1。 剂量 ( μ 酚红量 ( W g/ml) (土The test results are shown in Table 1. Dose (μ phenol red (W g / ml) (Earth

样品 增加百分率(％) Sample percentage increase (%)

mol/kg) SD) mol / kg) SD)

生理盐水 20ml/kg 0.70±0. 25 Normal saline 20ml / kg 0.70 ± 0. 25

39.7 0·87±0· 20 34.3 盐酸氨溴索 79.4 0.91 ±0. 26 24.3 39.7 0 · 87 ± 0 · 20 34.3 Ambroxol hydrochloride 79.4 0.91 ± 0. 26 24.3

158.7 0·94±0· 34 30.0 158.7 0 · 94 ± 0 · 34 30.0

39.7 0.86±0. 18 22.8 乙酰半胱氨酸 79.4 0.90±0· 25 27.139.7 0.86 ± 0. 18 22.8 Acetylcysteine 79.4 0.90 ± 0 · 25 27.1

158.7 0·95 ±0. 31 35.7 158.7 0.95 ± 0. 31 35.7

39.7 0.93 ±0. 34 32.9 厄多司坦 79.4 0.96 ±0. 36 37.139.7 0.93 ± 0. 34 32.9 Erdostan 79.4 0.96 ± 0. 36 37.1

158.7 0.98 ±0. 35 40.0 39.7 0.98 + 0. 31 40.0 氨溴索和乙酰半158.7 0.98 ± 0. 35 40.0 39.7 0.98 + 0.31 40.0 Ambroxol and acetyl semi

79.4 1.04±0. 28 48.6 胱氨酸盐（1： 1 ) 79.4 1.04 ± 0. 28 48.6 Cysteine (1: 1)

158.7 1.08±0. 33 54.3 158.7 1.08 ± 0. 33 54.3

39.7 1.28 ±0. 20 64.4 氨溴索和厄多司39.7 1.28 ± 0. 20 64.4 Ambroxol and Erdos

79.4 1·31 ±0. 21 66.6 坦盐 ( 1： 1 ) 79.4 1.31 ± 0. 21 66.6 Tan salt (1: 1)

158.7 1.21 ±0. 35 72.5 试验结果显示， 与阴性对照组相比， 盐酸氨溴索和乙酰半胱氨酸、 厄多 司坦口服给药三天， 均能增加小鼠呼吸道酚红分泌量， 而氨溴索和厄 多司坦盐氨溴索和乙酰半胱氨酸盐和皆能非常明显地增加小鼠呼吸道 酚红分泌量， 与单一药物相比具有显著性差异。 158.7 1.21 ± 0. 35 72.5 The test results showed that compared with the negative control group, ambroxol hydrochloride, acetylcysteine, and erdosteine were administered orally for three days, which could increase the phenol red secretion in the respiratory tract of mice. Ambroxol and erdosteine salt, ambroxol and acetylcysteine, can significantly increase the phenol red secretion in the respiratory tract of mice, which has a significant difference compared with a single drug.

实施例 2:Example 2:

30mg 30mg

厄多司坦 150mg 微晶纤维素 27.5mg 乳糖果一水合物 适量 Erdostein 150mg Microcrystalline Cellulose 27.5mg Milk Candy Monohydrate Moderate

硬脂酸镁 0.5mg 每片 208mg 按上述原料、 辅料混合均匀后， 按照常规湿法制粒， 干燥， 压片, Magnesium stearate 0.5mg 208mg per tablet After mixing the above raw materials and auxiliary materials uniformly, granulate according to the conventional wet method, dry, and tablet,

实施例 3:Example 3:

30mg 乙酰半胱氨酸 30mg 30mg acetylcysteine 30mg

NaCl 0.9g NaCl 0.9g

注射用水 Water for Injection

每支 100ml 取氯化钠， 用注射用水搅拌溶解， 然后分别加入氨溴索、 乙酰半 胱氨酸， 继续搅拌使完全溶解， 添加注射用水至总量， 滤过至澄明， 灌封， 灭菌， 即得。 实施例 4:100ml each Take sodium chloride, stir and dissolve it with water for injection, then add ambroxol and acetylcysteine separately, continue to stir to completely dissolve, add water for injection to the total amount, filter to clear, potting, and sterilize. . Example 4:

缓释微丸制备Preparation of sustained-release pellets

缓释部分处方 （丸 1 )Sustained Release Partial Prescription (Pill 1)

丸芯处方Pill core prescription

氨溴索 30g Ambroxol 30g

厄多司坦 150g Erdosteine 150g

微晶纤维素 15g Microcrystalline cellulose 15g

羟丙甲纤维素 5g Hypromellose 5g

纯水 200ml 200ml pure water

制成 1000粒 包衣处方 Made into 1000 capsules

25%乙基纤维素水分散液 184g 25% ethyl cellulose aqueous dispersion 184g

纯水 123g Pure water 123g

粒 分别将微晶纤维素、 氨溴索、 厄多司坦预先粉碎过 100目筛， 按丸 1处方称取， 混合均匀， 羟丙甲基纤维素水溶液做粘合剂， 制微丸， 将 其于 50〜60°C干燥， 选 20~30目的小丸， 备用。 The granules were respectively crushed with microcrystalline cellulose, ambroxol, and erdosteine through a 100-mesh sieve in advance, weighed according to the prescription of pill 1, and mixed uniformly. A hypromellose aqueous solution was used as a binder to prepare pellets. It is dried at 50 to 60 ° C, and pellets of 20 to 30 mesh are selected and used.

将制备且选好的微丸， 置流化床中， 采用底喷方式， 通过热空气悬 浮流化， 进风温度为 55°C， 料床温度控制在 30°C时， 调节蠕动泵使其 按每分钟 5g浆液的速度提供包衣液， 雾化压力 2bar， 开始对流化的小 丸连续喷浆， 喷浆结束后， 降低风量， 使微丸于微沸状态下于 40°C干 燥片刻。取出后置于 40°C烘箱中干燥 24小时，增重约 18°/。，测定含量，The prepared and selected pellets are placed in a fluidized bed, and the bottom spray method is adopted to suspend fluidization with hot air. The inlet air temperature is 55 ° C, and the bed temperature is controlled at 30 ° C. The coating solution is provided at a rate of 5 g per minute, the atomization pressure is 2 bar, and the small The pellets are continuously sprayed. After the spraying is completed, the air volume is reduced, and the pellets are dried at 40 ° C for a while in a microboiling state. After taking out, it was dried in an oven at 40 ° C for 24 hours, and the weight was increased by about 18 ° /. , Determine the content,

实施例 5Example 5

药盒的配置Configuration of the kit

一种临床上使用的或者家庭使用的药盒， 其中配置有两种或者三 种药物的片剂， 即氨溴索， 其含量为 l-2000mg和厄多司坦， 其含量为 l-2000mg, 或者氨溴索， 其含量为 l-2000mg和乙酰半胱氨酸， 其含量 为 l-2000mg_o 本领域技术人员采用公知的方法结合上述披露的内容可以完成本 发明组合物的配置。A clinically used or home-used kit, which is configured with two or three medicine tablets, namely ambroxol, whose content is l-2000mg and erdosteine, whose content is l-2000mg, or ambroxol, an amount of l-2000mg acetylcysteine, a level of contents l-2000mg_o skilled in the art using well known methods disclosed above may be combined to complete the configuration of the composition of the present invention.

Claims

权利要求书 Claim

1 . 一种用于防治呼吸道充血及感染的各种炎症以及祛痰的药物组合 物， 所述的药物组合物包括顺序给予或同时给予药学上可接受形式的 氨溴索和选自厄多司坦、 乙酰半胱氨酸， 其中， 氨溴索的含量为 l-2000mg , 厄多司坦的含量为 l-2000mg， 乙酰半胱氨酸的含量为

What is claimed is: 1. A pharmaceutical composition for preventing and treating various inflammations and expectorants of respiratory congestion and infection, said pharmaceutical composition comprising sequential or simultaneous administration of ambroxol in a pharmaceutically acceptable form and selected from the group consisting of erdox And acetylcysteine, wherein the content of ambroxol is 1-2000mg, the content of erdosteine is 1-2000mg, and the content of acetylcysteine is

2. 根据权利要求 1所述的药物组合物， 其中所述的氨溴索为碱或其可 药用盐。 2. The pharmaceutical composition according to claim 1, wherein the ambroxol is a base or a pharmaceutically acceptable salt thereof.

3. 根据权利要求 1或 2所述的药物组合物， 其中该药物组合物的制剂 形式为注射剂、 粉针剂、 喷雾剂、 片剂、 缓释剂、 滴丸、 冲剂、 胶囊 剂或缓释微丸。 3. The pharmaceutical composition according to claim 1 or 2, wherein the preparation form of the pharmaceutical composition is an injection, a powder injection, a spray, a tablet, a sustained release agent, a dripping pill, a granule, a capsule, or a sustained release microcapsule. pill.

4.根据权利要求 1或 2所述的药物组合物在制备祛痰的药物中的应用。 4. The use of the pharmaceutical composition according to claim 1 or 2 in the preparation of an expectorant medicine.

5. 一种药盒， 其特征在于含有氨溴索和厄多司坦或者它们的药学上可 接受的盐， 其中， 氨溴索的含量为 l-2000mg， 厄多司坦的含量为 l-2000mg。5. A kit comprising ambroxol and erdosteine or a pharmaceutically acceptable salt thereof, wherein the content of ambroxol is 1-2000 mg and the content of erdosteine is 1- 2000mg.

6. 一种药盒， 其特征在于含有氨溴索和乙酰半胱氨酸或者它们的药学 上可接受的盐， 其中， 氨溴索的含量为 l-2000mg， 乙酰半胱氨酸的含 量为 l-2000mg。 6. A kit comprising ambroxol and acetylcysteine or a pharmaceutically acceptable salt thereof, wherein the content of ambroxol is 1-2000mg and the content of acetylcysteine is l-2000mg.