WO2013177880A1 - 复方盐酸氨溴索组合物及其制备方法 - Google Patents

复方盐酸氨溴索组合物及其制备方法 Download PDF

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WO2013177880A1
WO2013177880A1 PCT/CN2012/082337 CN2012082337W WO2013177880A1 WO 2013177880 A1 WO2013177880 A1 WO 2013177880A1 CN 2012082337 W CN2012082337 W CN 2012082337W WO 2013177880 A1 WO2013177880 A1 WO 2013177880A1
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Prior art keywords
scopolamine
ambroxol hydrochloride
preparation
lyophilized powder
powder
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PCT/CN2012/082337
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English (en)
French (fr)
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汪六一
汪金灿
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海南卫康制药(潜山)有限公司
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Priority to BR112014004737-5A priority Critical patent/BR112014004737A2/pt
Priority to AU2012381574A priority patent/AU2012381574B2/en
Priority to RU2014102274A priority patent/RU2014102274A/ru
Priority to EP12877935.2A priority patent/EP2857012A4/en
Priority to US14/237,500 priority patent/US9000004B2/en
Publication of WO2013177880A1 publication Critical patent/WO2013177880A1/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
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to the field of medicine, and in particular to a compound ambroxol hydrochloride composition and a preparation method thereof.
  • COPD chronic obstructive pulmonary diseases
  • Airflow limitation is not completely reversible and progressive.
  • C0PD mainly affects the lungs, but it can also cause adverse effects on the whole body (or outside the lungs).
  • C0PD is a common disease of the respiratory tract. With the increase of age, the airway cilia clearance function of the elderly is diminished, the lung antioxidant activity is reduced, and the elderly are prone to C0PD.
  • Chronic stimuli such as tobacco smoke act on the lungs, causing abnormal inflammation in the lungs.
  • C0PD can affect the airway, lung parenchyma and pulmonary blood vessels, and appears to be a chronic inflammatory response mainly characterized by neutrophils, macrophages, and lymphocyte infiltration. These cells release inflammatory mediators that interact with structural cells of the airways and lung parenchyma, which in turn promotes the accumulation of T lymphocytes (especially CD+8) and neutrophils and eosinophils in the lung tissue, releasing leukotriene B4 ( LTB4), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF- ⁇ ) and other mediators cause damage to the lung structure.
  • LTB4 leukotriene B4
  • IL-8 interleukin-8
  • TNF- ⁇ tumor necrosis factor alpha
  • C0PD involves the central airway, peripheral airways, lung parenchyma and pulmonary vessels.
  • the central airway (trachea, bronchus, and bronchioles with an inner diameter greater than 2-4 mm) infiltrated the inflammatory cells of the epithelium, increased mucus secretory glands, and increased goblet cells increased mucus secretion.
  • peripheral airways small bronchi and bronchioles with an inner diameter of less than 2 mm
  • C0PD pulmonary parenchymal involvement is characterized by central lobe emphysema, involving respiratory bronchioles, Catheter expansion and destruction.
  • the condition is mild, the lesion often occurs in the upper part of the lung.
  • the whole lung can be involved, accompanied by destruction of the pulmonary capillary bed.
  • the changes in pulmonary blood vessels of C0PD are characterized by thickening of the vessel wall and can occur early. It is characterized by intimal thickening, smooth muscle hyperplasia and inflammatory cell infiltration of vascular wall. In the case of advanced secondary pulmonary heart disease, multiple pulmonary arteriolar in situ thrombosis may occur. Acute exacerbation of C0PD is associated with deep vein thrombosis and pulmonary embolism.
  • a compound of the ambroxol hydrochloride composition is: a mass percentage of 0. 1% ⁇ 99. 9% of ambroxol hydrochloride and 99. 9% ⁇ 0. 1% of scopolamine .
  • a method for preparing a compound preparation using a compound ambroxol hydrochloride composition characterized in that the specific operation steps are:
  • the activated carbon is filtered off, and the liquid is filtered through a microporous membrane of 0. 45 ⁇ m and 0.22 ⁇ m;
  • the filtered liquid can be filled into a large plate or a vial
  • Various dosage forms are prepared from lyophilized powder.
  • the dosage form is a tablet, an elixir, a suppository, a capsule, an ointment, a cream, a paste, an ophthalmic preparation, a pill, an implant, a syrup, an aerosol, a powder, a spray, a film, Granules, Oral solution, oral suspension, oral emulsion, powder, nasal preparation.
  • Ambroxol hydrochloride mainly acts on the secretory cells of the respiratory tract, regulates the secretion of mucous and serous substances, increases the secretion of the serum, and also cleaves the polysaccharide fiber of the acid glycoprotein in the sputum, inhibiting the acidic protein in the mucous gland and goblet cells. Synthetic, reduce the viscosity of the sputum, make the sputum thin and easy to discharge; at the same time, the medicine can also increase the frequency and intensity of the movement of the cilia of the respiratory tract, promote the discharge of sputum, and increase the self-purification of the respiratory tract.
  • ambroxol hydrochloride has an obvious antioxidant effect and plays an important role in the pathogenesis of reactive free oxygen group lung diseases. It can scavenge oxides H-, Hocl attenuates the high reactivity of bronchial mucosal damage and stimulates the secretion of PS in cells. In addition, ambroxol activates the intracellular glutathione system and promotes the synthesis of intracellular glutathione (GSH) to counteract the destruction of oxygen free radicals.
  • GSH intracellular glutathione
  • Scopolamine can counteract the oxygen free radicals produced by damaged cells and has antioxidant and peroxide scavenging effects.
  • scopolamine can effectively inhibit the formation of superoxide and myocardial damage induced by pyrogallol, and the cardiac dysfunction caused by oxygen free radicals. Have a certain effect.
  • Scopolamine can significantly reduce the LPO content in rabbit renal meridian blood after ischemia-reperfusion, reduce the lipid peroxidation induced by free radicals, and protect against renal ischemia-reperfusion injury in rabbits; prevent exogenous H202-induced damage to rat red blood cells Membrane protein sparse; There is a significant dose-dependent scavenging effect on superoxide anion radicals produced in the hypoxanthine-xanthine oxidase system, and the scavenging effect is slightly lower than that of superoxide dismutase (S0D).
  • S0D superoxide dismutase
  • Scopolamine not only inhibits endotoxin-induced lipopolysaccharide (LPS)-induced expression of plasminogen activator inhibitor 1 (Pal-1) protein and mRNA, but also inhibits basal levels of Pal-1 expression, thereby exerting an antithrombotic effect.
  • Scopolamine may inhibit the expression of Pal-1 in endothelial cells induced by LPS through the NF- K B pathway.
  • Scopolamine inhibits the synthesis of thromboxane B2, prevents platelet aggregation and release, prevents microthrombus formation, and inhibits deposition of antigen-antibody complexes.
  • Scopolamine has smooth muscle relaxation, relieves vasospasm, and improves microcirculation, which inhibits glandular secretion. Scopolamine acts on cholinergic receptors in the airway mucosa and smooth muscle, effectively inhibits cholinergic nerve function in the airway, reduces vagal tone, and promotes bronchial, bronchiolar dilatation and airway secretions, thereby reducing wheezing. The wheezing sound is reduced, the clinical symptoms are improved, and the recovery of the disease is promoted. In addition, scopolamine also has the effect of calming the cerebral cortex, reducing the body's oxygen consumption, relieving small arteriospasm, improving brain tissue hypoxia, and blocking multiple organ function damage.
  • the preparation method provided by the invention is scientific and reasonable, and is convenient to be prepared into various dosage forms, and the prepared compound preparation can: 1) reduce the viscosity of the sputum liquid, make the sputum liquid thin, promote the sputum discharge, and increase the self-purification effect of the respiratory tract; Increase the body's antioxidant effect, which is conducive to COD patients to enhance their own immunity; 3) Excitable respiratory center, relieve bronchial and vascular smooth muscle spasm, reduce the load before and after the heart, is conducive to the recovery of heart function, but also relieve heart, brain, Small arterial spasm in the lungs, kidneys, etc., improve microcirculation and hypoxia of tissue cells, improve airway epithelial surface clearance, and thus prevent and treat COPD o.
  • Embodiment 1 Preparation of a freeze-dried powder of ambroxol hydrochloride for injection, in the form of 1000
  • the dosage of ambroxol hydrochloride, scopolamine and mannitol is added to the water for injection, stirred and dissolved, and then added with a NaOH solution to adjust the P H value of 5.0, 0. 1% of activated carbon is stirred for 30 minutes, and the activated carbon is filtered off. After filtering through 0. 45 ⁇ ⁇ and 0. 22 ⁇ ⁇ microporous membrane, canned, sent to the freeze dryer, cooled to -40 ° C, after 2 hours of incubation, slowly warmed to -5 ° C ⁇ 0 After drying at °C, the temperature is raised to 35 ° C, and then kept for 3 hours, the freeze-drying is finished, and the box is discharged.
  • the dosage of ambroxol hydrochloride, scopolamine and mannitol is added to the water for injection, stirred and dissolved, and then added with a NaOH solution to adjust the P H value of 5.0, 0. 1% of activated carbon is stirred for 30 minutes, and the activated carbon is filtered off. Filtration through 0. 45 ⁇ ⁇ and 0. 22 ⁇ ⁇ microporous membrane, canned into a large dish, sent to a freeze dryer, cooled to -40 ° C, after 2 hours of incubation, slowly warmed to -5 ° C ⁇ 0 °C sublimation drying, and then warming to 35 ° C, heat preservation for 3 hours, freeze drying, out of the box.
  • the lyophilized lyophilized product of the large plate was pulverized under aseptic conditions, and passed through a 180 mesh sieve to obtain a sterile lyophilized powder of ambroxol hydrochloride and scopolamine.
  • sucralose and menthol Mix the prescribed amount of sucralose and menthol, add ambroxol hydrochloride lyophilized powder and mix well, then add microcrystalline cellulose, lactose crospovidone, hydroxypropyl cellulose to mix evenly, and finally add stearin.
  • the magnesium acid and the silica are uniformly mixed, and the tablet is directly compressed, and the humidity is controlled to be 50% or less.
  • Example 3 preparation of an ambroxol hydrochloride scopolamine injection, based on 1000
  • the activated amount of ambroxol hydrochloride, scopolamine and mannitol are added to the water for injection, stirred and dissolved, and then added with a NaOH solution to adjust the P H value of 5.0, 0. 1% of activated carbon is stirred for 30 minutes, and the activated carbon is filtered off.
  • the liquid is filtered through a 0.45 ⁇ m and 0.22 ⁇ microporous membrane filter, canned into a large dish, sent to a freeze dryer, cooled to -40 ° C, and after 2 hours of incubation, slowly warmed to -5 ° C ⁇ 0 ° C sublimation is dried, and after heating to 35 ° C, the temperature is kept for 3 hours, the freeze-drying is finished, and the box is discharged.
  • the lyophilized lyophilized product of the large plate was pulverized under aseptic conditions, and passed through a 180 mesh sieve to obtain a sterile lyophilized powder of ambroxol hydrochloride and scopolamine.

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Abstract

一种用于治疗慢性阻塞性肺病的组合物，所述组合物的活性成分为0.1%-99.9%的盐酸氨溴索和99.9%-0.1%的东莨菪碱，该组合物有很强的协同作用。

Description

复方盐酸氨溴索组合物及其制备方法 技术领域- 本发明涉及医药领域， 尤其涉及一种复方盐酸氨溴索组合物及其制备方 法。 说
背景技术：
慢性阻塞性月巿病 ( chronic obstructive pulmonary diseases , COPD ) 是一种具有气流受限特征的可以预防和治书疗的疾病， 气流受限不完全可逆、 呈进行性发展。 C0PD主要累及肺脏， 但也可引起全身（或称肺外）的不良效应。 C0PD是呼吸道常见病， 随着年龄增加， 老年人的气道纤毛清除功能减退， 肺 抗氧化作用减退， 老年人容易患 C0PD。
烟草烟雾等慢性刺激物作用于肺部， 使肺部出现异常炎症反应。 C0PD可 累及气道、 肺实质和肺血管， 表现为出现以中性粒细胞、 巨噬细胞、 淋巴细 胞浸润为主的慢性炎症反应。 这些细胞释放炎症介质与气道和肺实质的结构 细胞相互作用， 进而促使 T淋巴细胞 （尤其是 CD+8) 和中性粒细胞及嗜酸性粒 细胞在肺组织聚集， 释放白三烯 B4 (LTB4)、 白介素 8 ( IL-8 )、 肿瘤坏死因子 α (TNF- α ) 等多种介质， 引起肺结构的破坏。 氧化、 抗氧化失衡和蛋白酶、 抗蛋白酶失衡以及自主神经系统功能紊乱， 胆碱能神经张力增高等进一步加 重 C0PD肺部炎症和气流受限。 遗传易患性在发病中起一定作用。
C0PD累及中央气道、 外周气道、 肺实质和肺血管。 中央气道 （气管、 支 气管以及内径大于 2-4mm的细支气管）表层上皮炎症细胞浸润， 粘液分泌腺增 大和杯状细胞增多使粘液分泌增加。 在外周气道（内径小于 2mm的小支气管和 细支气管） 内， 慢性炎症导致气道壁损伤和修复过程反复发生。 修复过程中 发生气道壁结构重构， 胶原含量增加及瘢痕组织形成， 这些改变造成气道狭 窄， 引起固定性气道阻塞。
C0PD肺实质受累表现为小叶中央型肺气肿， 累及呼吸性细支气管， 出现 管腔扩张和破坏。 病情较轻时病变部位常发生于肺的上部区域， 当病情进展 后， 可累及全肺， 伴有肺毛细血管床的破坏。
C0PD肺血管的改变以血管壁的增厚为特征， 早期即可出现。 表现为内膜 增厚， 平滑肌增生和血管壁炎症细胞浸润。 晚期继发肺心病时， 可出现多发 性肺细小动脉原位血栓形成。 C0PD急性加重期易合并深静脉血栓形成及肺血 栓栓塞症。 发明内容：
本发明的目的在于提供一种复方盐酸氨溴索组合物及其制备方法， 该复 方制剂用于治疗慢性阻塞性肺病， 有很强的协同作用， 疗效迅速。
本发明的具体技术方案为：
一种复方盐酸氨溴索组合物， 其特征在于， 该组合物主药为： 质量百分 比为 0. 1%〜99. 9%的盐酸氨溴索和 99. 9%〜0. 1%的东莨菪碱。
一种用复方盐酸氨溴索组合物制备复方制剂的方法， 其特征在于， 具体 操作步骤为：
a.将 0. 1%〜99. 9%的盐酸氨溴索、 99. 9%〜0. 1%的东莨菪碱和主药 5〜10倍 的甘露醇加到注射用水中；
b.搅拌溶解后加入 NaOH溶液调节 pH值到 5. 0；
c加入 0. 1%的活性炭搅拌 30分钟；
d.滤除活性炭， 药液再经 0. 45 μ m和 0. 22 μ m微孔滤膜过滤；
e.过滤后的药液罐装至大盘或西林瓶中；
f.送入冷冻干燥机中， 降温至 -40°C， 保温 2小时；
g.缓慢升温至 -5 °C〜0°C升华干燥， 再升温至 35°C后， 保温 3小时； h.冷冻干燥结束后出箱， 得到注射用盐酸氨溴索和东莨菪碱的冻干粉针; i.在无菌条件下粉碎冻干粉针， 过 180目筛， 得到盐酸氨溴索和东莨菪碱 的无菌冻干粉；
j.以冻干粉为原料制备各种剂型。
所述剂型有片剂、 酊剂、 栓剂、 胶囊剂、 软膏剂、 乳膏剂、 糊剂、 眼用 制剂、 丸剂、 植人剂、 糖浆剂、 气雾剂、 粉雾剂、 喷雾剂、 膜剂、 颗粒剂、 口服溶液剂、 口服混悬剂、 口服乳剂、 散剂、 鼻用制剂。
盐酸氨溴索主要作用于呼吸道分泌细胞， 调节粘液性及浆液性物质的分 泌， 使浆液分泌增加， 还能够裂解痰液中的酸性糖蛋白的多糖纤维， 抑制粘 液腺和杯状细胞中酸性蛋白合成， 降低痰液的粘稠度， 使痰液变得稀薄， 易 于排出； 同时该药也可增加呼吸道纤毛的运动频率和强度， 促进痰液排出， 增加呼吸道自净作用。 而且盐酸氨溴索具有明显的抗氧化作用， 在反应性的 自由氧基团的肺部疾病发病中都起到重要的作用。它可以清除氧化物 H-， Hocl 减弱支气管粘膜损害的高反应性， 刺激细胞 PS的分泌。 此外， 氨溴索还能激 活细胞内的谷胱甘肽系统， 促进细胞内的谷胱甘肽 (GSH)的合成， 从而对抗氧 自由基的破坏作用。
东莨菪碱可对抗受损细胞产生的氧自由基， 具有抗氧化和清除过氧化物 的作用。 在长时间接触邻苯三酚的成年大鼠心肌的研究中发现， 东莨菪碱能 有效抑制超氧化物的生成和邻苯三酚所引起的大鼠心肌功能损伤， 对氧自由 基引起的心脏功能失调有一定效果。 东莨菪碱可显著降低缺血再灌注的兔肾 经脉血中 LP0含量， 减少自由基引发的脂质过氧化反应， 对兔肾缺血再灌注损 伤具有保护作用； 可防止外源性 H202损伤大鼠红细胞膜蛋白疏基； 对次黄嘌 呤-黄嘌呤氧化酶体系中产生的超氧阴离子自由基有显著的剂量依赖性清除 作用， 清除效果略低于超氧化物歧化酶 （S0D)。
东莨菪碱不仅抑制内毒素脂多糖（LPS) 诱导的内皮细胞表达纤溶酶原激 活物抑制剂 1 (Pal-1 ) 蛋白和 mRNA表达， 而且抑制其基础水平的 Pal_l表达， 从而发挥抗血栓形成作用。 东莨菪碱可能通过 NF- K B途径抑制 LPS所致的内皮 细胞 Pal-1表达增强。 东莨菪碱能抑制血栓素 B2的合成， 防止血小板聚集和释 放， 防止微血栓形成， 抑制抗原抗体复合物沉积。
东莨菪碱具有平滑肌松弛、 解除血管痉挛、 改善微循环的作用， 可抑制 腺体分泌。 东莨菪碱可作用于气道黏膜及平滑肌上的胆碱能受体， 有效地抑 制气道的胆碱能神经功能， 降低迷走神经张力， 促使支气管、 毛细支气管扩 张和气道分泌物减少， 从而使喘息减轻， 哮鸣音减少， 临床症状好转， 促进 疾病的恢复。 此外， 东莨菪碱还有镇静大脑皮层的作用， 更有降低机体耗氧 量， 解除小动脉痉挛， 改善脑组织缺氧状态， 阻断多器官功能损伤等良效。 本发明提供的制备方法科学合理， 方便制成各种剂型， 制备的复方制剂 可： 1 ) 降低痰液的粘稠度， 使痰液变得稀薄， 促进痰液排出， 增加呼吸道自 净作用； 2 ) 增加人体抗氧化作用， 有利于 C0PD患者增强自身免疫力； 3 ) 可 兴奋呼吸中枢， 解除支气管与血管平滑肌痉挛， 降低心脏前后负荷， 有利于 心功能的恢复， 同时也能解除心、 脑、 肺、 肾等组织微小动脉痉挛， 改善微 循环和组织细胞的缺氧状态， 改善气道上皮表面清除功能， 从而预防和治疗 COPD o 具体实施方式：
为了使本发明实现的技术手段、 创作特征、 达成目的与功效易于明白了 解， 下面结合具体实施例， 进一步阐述本发明。
实施例一、 一种注射用盐酸氨溴索东莨菪碱冻干粉针的制备， 以 1000支 计
1.处方
盐酸氨溴索 15g
东莨菪碱 0. 02g
甘露醇 100g
注射用水 2000ml
2.制备工艺
将处方量的盐酸氨溴索、 东莨菪碱和甘露醇加到注射用水中， 搅拌溶解 后加入 NaOH溶液调节 PH值 5. 0， 加入 0. 1%的活性炭搅拌 30分钟， 滤除活性炭， 药液再经 0. 45 μ πι和 0. 22 μ πι微孔滤膜过滤， 罐装， 送入冷冻干燥机中， 降温 至 -40°C， 保温 2小时后， 缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C后， 保温 3小时， 冷冻干燥结束， 出箱。
实施例二、 一种盐酸氨溴索东莨菪碱片的制备， 以 1000粒计
1.处方
名称 用量
盐酸氨溴索 15g
东莨菪碱 0. 02g 微晶纤维素
交联聚维酮
羟丙基纤维素
甘露醇
三氯蔗糖
薄荷脑
乳糖
硬脂酸镁
二氧化硅
2.制备工艺
将处方量的盐酸氨溴索、 东莨菪碱和甘露醇加到注射用水中， 搅拌溶解 后加入 NaOH溶液调节 PH值 5. 0， 加入 0. 1%的活性炭搅拌 30分钟， 滤除活性炭， 药液再经 0. 45 μ πι和 0. 22 μ πι微孔滤膜过滤， 罐装至大盘中， 送入冷冻干燥机 中， 降温至 -40°C， 保温 2小时后， 缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C后， 保温 3小时， 冷冻干燥结束， 出箱。 在无菌条件下粉碎大盘冻干的冻 干品， 过 180目筛， 得到盐酸氨溴索和东莨菪碱的无菌冻干粉。
将处方量的三氯蔗糖、 薄荷脑混合， 加入盐酸氨溴索东莨菪碱冻干粉混 合均匀， 再加入微晶纤维素、 乳糖交联聚维酮、 羟丙基纤维素混合均匀， 最 后加入硬脂酸镁、 二氧化硅混合均匀， 用直接压片法制片， 制片时控制湿度 在 50%以下。
实施例三、 一种盐酸氨溴索东莨菪碱注射液的制备， 以 1000支计
1.处方
盐酸氨溴索 15g
东莨菪碱 0. 02g
氯化钠 16g
注射用水 2000ml
2.制备工艺
将处方量的盐酸氨溴索、 东莨菪碱和甘露醇加到注射用水中， 搅拌溶解 后加入 NaOH溶液调节 PH值 5. 0， 加入 0. 1%的活性炭搅拌 30分钟， 滤除活性炭， 药液再经 0.45 μπι和 0.22 μπι微孔滤膜过滤， 罐装至大盘中， 送入冷冻干燥机 中， 降温至 -40°C， 保温 2小时后， 缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C后， 保温 3小时， 冷冻干燥结束， 出箱。 在无菌条件下粉碎大盘冻干的冻 干品， 过 180目筛， 得到盐酸氨溴索和东莨菪碱的无菌冻干粉。
将冻干粉和氯化钠加注射用水 80%, 搅拌溶解后， 力口 0.05%活性炭搅拌吸 附 15分钟， 粗滤脱碳， 用枸橼酸 -憐酸氢二钠缓冲液 （pH4.0) 调节 PH至 4.5〜 5.5, 加注射用水至全量， 再用 0.22 μπι滤膜精滤， 测定 ρΗ、 渗透压和含量合 格后， 用安瓿瓶罐装 2ml封口， 于 121°C灭菌 15分钟。
以上显示和描述了本发明的基本原理、 主要特征以及本发明的优点。 本 行业的技术人员应该了解， 本发明不受上述实施例的限制， 上述实施例和说 明书中描述的只是说明本发明的原理， 在不脱离本发明精神和范围的前提下， 本发明还会有各种变化和改进， 这些变化和改进都落入要求保护的本发明范 围内。 本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims

权利 要 求 书
1.一种复方盐酸氨溴索组合物， 其特征在于， 该组合物主药为： 质量百 分比为 0. 1%〜99. 9%的盐酸氨溴索和 99. 9%〜0. 1%的东莨菪碱。
2.—种用权利要求 1所述组合物制备复方制剂的方法， 其特征在于， 具体 操作步骤为：
a.将 0. 1%〜99. 9%的盐酸氨溴索、 99. 9%〜0. 1%的东莨菪碱和主药 5〜10倍 的甘露醇加到注射用水中；
b.搅拌溶解后加入 NaOH溶液调节 pH值到 5. 0；
c加入 0. 1%的活性炭搅拌 30分钟；
d.滤除活性炭， 药液再经 0. 45 μ m和 0. 22 μ m微孔滤膜过滤；
e.过滤后的药液罐装至大盘或西林瓶中；
f.送入冷冻干燥机中， 降温至 -40°C， 保温 2小时；
g.缓慢升温至 -5°C〜0°C升华干燥， 再升温至 35°C后， 保温 3小时； h.冷冻干燥结束后出箱， 得到注射用盐酸氨溴索和东莨菪碱的冻干粉针; i.在无菌条件下粉碎冻干粉针， 过 180目筛， 得到盐酸氨溴索和东莨菪碱 的无菌冻干粉；
j .以冻干粉为原料制备各种剂型。
3.根据权利要求 2所述的制备复方制剂的方法， 其特征在于： 所述剂型有 片剂、 酊剂、 栓剂、 胶囊剂、 软膏剂、 乳膏剂、 糊剂、 眼用制剂、 丸剂、 植 人剂、 糖浆剂、 气雾剂、 粉雾剂、 喷雾剂、 膜剂、 颗粒剂、 口服溶液剂、 口 服混悬剂、 口服乳剂、 散剂、 鼻用制剂。
1
PCT/CN2012/082337 2012-05-28 2012-09-28 复方盐酸氨溴索组合物及其制备方法 WO2013177880A1 (zh)

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