WO2014008648A1 - 一种还原型谷胱甘肽对乙酰氨基酚组合物及其制备方法 - Google Patents

一种还原型谷胱甘肽对乙酰氨基酚组合物及其制备方法 Download PDF

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WO2014008648A1
WO2014008648A1 PCT/CN2012/078550 CN2012078550W WO2014008648A1 WO 2014008648 A1 WO2014008648 A1 WO 2014008648A1 CN 2012078550 W CN2012078550 W CN 2012078550W WO 2014008648 A1 WO2014008648 A1 WO 2014008648A1
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acetaminophen
reduced glutathione
add
composition
preparation
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PCT/CN2012/078550
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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 US14/240,230 priority Critical patent/US20140179615A1/en
Application filed by 海南卫康制药(潜山)有限公司 filed Critical 海南卫康制药(潜山)有限公司
Priority to EP12881084.3A priority patent/EP2769717A4/en
Priority to RU2014110668A priority patent/RU2620340C2/ru
Priority to AU2012385429A priority patent/AU2012385429B2/en
Priority to BR112014004738A priority patent/BR112014004738A2/pt
Priority to PCT/CN2012/078550 priority patent/WO2014008648A1/zh
Publication of WO2014008648A1 publication Critical patent/WO2014008648A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • 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
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • 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
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
    • B29B9/00—Making granules
    • B29B9/12—Making granules characterised by structure or composition
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention relates to a pharmaceutical composition and a process for the preparation of the composition, and more particularly to a reduced glutathione acetaminophen composition and a process for the preparation thereof. Background technique
  • Reduced glutathione is a tripeptide that combines glutamic acid, cysteine and glycine, and has a thiol group, which has antioxidant effects and integrated detoxification.
  • the thiol group on cysteine is a reduced glutathione reactive group (so the reduced glutathione is often abbreviated as G-SH), easy to be associated with certain drugs (such as paracetamol), toxins (such as free radicals, iodine).
  • G-SH reduced glutathione reactive group
  • drugs such as paracetamol
  • toxins such as free radicals, iodine
  • Acetate, mustard gas, lead, mercury, arsenic and other heavy metals combine to have integrated detoxification.
  • reduced glutathione (especially reduced glutathione in hepatocytes) can participate in biotransformation, thereby converting harmful toxic substances in the body into harmless substances and excreting them. Reduced glutathione also helps maintain the function of the normal immune system.
  • Acetaminophen is an acetanilide antipyretic analgesic. By inhibiting cyclooxygenase, it selectively inhibits hypothalamic thermoregulation of central prostaglandin synthesis, leading to peripheral vasodilatation and sweating to achieve antipyretic effect. Its antipyretic effect is similar to that of aspirin; by inhibiting the synthesis of prostaglandins And release, improve pain threshold and play an analgesic effect, belong to peripheral analgesics, weaker than aspirin, only effective for mild to moderate pain. At present, the drug of choice for antipyretic and analgesic drugs is acetaminophen.
  • acetaminophen is one of the most widely used drugs in the world, and it is the number one antipyretic in the international pharmaceutical market. Analgesic, and also the most productive in China One of the big breeds.
  • acetaminophen has been debated for many years and is currently believed to act by inhibiting cyclooxygenase-3 (COX-3).
  • COX-3 cyclooxygenase-3
  • 90% of the drug is metabolized by the liver, 60% of which is combined with glucuronic acid, 30% of which is combined with sulfuric acid, and all of which form non-toxic substances are excreted by the kidneys.
  • 4%-5% of the drug is metabolized by the liver cytochrome P450 oxidase system to produce N-acetylanilinoquinone (NAPQI), which is covalently bound to reduced glutathione and loses its toxicity and is excreted by the kidneys.
  • NAPQI N-acetylanilinoquinone
  • NAPQI When the reduced glutathione storage falls below 30% of normal, NAPQI not covalently bound to it covalently binds to hepatocyte macromolecules, resulting in damage and necrosis of hepatocytes.
  • the object of the present invention is to provide a reduced glutathione acetaminophen composition, the main drug of which is: a component ratio of reduced glutathione of 0.1% to 99.9%, acetaminophen The composition ratio is 99.9% to 0.1%.
  • the composition is effective in preventing damage and necrosis of hepatocytes caused by overdose of acetaminophen, and has a good effect on cancer pain and chemoradiotherapy.
  • a further object of the present invention is to prepare various dosage forms based on a reduced glutathione acetaminophen composition.
  • dosage forms based on a reduced glutathione acetaminophen composition.
  • the main drug of the composition is reduced glutathione having a composition ratio of 0.1% to 99.9%, and acetaminophen having a composition ratio of 99.9% to 0.1%.
  • the preparation of the reduced glutathione acetaminophen composition usually in the form of tablets, sustained release / controlled release agents, capsules, pills, syrups, films, granules, oral solutions, oral suspension Agents, oral emulsions, oral powders, and any pharmaceutically acceptable dosage form.
  • the preparation of the tablet-like reduced glutathione acetaminophen composition which is composed of the following composition and the total content of each composition, is:
  • Magnesium stearate 0. 5% - 1% The specific steps of the preparation are as follows: 1. Dissolve the reduced glutathione in an ethanol solution, dissolve the PVP in the reduced glutathione ethanol solution, add the micro-silica gel and mix, add stearic acid and 16 The alcohol was heated to 60 ° C in a water bath to melt; then, the microcrystalline cellulose was added. lactose. a homogeneous mixture of talcum powder is added to the above melted system, stirred for 1 hour;
  • 10% starch slurry preparation Dissolve sodium dodecyl sulfate in about purified water, then add starch to disperse evenly, heat paste, to make 10% starch slurry;
  • a further technical solution of the present invention is to prepare an orally solution-formulated reduced glutathione acetaminophen composition, which is composed of the following composition and the total content of each composition is:
  • the specific steps of the preparation are as follows: the reduced glutathione is dissolved in 100 ml of water, and after hydroxypropyl- ⁇ -cyclodextrin is added, it is reserved, and the sucrose, cyclamate, sodium saccharin, and citric acid are weighed according to the prescription.
  • Sodium, citric acid pour into the batching tank, add water to 500mL, heat and boil for 15min, filter with ⁇ microporous membrane, place in another storage tank, cool to below 70 °C, reserve; add propylene glycol to the ingredient tank, Heat to 70 ° C.
  • Add acetaminophen dissolve it completely at 70 ° C, add glycerin to mix, add the stock solution into the batching tank, mix, add bayberry flavor, red rose pigment dissolve and mix.
  • a further technical solution of the present invention is to prepare a granule-like reduced glutathione-p-acetylphenol composition, which is composed of the following composition and the total content of each composition is:
  • the specific steps of the preparation are as follows: 1. Dissolve the reduced glutathione in a 10% ethanol solution, dissolve the PVP in the reduced glutathione ethanol solution, add the micro-silica gel to mix, add stearic acid and Cetyl alcohol, heated to 60 ° C in a water bath, melted, and then, a homogeneous mixture of microcrystalline cellulose, lactose, magnesium stearate, talc is added to the above melted system, stirred for 1 h ;
  • the invention has the beneficial effects that the combination of reduced glutathione and acetaminophen can effectively prevent hepatocyte damage and necrosis caused by overdose of acetaminophen, and reduced glutathione and acetamino group. Combined with phenol, it has a good effect on cancer pain and chemoradiotherapy.
  • a reduced glutathione acetaminophen composition the main drug of the composition is
  • the acetaminophen has a composition ratio of 99.9% to 0.1%.
  • Preparation 1. Dissolve reduced glutathione in 4.32ml of 10% ethanol solution, dissolve PVP in reduced glutathione ethanol solution, add micro-silica gel and mix, add stearic acid and cetyl alcohol. The water bath is heated to 60 ° C to melt. Then, the microcrystalline cellulose will be. lactose. A homogeneous mixture of talc was added to the above melted system and stirred for 1 h.
  • the granules were sieved through a 16-mesh sieve, and the wet granules were dried at 40 ° C to 60 ° C, and granulated with a 16-mesh sieve and uniformly mixed with the above-mentioned two-step dry granules, and magnesium stearate was added thereto, followed by tableting.
  • Example 2 (oral solution): Acetaminophen 24g Reduced glutathione 7.2g Hydroxypropyl- ⁇ -cyclodextrin 27.7g Propanedione 250mL
  • Preparation 1. Dissolve reduced glutathione in 4.32ml of 10% ethanol solution, dissolve PVP in reduced glutathione ethanol solution, add micro-silica gel and mix, add stearic acid and cetyl alcohol. The water bath is heated to 60 ° C to melt. Then, the microcrystalline cellulose, lactose, magnesium stearate, and talc are evenly distributed. 2. Spread the above viscous mixture in a tray and leave it at room temperature for 20 minutes. When it is agglomerated, granulate with a 16 mesh sieve. Dry the whole granules at 30 °C.
  • mice Fifty mice were randomly divided into 5 groups, namely, a control group, a model group, a group of the examples, a second group, and a third group, 10 in each group. The experiment was started two days after free eating and fasted for 16 h before the experiment. Experimental treatment: The control group was intragastrically administered with normal saline, and the model group was intragastrically administered with acetaminophen solution (0.5 g/kg). One group was administered with the first example (0.5 g/kg), and the second group was used.
  • Example 2 was intragastrically administered (0.5 g/kg), and the third group was administered with the third example (0.5 g/kg) for 4 consecutive days, each interval was 24 h, after the last administration for 1 h, the control group used 1 Sodium carboxymethylcellulose (0.15 g/kg) was intragastrically administered, and after 24 hours, the mice were sacrificed by cervical vertebrae.

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Abstract

一种还原型谷胱甘肽对乙酰氨基酚组合物及其制备方法。该组合物的主药为还原型谷胱甘肽0.1%~99.9%，对乙酰氨基酚99.9%~1%，可制成如片剂、缓释/控释剂、胶囊剂、丸剂、糖浆剂、膜剂、颗粒剂、口服溶液剂、口服混悬剂、口服乳剂、口服散剂等药学上可接受的任意剂型。该组合物能有效防止对乙酰氨基酚用药过量所导致的肝细胞的损害和坏死，并对癌症疼痛以及放化疗有良好效果。

Description

一种还原型谷胱甘肽对乙酰氨基酚组合物及其制备方法 技术领域
本发明涉及药品组合物及该组合物的制备方法， 具体的说是一种还原型 谷胱甘肽对乙酰氨基酚组合物及其制备方法。 背景技术
还原型谷胱甘肽 （glutathione , GSH ) 是由谷氨酸、 半胱氨酸和甘氨 酸结合， 含有巯基的的三肽， 具有抗氧化作用和整合解毒作用。 半胱氨 酸上的巯基为还原型谷胱甘肽活性基团 （故还原型谷胱甘肽常简写为 G-SH ) , 易与某些药物 （如扑热息痛）、 毒素 （如自由基、 碘乙酸、 芥子 气， 铅、 汞、 砷等重金属） 等结合， 而具有整合解毒作用。 故还原型谷 胱甘肽 （尤其是肝细胞内的还原型谷胱甘肽） 能参与生物转化作用， 从 而把机体内有害的毒物转化为无害的物质， 排泄出体外。 还原型谷胱甘 肽还能帮助保持正常的免疫系统的功能。
对乙酰氨基酚为乙酰苯胺类解热镇痛药。 通过抑制环氧化酶， 选择性抑 制下丘脑体温调节中枢前列腺素的合成， 导致外周血管扩张、 出汗而达到解 热的作用， 其解热作用强度与阿司匹林相似； 通过抑制前列腺素等的合成和 释放， 提高痛阈而起到镇痛作用， 属于外周性镇痛药， 作用较阿司匹林弱， 仅对轻、 中度疼痛有效。 目前在解热镇痛药物中认为首选药物应是对乙酰氨 基酚， 因为它的副作用小， 疗效好， 对乙酰氨基酚是全世界应用最广泛的药 物之一， 是国际医药市场上头号解热镇痛药， 同时也是我国原料药中产量最 大的品种之一。
对乙酰氨基酚的作用机制多年来一直存在争论， 目前一般认为是通过抑 制环氧化酶 -3(COX-3) 起作用。 该药口服后 90%经肝脏代谢， 其中 60%与葡 萄糖醛酸结合， 30%与硫酸结合， 均形成无毒性物质经肾脏排出。 4%-5%的 药物， 经肝脏细胞色素 P450氧化酶系统代谢产生 N-乙酰苯亚胺基醌 (NAPQI), 后者与还原型谷胱甘肽共价结合而失去毒性由肾脏排出。 当摄入 对乙酰氨基酚剂量远远超过治疗剂量时， 可导致葡萄糖醛酸化和硫酸化通路 饱和， 大量的对乙酰氨基酚转由细胞色素 P450系统代谢导致还原型谷胱甘 肽被迅速消耗。
还原型谷胱甘肽储存量下降到正常的 30%以下时， 未与其共价结合的 NAPQI与肝细胞大分子共价结合而导致肝细胞的损害和坏死。
还原型谷胱甘肽和对乙酰氨基酚合用能够有效的防止对乙酰氨基酚用 药过量所导致的肝细胞的损害和坏死， 并且还原型谷胱甘肽和对乙酰氨基酚 合用， 对于癌症疼痛以及放化疗具有良好效果。 发明内容
本发明的目的是提供一种还原型谷胱甘肽对乙酰氨基酚组合物， 该组合 物主药为： 还原型谷胱甘肽的组分比为 0.1%〜99.9%， 对乙酰氨基酚的组分 比为 99.9%〜0.1%。 该组合物能有效的防止对乙酰氨基酚用药过量所导致的 肝细胞的损害和坏死， 并且对于癌症疼痛以及放化疗具有良好效果。
本发明进一步目的是基于还原型谷胱甘肽对乙酰氨基酚组合物为原料， 进行制备各种剂型。 如片剂、 缓释 /控释剂、 胶囊剂、 丸剂、 糖浆剂、 膜剂、 颗粒剂、 口服溶液剂、 口服混悬剂、 口服乳剂、 口服散剂等药学上可接受的 任意剂型。
本发明为了实现上述目的， 采用的技术方案是，
一种还原型谷胱甘肽对乙酰氨基酚组合物， 其特征在于：
所述该组合物主药为还原型谷胱甘肽， 其组分比为 0.1%〜99.9%， 对乙酰氨基酚， 其组分比为 99.9%〜0.1%。
所述制备该还原型谷胱甘肽对乙酰氨基酚组合物， 常以片剂、缓释 /控释剂、 胶囊剂、 丸剂、 糖浆剂、 膜剂、 颗粒剂、 口服溶液剂、 口服混悬剂、 口服乳剂、 口服散剂以及药学上可接受的任意剂型出现。
所述制备片剂状还原型谷胱甘肽对乙酰氨基酚组合物， 由以下组合物构成 以及各组合物所占总含量的组分为：
对乙酰氨基酚 35%—— -45%
还原型谷胱甘肽 10%— -15%
淀粉 5%—— -8%
十二垸基硫酸钠 0.005% —— 0.
硬脂酸 5%—— -10%
十六醇 5%—— -10%
聚维酮 （PVP) 2.5%— -5%
微晶纤维素 5%—— -10%
微粉硅胶 0.6%— — 1%
乳糖 5%—— -8%
滑石粉 3%—— -5%
10%淀粉浆 5%—— 15%
硬脂酸镁 0. 5%— — 1% 所述制备的具体步骤为： 1、将还原型谷胱甘肽溶于乙醇溶液中，将 PVP 溶于还原型谷胱甘肽乙醇溶液中， 加微粉硅胶混匀， 加硬脂酸与十六醇， 水 浴加热到 60°C， 使熔； 然后， 将微晶纤维素。 乳糖。 滑石粉的均匀混合物加 至上述溶化的系统中， 搅拌 lh;
2、 将上述黏稠的混合物摊于盘中， 室温放置 20min， 待成团块时， 用 16目筛制粒。 30°C干燥整粒；
3、 10%淀粉浆的制备： 将十二垸基硫酸钠溶于约纯化水中， 再加入淀 粉分散均匀， 加热糊化， 制成 10%的淀粉浆；
4、取处方量对乙酰氨基酚与淀粉混合均匀， 加适量 10%淀粉浆制软材， 过 16目筛制粒， 将湿粒于 40°C~60°C干燥， 用 16目筛整粒并与上述 2步骤 干燥颗粒混合均匀， 加入硬脂酸镁， 压片即得。
本发明还具有进一步的技术方案是制备口服溶液剂状还原型谷胱甘肽 对乙酰氨基酚组合物， 由以下组合物构成以及各组合物所占总含量的组分 为：
对乙酰氨基酚 5%—— -10%
还原型谷胱甘肽 1%— -4%
羟丙基 -β-环糊精 7%—— -10%
丙二醇 30%— —40%
甘油 8%—— -12%
蔗糖 35%— —45%
甜蜜素 1%— -2%
糖精钠 0.05%- —— 0.1%
柠檬酸钠 0.5%- —0.8% 柠檬酸 0.035—— 0.05%
杨梅香精 0.001%—— 0.002%
玫瑰红色素 0.001%—— 0.003%
所述制备的具体步骤为： 将还原型谷胱甘肽溶于 100ml水中， 加入羟丙 基 -β-环糊精包合后， 备用， 按处方称好蔗糖、 甜蜜素、 糖精钠、 柠檬酸钠、 柠檬酸， 倒入配料罐中， 加水至 500mL， 加热煮沸 15min， ΙΟμηι微孔滤膜 过滤， 放置另一贮藏罐中， 温度冷至 70°C以下， 备用； 在配料罐中加入丙二 醇， 加热至 70°C . 加入对乙酰氨基酚， 在 70°C使其完全溶解， 加入甘油混 匀，将备用液加入配料罐中混匀， 加入杨梅香精，玫瑰红色素溶解混匀即可。
本发明还具有进一步的技术方案是制备颗粒剂状还原型谷胱甘肽对乙酰^ 基酚组合物， 由以下组合物构成以及各组合物所占总含量的组分为：
对乙酰氨基酚
还原型谷胱甘肽
玉米淀粉
Figure imgf000006_0001
十二垸基硫酸钠 0. 03%—— 0. 07%
硬脂酸
十六醇
Figure imgf000006_0002
聚维酮 （PVP ) 5%—— 10%
交联聚维酮 1.5%—— 2.0%
预胶化淀粉 10%—— 20%
微粉硅胶 0.3%—— 0.8%
微晶纤维素 5%—— 7%
乳糖 3%—— 6% 滑石粉 2%— 5%
硬脂酸镁 0. 2%—— 0. 6%
所述制备的具体步骤为： 1、 将还原型谷胱甘肽溶于 10%乙醇溶液中， 将 PVP溶于还原型谷胱甘肽乙醇溶液中，加微粉硅胶混匀，加硬脂酸与十六 醇， 水浴加热到 60°C， 使熔， 然后， 将微晶纤维素、 乳糖、 硬脂酸镁、 滑石 粉的均匀混合物加至上述溶化的系统中， 搅拌 lh;
2、 将上述黏稠的混合物摊于盘中， 室温放置 20min， 待成团块时， 用 16目筛制粒； 30°C干燥整粒；
3、 将对乙酰氨基酚和玉米淀粉混合均匀， 然后用预胶化淀粉和聚维酮 制成淀粉浆作为粘合剂， 均匀喷到沸腾流化的对乙酰氨基酚和玉米淀粉的混 合物上， 在进风 55 °C下流化制粒， 制成湿粒后， 在 80°C干燥， 然后在 50°C 冷却至水分符合要求后整粒， 整粒结束加入硬脂酸和交联聚维酮混合均匀， 再加入步骤 2后混合均匀后即得。
本发明具有的有益效果是还原型谷胱甘肽和对乙酰氨基酚合用能够有 效的防止对乙酰氨基酚用药过量所导致的肝细胞的损害和坏死， 并且还原型 谷胱甘肽和对乙酰氨基酚合用， 对于癌症疼痛以及放化疗具有良好效果。 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。
一种还原型谷胱甘肽对乙酰氨基酚组合物， 该组合物主药为
还原型谷胱甘肽， 其组分比为 0.1%〜99.9%，
对乙酰氨基酚， 其组分比为 99.9%〜0.1%。 实施例一 （片剂）：
对乙酰氨基酚 30g
还原型谷胱甘肽 9g
淀粉 3g
十二垸基硫酸钠 0.06g
硬脂酸 6.0g
十六醇 6.0g
聚维酮 （PVP) 3.1g
微晶纤维素 5.88g
微粉硅胶 0.54g
乳糖 4.98g
滑石粉 2.49g
10%淀粉浆 适量
硬脂酸镁 0. 47g
共制 100片
制备： 1、 将还原型谷胱甘肽溶于 4.32ml的 10%乙醇溶液中， 将 PVP溶 于还原型谷胱甘肽乙醇溶液中， 加微粉硅胶混匀， 加硬脂酸与十六醇， 水浴 加热到 60°C， 使熔。 然后， 将微晶纤维素。 乳糖。 滑石粉的均匀混合物加至 上述溶化的系统中， 搅拌 lh。
2、 将上述黏稠的混合物摊于盘中， 室温放置 20min， 待成团块时， 用 16目筛制粒。 30°C干燥整粒。
3、 10 %淀粉浆的制备：将 0.06g十二垸基硫酸钠溶于约 20ml纯化水中， 再加入淀粉约 2g分散均匀， 加热糊化， 制成 10%的淀粉浆。 4、取处方量对乙酰氨基酚与淀粉混合均匀， 加适量 10%淀粉浆制软材， 甘
油
过 16目筛制粒， 将湿粒于 40°C~60°C干燥， 用 16目筛整粒并与上述 2步骤 干燥颗粒混合均匀， 加入硬脂酸镁， 压片即得。
；施例二 （口服溶液剂）: 对乙酰氨基酚 24g 还原型谷胱甘肽 7.2g 羟丙基 -β-环糊精 27.7g 丙二酽 250mL
50mL
300g
8g 糖精钠 0.5 g 柠檬酸钠 2.9 g 柠檬酸 0.4 g 杨梅香精 1 ml l g 共制 100支 将 7.2g还原型谷胱甘肽溶于 100ml水中，加入 27.7g羟丙基 -β-环糊精包 合后，备用，按处方称好蔗糖 300g、甜蜜素 8g、糖精钠 0.5g、柠檬酸钠 2.9g、 柠檬酸 0.4g， 倒入配料罐中， 加水至 500mL， 加热煮沸 15min， ΙΟμηι微孔 滤膜过滤， 放置另一贮藏罐中， 温度冷至 70°C以下， 备用。 在配料罐中加入 丙二醇 250ml，加热至 70°C .加入对乙酰氨基酚 24g，在 70 °C使其完全溶解， 加入甘油 50ml混匀， 将备用液加入配料罐中混匀， 加入杨梅香精 lml， 玫瑰 红色素 lg溶解混匀。 实施例三 （颗粒剂）:
对乙酰氨基酚 30g
还原型谷胱甘肽 9g
玉米淀粉 12.05g
十二垸基硫酸钠 0.06g
硬脂酸 1.72g
十六醇 6.0g
聚维酮 （PVP) 7.2g
交联聚维酮 1.72g
预胶化淀粉 13.05g
微粉硅胶 0.54g
微晶纤维素 5.88g
乳糖 4.98g
滑石粉 2.49g
硬脂酸镁 0. 47g
共制 100袋
制备： 1、 将还原型谷胱甘肽溶于 4.32ml的 10%乙醇溶液中， 将 PVP溶 于还原型谷胱甘肽乙醇溶液中， 加微粉硅胶混匀， 加硬脂酸与十六醇， 水浴 加热到 60°C， 使熔。 然后， 将微晶纤维素、 乳糖、 硬脂酸镁、 滑石粉的均匀 2、 将上述黏稠的混合物摊于盘中， 室温放置 20min， 待成团块时， 用 16目筛制粒。 30°C干燥整粒。
3、 将对乙酰氨基酚和玉米淀粉混合均匀， 然后用预胶化淀粉和聚维酮 制成淀粉浆作为粘合剂， 均匀喷到沸腾流化的对乙酰氨基酚和玉米淀粉的混 合物上， 在进风 55°C下流化制粒， 制成湿粒后， 在 80°C干燥， 然后在 50°C 冷却至水分符合要求后整粒， 整粒结束加入硬脂酸和交联聚维酮混合均匀， 再加入步骤 2后混合均匀后即得。
实验资料：
1材料 动物健康雄性昆明种小鼠， 体重 20— 22 g。
2方法与结果
将 50只小鼠随机分为 5组， 即对照组， 模型组， 实施例一组， 实施例 二组，实施例三组，每组 10只。 自由进食两天后开始实验，实验前禁食 16 h。 实验处理： 对照组用生理盐水灌胃， 模型组用对乙酰氨基酚溶液 (0.5g/kg)灌 胃， 实施例一组用实施例一灌胃（0.5g/kg)， 实施例二组用实施例二灌胃 (0.5g/kg), 实施例三组用实施例三灌胃 (0.5g/kg)， 连续 4d给药， 每次间隔为 24h， 末次给药 l h后， 对照组用 1 %羧甲基纤维素钠 (0.15g/kg)灌胃， 24h后 脱颈椎处死小鼠。
血清的制备 小鼠颈动脉取血， 静置， 3 000 r / min离心 15 min， 分离 血清， 置冰箱 (-20 °C)中冷冻保存， 备用。
测定指标与方法 取经分离的血清， 在 Sigma95308全自动生化分析仪 上测定天冬氨酸氨基转移酶 (AST/GOT)、 丙氨酸氨基转移酶 (ALT/GPT)的活 性。 实施例对肝脏损伤的影响
Figure imgf000012_0001
与对照组比较， #Ρ<0·05， ##Ρ<0.01 ; 与模型组比较， *Ρ<0·05， "Ρ<0.01 以上结果表明， 对于高剂量的对乙酰氨基酚和还原型谷胱甘肽组合物， 对于肝脏几乎没有损伤。
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， 如缓释 /控释剂、 胶囊剂、 丸剂、糖 浆剂、 膜剂、 口服混悬剂、 口服乳剂、 口服散剂以及药学上可接受的任意剂 型出现， 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 禾' J 书
1、 一种还原型谷胱甘肽对乙酰氨基酚组合物， 其特征在于： 所述该组合 物主药为
还原型谷胱甘肽， 其组分比为 0.1%〜99.9%，
对乙酰氨基酚， 其组分比为 99.9%〜0.1%；
所述制备该还原型谷胱甘肽对乙酰氨基酚组合物， 常以片剂、 缓释 /控释 剂、 胶囊剂、 丸剂、 糖浆剂、 膜剂、 颗粒剂、 口服溶液剂、 口服混悬剂、 口 服乳剂、 口服散剂以及药学上可接受的任意剂型出现。
2、 根据权利要求 1所述组合物， 其特征在于： 所述制备片剂状还原型谷 胱甘肽对乙酰氨基酚组合物， 由以下组合物构成以及各组合物所占总含量的 组分为
对乙酰氨基酚 35%—— -45%
还原型谷胱甘肽 10%— -15%
淀粉 5%—— -8%
十二垸基硫酸钠 0.005% —— 0.01%
硬脂酸 5%—— -10%
十六醇 5%—— -10%
聚维酮 （PVP) 2.5%— -5%
微晶纤维素 5%—— -10%
微粉硅胶 0.6%— — 1%
乳糖 5%—— -8%
滑石粉 3%—— -5%
10%淀粉浆 5%—— 15%
硬脂酸镁 0. 5%— — 1%。
3、根据权利要求 2所述制备片剂状还原型谷胱甘肽对乙酰氨基酚组合 其特征在于所述制备的具体步骤为：
a、将还原型谷胱甘肽溶于乙醇溶液中，将 PVP溶于还原型谷胱甘肽乙醇 溶液中， 加微粉硅胶混匀， 加硬脂酸与十六醇， 水浴加热到 60°C， 使熔； 然 后， 将微晶纤维素。 乳糖。 滑石粉的均匀混合物加至上述溶化的系统中， 搅 拌 lh;
甘
室温放置 20min， 待成团块时， 用 16 目筛制粒。 30°C干燥整粒；
c、 10 %淀粉浆的制备： 将十二垸基硫酸钠溶于约纯化水中， 再加入淀粉 糊
分散均匀， 制成 10 %的淀粉浆；
d、 取处方量对乙酰氨基酚与淀粉混合均匀， 加适量 10 %淀粉浆制软 过 16目筛制粒， 将湿粒于 40°C~60°C干燥， 用 16目筛整粒并与上述
Figure imgf000014_0001
4、 根据权利要求 1所述组合物， 其特征在于： 所述制备口服溶剂状还原 型谷胱甘肽对乙酰氨基酚组合 由以下组合物构成以及各组合物所占总 量的组分为
对乙酰氨基酚 5%- -10%
还原型谷胱甘肽 1%- -4%
羟丙基 -β-环〉 7%- -10%
丙二酽子 30%- -40%
糖精钠
柠檬酸钠
Figure imgf000014_0002
柠檬酸 0.035— -0.05%
杨梅香精 0.001%- —0.002%
玫瑰红色素 0.001%- — 0.003%
5、 根据权利要求 4所述制备的口服溶剂状还原型谷胱甘肽对乙酰氨 基酚组合物， 其特征在于所述制备的具体步骤为： 将还原型谷胱甘肽溶于 100ml水中， 加入羟丙基 - β -环糊精包合后， 备用， 按处方称好蔗糖、 甜 蜜素、 糖精钠、 柠檬酸钠、 柠檬酸， 倒入配料罐中， 加水至 500mL， 加热 煮沸 15min， ΙΟ μ ηι微孔滤膜过滤， 放置另一贮藏罐中， 温度冷至 70 °C以 下， 备用； 在配料罐中加入丙二醇， 加热至 70 °C . 加入对乙酰氨基酚， 在 70°C使其完全溶解， 加入甘油混匀， 将备用液加入配料罐中混匀， 加入 杨梅香精， 玫瑰红色素溶解混匀即可。
6、 根据权利要求 1所述组合物， 其特征在于： 所述制备口服溶剂状还原 型谷胱甘肽对乙酰氨基酚组合物， 由以下组合物构成以及各组合物所占总含 量的组分为
对乙酰氨基酚 30%— —40%
还原型谷胱甘肽 8%—— -12%
玉米淀粉 10%— —15%
十二垸基硫酸钠 0. 03%- — 0. 07%
硬脂酸 1.5%— —2.0%
十六醇 5%—— -7%
聚维酮 （PVP) 5%—— -10%
交联聚维酮 1.5%- —— 2.0%
预胶化淀粉 10%- —— 20%
微粉硅胶 0.3%- —— 0.8%
微晶纤维素 5%— —7%
乳糖 3%— —6%
滑石粉 2%— —5%
硬脂酸镁 0. 2%- — 0. 6%。
7、根据权利要求 6所述制备的颗粒剂状还原型谷胱甘肽对乙酰氨基酚组 合物， 其特征在于所述制备的具体步骤为：
a、将还原型谷胱甘肽溶于 10%乙醇溶液中，将 PVP溶于还原型谷胱甘肽 乙醇溶液中， 加微粉硅胶混匀， 加硬脂酸与十六醇， 水浴加热到 60°C， 使熔， 然后， 将微晶纤维素。 乳糖。 滑石粉的均匀混合物加至上述溶化的系统中， 搅拌 lh;
b、 将上述黏稠的混合物摊于盘中， 室温放置 20min， 待成团块时， 用 16 目筛制粒； 30°C干燥整粒；
c、 将对乙酰氨基酚和玉米淀粉混合均匀， 然后用预胶化淀粉和聚维酮制 成淀粉浆作为粘合剂， 均匀喷到沸腾流化的对乙酰氨基酚和玉米淀粉的混合 物上， 在进风 55 °C下流化制粒， 制成湿粒后， 在 80°C干燥， 然后在 50°C冷 至水分符合要求后整粒， 整粒结束加入硬脂酸和交联聚维酮混合均匀， 再 入步骤 2后混合均匀后即得。
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WO2001068069A2 (en) * 2000-03-15 2001-09-20 King's College London Pharmaceutical composition comprising paracetamol
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AU2012385429B2 (en) 2015-07-02
EP2769717A1 (en) 2014-08-27
EP2769717A4 (en) 2015-05-27
US20140179615A1 (en) 2014-06-26
RU2620340C2 (ru) 2017-05-24
AU2012385429A1 (en) 2014-03-13
BR112014004738A2 (pt) 2017-03-21
RU2014110668A (ru) 2016-08-27

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