WO2020239053A1 - 包含水合氯醛的药物组合物及其用途 - Google Patents

包含水合氯醛的药物组合物及其用途 Download PDF

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WO2020239053A1
WO2020239053A1 PCT/CN2020/093146 CN2020093146W WO2020239053A1 WO 2020239053 A1 WO2020239053 A1 WO 2020239053A1 CN 2020093146 W CN2020093146 W CN 2020093146W WO 2020239053 A1 WO2020239053 A1 WO 2020239053A1
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acid
pharmaceutical composition
peg
chloral hydrate
composition according
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PCT/CN2020/093146
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French (fr)
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陶亮
云琦
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特丰制药有限公司
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    • 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
    • A61K9/08—Solutions
    • 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
    • A61K31/11—Aldehydes
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to a pharmaceutical composition containing chloral hydrate, polyethylene glycol and a pharmaceutically acceptable acid and its use in the preparation of a sedative hypnotic drug or an anticonvulsant drug.
  • Diagnosis and treatment of childhood diseases usually requires a variety of medical examinations, such as MRI, CT, electrocardiogram, electroencephalogram, eye examination, dental examination, etc.
  • medical examinations such as MRI, CT, electrocardiogram, electroencephalogram, eye examination, dental examination, etc.
  • children have immature psychological development, and their ability to control their own emotions and behaviors during diagnosis and treatment is far less than that of adults. They are prone to fear, restlessness, irritability, anxiety, and even restlessness, and then escape or refuse treatment, which makes diagnosis and treatment The process is difficult to proceed. For this reason, before diagnosis and treatment, children are often required to take sedative hypnotic agents to keep them calm, reduce anxiety and fear, and ensure the smooth progress of the diagnosis and treatment process.
  • Chloral hydrate oral solution mainly inhibits the ascending activation system of the brainstem reticulum, causing near-physiological sleep. It has a fast onset, long action time, no shortening of rapid eye movement sleep, mild action, no accumulation in the body, and few adverse reactions. Chloral hydrate oral solution is the longest used, most widely used, most mature, and most used sedative and hypnotic drug in pediatric examinations in Chinese hospitals. It has become the first choice for sedation and hypnosis in clinical pediatric examinations in China, and there is no suitable alternative drug.
  • the present invention provides a pharmaceutical composition containing chloral hydrate, wherein the chloral hydrate has higher stability, less impurity generation, and longer product validity.
  • the pharmaceutical composition can be administered to individuals through the rectum, so it is suitable for individuals who are unwilling to take orally or not.
  • the required administration volume is small, the administration is convenient, and it is not easy to leak.
  • the rectal administration of the pharmaceutical composition of the present invention causes less side effects such as bowel movements.
  • the pharmaceutical composition of the present invention has weak irritation to the mucous membrane and good patient compliance.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising chloral hydrate, polyethylene glycol, and a pharmaceutically acceptable acid.
  • the present invention provides a medicine kit comprising an enema applicator and a medicine bottle containing the above-mentioned pharmaceutical composition.
  • the present invention provides the use of the aforementioned pharmaceutical composition in the preparation of a sedative hypnotic drug or an anticonvulsant drug.
  • the present invention provides the above-mentioned pharmaceutical composition for use as a sedative hypnotic or anticonvulsant.
  • the present invention provides a method for inducing sedation and sleep in a patient (especially a pediatric patient), which comprises administering the pharmaceutical composition of the present invention to the patient.
  • the present invention provides a method of treating convulsions in a patient (especially a pediatric patient), which comprises administering the pharmaceutical composition of the present invention to the patient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising chloral hydrate, polyethylene glycol, and a pharmaceutically acceptable acid.
  • the pharmaceutical composition is an enema.
  • the pH of the pharmaceutical composition is 1.0-4.0, preferably 2.0-3.0.
  • the pharmaceutically acceptable acid is an inorganic acid or an organic acid, wherein
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and any combination thereof;
  • the organic acid is selected from formic acid, acetic acid, acetic anhydride, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, Oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, metatartaric acid, ascorbic acid, gallic acid, benzoic acid, salicylic acid Acid, cinnamic acid, naphthoic acid, pamoic acid, niacin, orotic acid, phytic acid, methyl sulfuric acid, dodecyl sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionine Acid,
  • the pharmaceutically acceptable acid is hydrochloric acid.
  • the polyethylene glycol is PEG 200, PEG 300, PEG 400 or PEG 600, preferably PEG 400.
  • the content of the chloral hydrate is 5-50w/w%, preferably 10-45w/w%, more preferably 20-40w/w %.
  • the polyethylene glycol content is 20-90w/w%, preferably 40-80w/w%, more preferably 50-70w/w/ w%.
  • the pharmaceutical composition further comprises glycerin, and based on the total weight of the pharmaceutical composition, the content of the glycerin is 0.1-10 w/w%, preferably 0.5-5 w/w%.
  • the pharmaceutical composition of the present invention based on the total weight of the pharmaceutical composition, the sum of the content of chloral hydrate, polyethylene glycol and pharmaceutically acceptable acid does not exceed 100 w/w%, and the pharmaceutical composition The sum of the contents of each combination in the composition is 100w/w%.
  • the pharmaceutical composition of the present invention based on the total weight of the pharmaceutical composition, the sum of the content of chloral hydrate, polyethylene glycol, glycerin and pharmaceutically acceptable acid does not exceed 100 w/w%, and The total content of each combination in the pharmaceutical composition is 100 w/w%.
  • the present invention provides a kit comprising an enema applicator and a medicine bottle containing the pharmaceutical composition of the invention.
  • the enema applicator comprises an applicator tube body, an applicator push rod and a medicine taking cap, and the applicator push rod is located inside the applicator tube body.
  • One end of the medicine taking cap is detachably connected with the tube body of the applicator, and the other end of the medicine taking cap is fixed with a medicine taking needle.
  • the present invention provides the use of the above-mentioned pharmaceutical composition in the preparation of a sedative hypnotic drug or an anticonvulsant drug.
  • the present invention provides the above-mentioned pharmaceutical composition for use as a sedative hypnotic or anticonvulsant.
  • the present invention provides a method for inducing sedation and sleep in a patient (especially a pediatric patient), which comprises administering the pharmaceutical composition of the present invention to the patient.
  • the present invention provides a method of treating convulsions in a patient (especially a pediatric patient), which comprises administering the pharmaceutical composition of the present invention to the patient.
  • chloral hydrate was purchased from Qingdao Yulong Seaweed Co., Ltd.
  • hydrochloric acid was purchased from Nanjing Chemical Reagent Co., Ltd.
  • the remaining reagents were purchased from Beijing Fengli Jingqiu Pharmaceutical Co., Ltd. and other companies.
  • the amount of degradation products is expressed in terms of the amount of degradation products per 1 g of chloral hydrate ( ⁇ g).
  • Example 1 The hospital preparation, the product of Example 1 and the product of Comparative Example 1 were placed under high temperature (60°C ⁇ 2°C) and light (4500lx ⁇ 500lx) conditions, and samples were taken on the 0th and 10th day for testing.
  • the test results are shown below table.
  • Example 1 produced a small amount of chloroform under high temperature and light conditions, far less than the amount of hospital preparations produced in the same time, and also less than the amount of production in the comparative example.
  • the above results indicate that the stability of chloral hydrate in the product of the present application has been significantly improved, and has better stability and safety.
  • Example 1 Use the product of Example 1, the product of the comparative example and the hospital preparation 1 (Nanjing) to conduct a rectal mucosal irritation test to observe whether the rabbit rectum is exposed to a single chloral hydrate preparation for redness, swelling, hyperemia, exudation, degeneration or necrosis, etc. Local irritant reaction.
  • Example 1 32 juvenile New Zealand rabbits (purchased from Jinan Xilingjiao Breeding and Breeding Center), male and female, divided into Example 1 product group, comparative product group, hospital preparation group, and negative control group (0.9% sodium chloride injection) , A total of 4 groups, 4 animals/sex/group.
  • the animals in the product group of Example 1, the comparative product group, and the hospital preparation group were given 250 mg/kg (calculated as chloral hydrate) rectally, and the animals in the negative control group were given 0.9% of the same volume as the product group in Example 1 rectally.
  • Sodium chloride injection Before administration and 24 hours after administration, observe the animal's clinical manifestations (such as pain symptoms), stool characteristics (such as blood, mucus) and death after administration.
  • Four animals in each group were sacrificed 24 hours after the administration, the rectum was cut longitudinally from the anus from bottom to top, and the materials were taken for histopathological examination.
  • Body weight detection The body weight of each group of animals increased normally during the experiment.
  • the animals of the product group of Example 1 all showed vasodilation and hyperemia in the rectal mucosal layer.
  • the animals in the comparative product group and the hospital preparation group half of the animals had full-thickness necrosis and hemorrhage in the rectal mucosal layer, leaving only the structural outline, submucosal edema and hemorrhage; the other half of the animals had rectal mucosal vasodilation , Hyperemia. There were no obvious pathological changes in the rectum of animals in the negative control group.
  • the injury changes of the product group of Example 1, the comparative product group, and the hospital preparation group were drug-related pathological changes, and compared with the comparative product group and the hospital preparation group, the degree of lesions in the product group of Example 1 was significantly lighter.

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Abstract

一种包含水合氯醛、聚乙二醇和药学上可接受的酸的药物组合物及其在制备镇静催眠药物或抗惊厥药物中的用途。

Description

包含水合氯醛的药物组合物及其用途 发明领域
本发明涉及包含水合氯醛、聚乙二醇和药学上可接受的酸的药物组合物及其在制备用作镇静催眠剂药物或抗惊厥药物的用途。
发明背景
儿童疾病的诊断和治疗通常需要进行多种医学检查，如核磁共振、CT、心电图、脑电图、眼科检查、牙科检查等。而儿童作为特殊群体，心理发育尚未成熟，在诊疗过程中对自身情绪和行为的控制能力远不如成人，容易产生恐惧、不安、烦躁、焦虑乃至躁动，进而发生逃避或拒绝治疗等现象，使得诊疗过程难以进行。为此，在诊疗前，常常需要儿童服用镇静催眠剂来使其保持镇静，减轻焦虑和恐惧，以保障诊疗过程顺利进行。
目前，临床上一般采用水合氯醛口服溶液医院制剂作为儿科检查的镇静催眠药。水合氯醛主要抑制脑干网状结构上行激活系统，引起近生理性睡眠，其起效快，作用时间长，不缩短快速眼动相睡眠，作用温和，体内无蓄积，且不良反应少。水合氯醛口服溶液是中国医院儿科检查中应用时间最长、应用最为广泛、应用最为成熟、用量最大的镇静催眠药物，已成为中国临床儿科检查镇静催眠首选药物，目前尚未有合适的替代药物。
医院自制的产品稳定性较差，5％浓度产品需要冷藏，有效期仅30天，10％浓度产品室温(25℃)下储存，有效期为35天左右。文献报道，尝试在水合氯醛口服溶液中加入β-环糊精，来制备包合物，以提高稳定性。但该产品有效期仅提高至46.63天(宋永熙，李丽莹，李倩梅.水合氯醛胶浆剂的制备及稳定性预测[J].天津药学，2002，14(2)：48-48)，未有实质性的改善。目前仍然需要既便于向个体给药又能够保持其中水合氯醛长时间稳定的制剂。
发明概述
本发明提供包含水合氯醛的药物组合物，其中水合氯醛具有较高的稳定性，杂质生成量较少，产品的有效期较长。此外，可将所述药物组合物通过直肠个体给药，因此适用于不愿口服或不宜口服的个体，同时所需的给药体积小，给药方便，不易泄露。由本发明的药物组合物的直肠给药所导致的如排便反应等副作用小。同时，本发明的药物组合物对粘膜的刺激性弱，患者依从性好。
在一个方面中，本发明提供药物组合物，其包含水合氯醛、聚乙二醇和药学上可接受的酸。
在另一方面中，本发明提供药盒，其包含灌肠给药器和药瓶，所述药瓶中包含上述药物组合物。
在另一方面中，本发明提供上述药物组合物在制备用作镇静催眠剂药物或抗惊厥药物的用途。
在另一方面中，本发明提供上述药物组合物，其用作镇静催眠剂或抗惊厥药物。
在另一方面中，本发明提供对患者(特别是儿童患者)进行诱导镇静和睡眠的方法，其包括向所述患者给予本发明的药物组合物。
在另一方面中，本发明提供治疗患者(特别是儿童患者)的惊厥的方法，其包括向所述患者给予本发明的药物组合物。
发明详述
在一些实施方案中，本发明提供药物组合物，其包含水合氯醛、聚乙二醇和药学上可接受的酸。
在优选的实施方案中，所述药物组合物为灌肠剂。
在优选的实施方案中，所述药物组合物的pH为1.0～4.0，优选为2.0-3.0。
在优选的实施方案中，所述药学上可接受的酸为无机酸或有机酸，其中
所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸及其任意组合；
所述有机酸选自甲酸、醋酸、乙酸酐、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、 丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、偏酒石酸、抗坏血酸、没食子酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、植酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、1，5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸及其任意组合；
优选地，所述药学上可接受的酸为盐酸。
在优选的实施方案中，所述聚乙二醇为PEG 200、PEG 300、PEG 400或PEG 600，优选为PEG 400。
在优选的实施方案中，以所述药物组合物的总重量计，所述水合氯醛的含量为5-50w/w％，优选为10-45w/w％，更优选为20-40w/w％。
在优选的实施方案中，以所述药物组合物的总重量计，所述聚乙二醇的含量为20-90w/w％，优选为40-80w/w％，更优选为50-70w/w％。
在优选的实施方案中，所述药物组合物还包含甘油，并且以所述药物组合物的总重量计，所述甘油的含量为0.1-10w/w％，优选为0.5-5w/w％。
在本发明的药物组合物中，以所述药物组合物的总重量计，水合氯醛、聚乙二醇和药学上可接受的酸的含量的总和不超过100w/w％，并且所述药物组合物中各个组合的含量的总和为100w/w％。
在本发明的药物组合物中，以所述药物组合物的总重量计，水合氯醛、聚乙二醇、甘油和药学上可接受的酸的含量的总和不超过100w/w％，并且所述药物组合物中各个组合的含量的总和为100w/w％。
在一些实施方案中，本发明提供药盒，其包含灌肠给药器和药瓶，所述药瓶中包含本发明的药物组合物。
在优选的实施方案中，所述灌肠给药器包含给药器管体、给药器推杆和取药帽，所述给药器推杆位于所述给药器管体的内部，其特征在于，
所述取药帽的一端与所述给药器管体以可脱离的形式连接，且所述取药帽的另一端固定有取药针。
在另一实施方案中，本发明提供上述药物组合物在制备用作镇静催眠剂药物或抗惊厥药物的用途。
在另一实施方案中，本发明提供上述药物组合物，其用作镇静催眠剂或抗惊厥药物。
在另一实施方案中，本发明提供对患者(特别是儿童患者)进行诱导镇静和睡眠的方法，其包括向所述患者给予本发明的药物组合物。
在另一方面中，本发明提供治疗患者(特别是儿童患者)的惊厥的方法，其包括向所述患者给予本发明的药物组合物。
实施例
下面结合具体实施例对本发明的具体实施方案做进一步说明，但提供这些实施例并非意在限制本发明的范围。
在以下实施例中，水合氯醛购自青岛宇龙海藻有限公司，盐酸购自南京化学试剂股份有限公司，其余试剂购自北京凤礼精求医药股份有限公司等公司。
如本申请中所使用，降解物(例如三氯甲烷)的量以每1g水合氯醛中降解物的量(μg)的形式表示。
实施例1
称取100g PEG 400，向其中缓慢加入38％浓盐酸(10g，约8.4ml)，搅匀，得到盐酸稀释液。
称取7.3g甘油和500g PEG 400，置于配料罐中，搅匀。然后加入上述盐酸稀释液并搅匀，得到基质溶液。
在搅拌下向基质溶液中加入373g水合氯醛(24目)，加入完毕后，继续搅拌直至水合氯醛完全溶解(无可见水合氯醛固体)。将所得溶液用盐酸稀释液(根据与上述相同操作制得)调节pH值至2.1～2.7，然后向其中加入额外的PEG 400，直至制剂总重量为1kg。将制剂搅匀并过滤，得到本申请的产品。
对比例
称取7.3g甘油和500g PEG 400，置于配料罐中，搅匀，得到基质溶液。
在搅拌下向基质溶液中加入373g水合氯醛(24目)，加入完毕后，继续搅拌直至水合氯醛完全溶解(无可见水合氯醛固体)。然后向其中加入额外的PEG 400，直至制剂总重量为1kg。将制剂搅匀并过滤，得到对比例的产品。
测试例1稳定性研究
将医院制剂、实施例1的产品以及对比例1的产品分别置高温(60℃±2℃)和光照(4500lx±500lx)条件下，于第0天和第10天取样检测，检测结果见下表。
表1三氯甲烷生成量(μg/g)检测结果
Figure PCTCN2020093146-appb-000001
由以上结果可见，医院制剂在高温下第10天时三氯甲烷急剧升高，其中最高达到3945.72μg/g。光照时，医院制剂及对比例产品中三氯甲烷含量也显著升高。
实施例1的产品在高温和光照条件下三氯甲烷生成量较小，远小于相同时间内医院制剂的生成量，同时也小于对比例中的生成量。以上结果说明本申请的产品中水合氯醛的稳定性得到显著提升，具有更好的稳定性和安全性。
测试例2刺激性测试
使用实施例1的产品、对比例的产品以及医院制剂1(南京)进行直肠粘膜刺激性试验，观察家兔直肠单次接触水合氯醛制剂后是否产生红肿、充血、渗出、变性或坏死等局部刺激性反应。
一、方法
幼年新西兰兔32只(购自济南西岭角养殖繁育中心)，雌雄各半，分为实施例1产品组、对比例产品组、医院制剂组、阴性对照组(0.9％氯化钠注射液)，共4组，4只/性别/组。
实施例1产品组、对比例产品组、医院制剂组的动物分别直肠给予250mg/kg(以水合氯醛计)的药物，阴性对照组的动物直肠给予与实施例1产 品组相同体积的0.9％氯化钠注射液。给药前、给药后24小时通过肉眼观察动物的临床表现(如疼痛症状)、粪便性状(如血、粘液)及给药后死亡的情况。给药后24小时每组处死4只动物，从肛门自下而上纵行切开直肠，取材进行病理组织学检查。
二、结果
1、一般体征观察：试验期间各组家兔外观体征、行为活动正常，被毛有光泽，摄食、大小便正常、无死亡。实施例1产品组、对比例产品组、医院制剂组给药后动物出现步态不稳、活动量减少、嗜睡的症状，给药后半小时内恢复正常。阴性对照组动物无异常。
2、体重检测：试验期间各组动物体重均正常增长。
3、病理学检查
给药后24小时，实施例1产品组的动物均表现为直肠粘膜层血管扩张、充血。在对比例产品组和医院制剂组的动物中，有1/2的动物直肠粘膜层全层坏死、出血，仅残留结构轮廓，粘膜下层水肿、出血；另1/2的动物直肠粘膜层血管扩张、充血。阴性对照组均未见动物直肠有明显病理学改变。
实施例1产品组、对比例产品组、医院制剂组损伤改变为药物相关性病理学改变，且与对比例产品组和医院制剂组相比，实施例1产品组病变程度明显较轻。
除本文中描述的那些实施方案外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (10)

  1. 药物组合物，其包含水合氯醛、聚乙二醇和药学上可接受的酸。
  2. 权利要求1的药物组合物，其为灌肠剂。
  3. 权利要求1或2的药物组合物，其pH为1.0～4.0，优选为2.0-3.0。
  4. 权利要求1-3中任一项的药物组合物，其中所述药学上可接受的酸为无机酸或有机酸，其中
    所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸及其任意组合；
    所述有机酸选自甲酸、醋酸、乙酸酐、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、丁二酸、戊二酸、己二酸、马来酸、富马酸、乳酸、苹果酸、枸橼酸、酒石酸、偏酒石酸、抗坏血酸、没食子酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、植酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、1，5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸及其任意组合；
    优选地，所述药学上可接受的酸为盐酸。
  5. 权利要求1-4中任一项的药物组合物，其中所述聚乙二醇为PEG 200、PEG 300、PEG 400或PEG 600，优选为PEG 400。
  6. 权利要求1-5中任一项的药物组合物，其中以所述药物组合物的总重量计，所述水合氯醛的含量为5-50w/w％，优选为10-45w/w％，更优选为20-40w/w％。
  7. 权利要求1-6中任一项的药物组合物，其中以所述药物组合物的总重量计，所述聚乙二醇的含量为20-90w/w％，优选为40-80w/w％，更优 选为50-70w/w％。
  8. 权利要求1-7中任一项的药物组合物，其还包含甘油，并且以所述药物组合物的总重量计，所述甘油的含量为0.1-10w/w％，优选为0.5-5w/w％。
  9. 药盒，其包含灌肠给药器和药瓶，所述药瓶中包含权利要求1-8中任一项的药物组合物。
  10. 权利要求1-8中任一项的药物组合物在制备用作镇静催眠剂药物或抗惊厥药物的用途。
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