CN101658489B - Nalmefene hydrochloride injection and preparation method thereof - Google Patents

Nalmefene hydrochloride injection and preparation method thereof Download PDF

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CN101658489B
CN101658489B CN 200810146735 CN200810146735A CN101658489B CN 101658489 B CN101658489 B CN 101658489B CN 200810146735 CN200810146735 CN 200810146735 CN 200810146735 A CN200810146735 A CN 200810146735A CN 101658489 B CN101658489 B CN 101658489B
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injection
nalmefene
nalmefene hydrochloride
hydrochloride
water
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CN 200810146735
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CN101658489A (en
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夏中宁
庄太能
林恒
舒军
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北京四环制药有限公司
海南四环医药有限公司
海南四环心脑血管药物研究院有限公司
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Abstract

The invention discloses a nalmefene hydrochloride injection, which is solution prepared from nalmefene hydrochloride and usable pharmaceutical excipients dissolved in injection water. The pharmaceutical excipients comprise an antioxidant and an osmotic pressure modifier. The nalmefene hydrochloride injection is characterized in that: the weight ratio of nalmefene to the antioxidant in the nalmefene hydrochloride is 1:0.1-1.0; and the antioxidant is mixed by one or more of tertiary butyl hydroxy anisole, 2,6-di-tert-butyl-4-methyl-phenol and rosemary. The injection is stable in property and ensures medication safety.

Description

一种盐酸纳美芬注射液及其制备方法 One kind of nalmefene hydrochloride injection and its preparation method

技术领域 FIELD

[0001] 本发明涉及一种药物剂型及其制备方法,特别涉及一种盐酸纳美芬注射液及其制备方法。 [0001] The present invention relates to a pharmaceutical dosage form and a preparation method, particularly to a nalmefene hydrochloride injection and its preparation method.

背景技术 Background technique

[0002] 盐酸纳美芬于1975年合成,是继纳洛酮(NAL)和纳曲酮(NTX)之后合成的又一新的纯阿片受体拮抗剂。 [0002] Nalmefene hydrochloride synthesized in 1975, it is another after naloxone (NAL) and naltrexone (of NTX) Synthesis of a new pure opioid receptor antagonist. 它与阿片受体μ、K、δ均能结合,其中与μ受体结合作用最强。 It opioid receptors μ, K, δ can bind, wherein the [mu] receptor binding and strongest. 盐酸纳美芬是水溶性NTX的衍生物,其6位亚甲基的化学结构使它表现出作用时间长,用药途径多,生物利用度高,副作用少,生理活性更强,更易穿透生物膜等特性,对维持呼吸、循环、消化、内分泌及神经系统的正常功能均有不同程度的效果,目前已应用于麻醉性镇痛剂呼吸抑制的拮抗、心力衰竭和休克的治疗及酒精中毒和成瘾的治疗以及减肥等。 Nalmefene hydrochloride is water soluble derivative of NTX, the chemical structure of which six methylene it exhibits long duration of action, multiple administration route, bioavailability, less side effects, stronger physiological activity, more penetrating biological film properties, the maintenance of respiratory, circulatory, digestive, endocrine and normal function of the nervous system have varying degrees of effectiveness, has been used narcotic analgesics antagonize respiratory depression, and alcoholism, and treatment of heart failure and shock addiction treatment and weight loss and so on.

[0003] 盐酸纳美芬的化学结构式为: [0003] Nalmefene hydrochloride is a chemical structural formula:

[0004] [0004]

· HCl · HCl

H2C H2C

[0005] Baxter Healthcare Corporat ion申请的盐酸纳美芬注射液于1995年经美国FDA 批准在美国上市,其上市的说明书中公开的处方为: [0005] Baxter Healthcare Corporat ion application of nalmefene hydrochloride injection in the United States in 1995 by the US FDA approved the listing of its prescription is disclosed in the specification:

[0006] 物料名称 投料量 [0006] Material Name feeding amount

[0007] 盐酸纳美芬 0. 1108g(相当于纳美芬0. Ig) [0007] Nalmefene hydrochloride 0. 1108g (equivalent nalmefene 0. Ig)

[0008] 氯化钠 9g [0008] Sodium chloride 9g

[0009] 盐酸 调节pH至3. 9 [0009] hydrochloric acid to adjust pH to 3.9

[0010] 注射用水 加至IOOOml [0010] Water for injection to IOOOml

[0011] 按该处方试生产样品进行稳定性考察,结果发现在考察期内pH变化较明显(由3. 9增加至5. 6左右,标准规定上限为5. 5),有关物质变化也较明显(由0.4%增加到1.7%,标准规定为1.5%)。 [0011] carried out according to this formulation, stability of pre-production samples, found in the review period than pH change significantly (approximately increased from 3.9 to 5.6, the upper limit is 5.5 standard), changes are more related substances significantly (consisting of 0.4% to 1.7%, 1.5% standard).

[0012] 中国专利文献CN1895251A也公开了“稳定的盐酸纳美芬注射液及制备方法”, 其核心为处方中加入亚硫酸氢钠、亚硫酸钠、焦亚硫酸、维生素C等无机抗氧剂,另外再加入一定量的抗氧增效剂乙二胺四乙酸二钠,但是按该处方进行的稳定性试验结果表明,无法达到其说明书的稳定效果,在考察期内有关物质也有较明显的变化(由0.7%增加到1.4%), pH变化也较明显(由3. 9增加到5. 3左右),虽然结果均未超标,但也接近上限, 用药的安全性、有效性存在一定的风险。 [0012] Chinese patent CN1895251A discloses also a "stable nalmefene hydrochloride injection and its preparation method," in which the prescription is sodium bisulfite, sodium sulfite, sodium pyrosulfite, vitamin C and other antioxidants inorganic addition adding an amount of antioxidant synergist disodium edetate, but the results of stability tests carried out according to this formulation show that the stabilizing effect can not achieve its specification, the review period in the related substances have a more significant changes ( from 0.7% to 1.4%), pH changes are more significant (increase of about 3.9 5.3), although the results were not exceeded, but also close to the upper limit of drug safety, effectiveness of certain risks.

[0013] 本发明研究者通过大量的研究和试验,结果发现处方中加入一定量的有机抗氧剂如:叔丁基羟基茴香醚(BHA)、2,6-二叔丁基-4-甲基苯酚(BHT)及迷迭香等也能使注射液的稳定性达到目的。 [0013] The researchers of the present invention, through extensive studies and experiments, and found that the prescription was added certain amount of organic antioxidants such as: tert-butyl hydroxy anisole (BHA), 2,6- di-tert-butyl-4-carboxylic acid phenol (of BHT) and the like rosemary can also achieve stability of the injection.

发明内容 SUMMARY

[0014] 本发明的目的在于提供了一种可直接用于静脉注射的稳定性好、效果显著的盐酸纳美芬注射液。 [0014] The object of the present invention to provide good stability A directly for intravenous injection, a significant effect of nalmefene hydrochloride injection.

[0015] 本发明的另一个目的在于提供一种盐酸纳美芬注射液的制备方法。 [0015] Another object of the present invention to provide a method for preparing one kind of nano nalmefene hydrochloride injection.

[0016] 为实现本发明的第一个目的,采用如下技术方案: [0016] To achieve the first object of the present invention, the following technical solution:

[0017] 一种盐酸纳美芬注射剂,是由盐酸纳美芬和可用药用辅料溶于注射用水形成的溶液,可药用的辅料包括抗氧剂和渗透压调节剂,其特征在于盐酸纳美芬以纳美芬计与抗氧剂的重量比为1:0. 1〜1.0 ; [0017] A nalmefene hydrochloride injection, a solution formed was dissolved in water for injection and nalmefene hydrochloride available from the pharmaceutical excipients, pharmaceutically acceptable excipients may include antioxidants and tonicity adjusting agent, wherein the sodium hydrochloride nalmefene to nalmefene terms of the weight ratio of antioxidant to 1: 1~1.0 0;

[0018] 所述的抗氧剂是叔丁基羟基茴香醚、2,6- 二叔丁基-4-甲基苯酚和迷迭香的一种或多种混合。 [0018] The antioxidant is t-butylhydroxyanisole, 2,6-di-t-butyl-4-methylphenol and one kind or more kinds of rosemary.

[0019] 所述的渗透压调节剂为氯化钠、氯化钾或葡萄糖等,其在注射液中的用量可按现有注射液标准。 Tonicity adjusting agent [0019] the other of sodium chloride or glucose in an amount of injection injection may be conventional standards.

[0020] 每Iml注射液中含盐酸纳美芬以纳美芬计可以为0. Img0 [0020] each injection containing Iml nalmefene hydrochloride to Nalmefene may range from 0. Img0

[0021] 本发明还公开一种盐酸纳美芬注射液的制备方法,首先取抗氧剂溶于注射用水中,加入渗透压调节剂,以盐酸调节pH至3. 5〜5. 5,补加注射用水至全量,加入液体量0. 5〜3. Omg/ml的活性炭,搅拌脱色,脱色完毕后过滤,向滤液中加入盐酸纳美芬,搅拌溶解后,过滤,充氮灌封灭菌而成注射液。 [0021] The present invention also discloses a method for the preparation of nalmefene hydrochloride injection is first dissolved in water for injection to take antioxidants, tonicity adjusting agent is added, the pH was adjusted with hydrochloric acid to 3. 5~5. 5, supplement water for injection to the total amount, the amount of liquid added 0. 5~3. Omg / ml of activated carbon, stirred for bleaching, bleaching after completion of filtration, nalmefene hydrochloride was added to the filtrate, stirred to dissolve, filtered, sterilized potting nitrogen from injection.

[0022] 本发明的这种盐酸纳美芬注射液,采用特定的有机抗氧剂,使注射液的稳定性得到了提高,保证了用药的安全性。 [0022] The present invention satisfied this nalmefene hydrochloride injection, the use of specific organic antioxidants, injection so that the stability has been improved to ensure the safety of the drug.

具体实施方式 Detailed ways

[0023] 下面结合具体实施例对本发明作进一步说明,以助于理解本发明的内容。 [0023] The following specific embodiments in conjunction with the present invention will be further described, to assist in understanding the present invention.

[0024] 实施例1 :本实施例制备1000支盐酸纳美芬注射液(规格:Iml : 0. Img), [0024] Example 1: Preparation of the present embodiment 1000 of nalmefene hydrochloride injection Example (size: Iml: 0. Img),

[0025] 使用下述成分: [0025] using the following ingredients:

[0026] 物料名称 投料量 [0026] Material Name feeding amount

[0027] 盐酸纳美芬 0. 1108g(相当于纳美芬0. Ig) [0027] Nalmefene hydrochloride 0. 1108g (equivalent nalmefene 0. Ig)

[0028] 氯化钠 9g [0028] Sodium chloride 9g

[0029] 叔丁基羟基茴香醚(BHA) 15mg [0029] tert-butyl hydroxy anisole (BHA) 15mg

[0030] 注射用水 加至IOOOml [0030] Water for injection to IOOOml

[0031] 工艺步骤:取丁基羟基茴香醚(BHA) 15mg和氯化钠9g加入到注射用水中,溶解后, 用盐酸调节PH至3. 8,补加注射用水至1000ml,加入1. Og活性炭,室温脱色30分钟,脱色完毕后以0. 22 μ m滤膜过滤,向滤液中加入盐酸纳美芬0. 1108g,搅拌溶解后,以0. 22μπι滤膜过滤后充氮灌封,121°C湿热灭菌20分钟,得到盐酸纳美芬注射液。 [0031] The process steps: taking butyl hydroxy anisole (BHA) 15mg and 9g of sodium chloride were added to water for injection, dissolved with hydrochloric acid to adjust the PH to 3.8, supplemented with water for injection to 1000ml, added 1. Og activated carbon, bleaching room temperature for 30 minutes after completion of bleaching to 0. 22 μ m membrane filter, was added to the filtrate nalmefene hydrochloride 0. 1108g, and dissolved with stirring to 0. 22μπι nitrogen membrane filtration after potting, 121 ° C heat sterilized for 20 minutes to obtain nalmefene hydrochloride injection.

[0032] 实施例2 :本实施例制备1000支盐酸纳美芬注射液(规格:Iml : 0. Img), [0032] Example 2: Preparation Example 1 000 of the present embodiment nalmefene hydrochloride injection (size: Iml: 0. Img),

[0033] 使用下述成分: [0033] using the following ingredients:

[0034] 物料名称 投料量[0035] 盐酸纳美芬 0. 1108g(相当于纳美芬0. Ig) [0034] Material name feeding amount [0035] nalmefene hydrochloride 0. 1108g (equivalent nalmefene 0. Ig)

[0036] 氯化钠 9g [0036] Sodium chloride 9g

[0037] 2,6- 二叔丁基-4-羟基-苯酚(BHT) 60mg [0037] 2,6-di-t-butyl-4-hydroxy - phenol (BHT) 60mg

[0038] 注射用水 加至IOOOml [0038] Water for injection to IOOOml

[0039] 工艺步骤:取2,6- 二叔羟基对甲酚(BHT) 60mg和氯化钠9g加入到注射用水中, 溶解后,用盐酸调节PH至3. 8,补加注射用水至1000ml,加入1. Og活性炭,室温脱色30分钟,脱色完毕后以0. 22 μ m滤膜过滤,向滤液中加入盐酸纳美芬0. 1108g,搅拌溶解后,以0. 22 μ m滤膜过滤后充氮灌封,121°C湿热灭菌20分钟,得到盐酸纳美芬注射液。 [0039] Process Step: 2,6-di-hydroxy-taking cresol (BHT) 60mg and 9g of sodium chloride were added to water for injection, dissolved with hydrochloric acid to adjust the PH to 3.8, supplemented with water for injection to 1000ml after active carbon was added 1. Og, decolorization temperature for 30 minutes after completion of bleaching to 0. 22 μ m membrane filter, 0. 1108g nalmefene hydrochloride was added to the filtrate, dissolved with stirring to 0. 22 μ m membrane filter after potting nitrogen, 121 ° C heat sterilized for 20 minutes to obtain nalmefene hydrochloride injection.

[0040] [0040]

成分: ingredient:

[0041] [0041]

[0042] [0042]

[0043] [0043]

[0044] [0044]

[0045] [0045]

[0046] [0046]

实施例3 :本实施例制备1000支盐酸纳美芬注射液(规格:Iml : 0. Img),使用下述 Example 3: This Example 1000 Preparation of nalmefene hydrochloride injection (size: Iml: 0. Img), using the following

物料名称 投料量 Material name feeding amount

盐酸纳美芬 0. 1108g(相当于纳美芬0. Ig) Nalmefene hydrochloride 0. 1108g (equivalent nalmefene 0. Ig)

氯化钠 9g Sodium chloride 9g

迷迭香 20mg Rosemary 20mg

注射用水 加至IOOOml Water for injection was added to IOOOml

工艺步骤:取迷迭香20mg和氯化钠9g加入到注射用水中,溶解后,用盐酸调节PH至3. 8,补加注射用水至1000ml,加入1. Og活性炭,室温脱色30分钟,脱色完毕后以0. 22 μ m滤膜过滤,向滤液中加入盐酸纳美芬0. 1108g,搅拌溶解后,以0. 22 μ m滤膜过滤后充氮灌封,121°C湿热灭菌20分钟,得到盐酸纳美芬注射液。 Process steps: taking 20mg rosemary and 9g sodium chloride were added to water for injection, dissolved with hydrochloric acid to adjust the PH to 3.8, supplemented with water for injection to 1000ml, added 1. Og of activated carbon, bleaching 30 minutes at room temperature, decolorized after completion of 0. 22 μ m to membrane filtration, 0. 1108g nalmefene hydrochloride was added to the filtrate, dissolved with stirring, in a nitrogen atmosphere after potting 0. 22 μ m membrane filter, 121 ° C heat sterilized 20 minutes to obtain nalmefene hydrochloride injection.

[0047] [0047]

成分: ingredient:

[0048] [0048]

[0049] [0049]

[0050] [0050]

实施例4 :本实施例制备1000支盐酸纳美芬注射液(规格:Iml : 0. Img),使用下述 Example 4: This Example 1000 Preparation of nalmefene hydrochloride injection (size: Iml: 0. Img), using the following

物料名称 投料量 Material name feeding amount

盐酸纳美芬 0. 1108g(相当于纳美芬0. Ig) Nalmefene hydrochloride 0. 1108g (equivalent nalmefene 0. Ig)

氯化钠 9g Sodium chloride 9g

[0051] 2,6-二叔丁基-4 甲基苯酚(BHT) 60mg [0051] 2,6-di-t-butyl-4-methylphenol (BHT) 60mg

[0052] 叔丁基羟基茴香醚(BHA) 15mg [0052] tert-butyl hydroxy anisole (BHA) 15mg

[0053] 注射用水 加至IOOOml [0053] Water for injection to IOOOml

[0054] 工艺步骤:取2,6_ 二叔丁基-4甲基苯酚(BHT)60mg、叔丁基羟基茴香醚(BHA) 15mg和氯化钠9g加入到注射用水中,溶解后,用盐酸调节pH至3. 8,补加注射用水至1000ml,加入1. Og活性炭,室温脱色30分钟,脱色完毕后以0. 22 μ m滤膜过滤,向滤液中加入盐酸纳美芬0. 1108g,搅拌溶解后,以0. 22 μ m滤膜过滤后充氮灌封,121°C湿热灭菌20分钟,得到盐酸纳美芬注射液。 [0054] Process Step: After taking 2,6_ di-t-butyl-4-methylphenol (BHT) 60mg, t-butylhydroxyanisole (BHA) 15mg and 9g of sodium chloride were added to water for injection, dissolved with hydrochloric acid pH was adjusted to 3.8, supplemented with water for injection to 1000ml, added 1. Og of activated carbon, bleaching room temperature for 30 minutes after completion of bleaching to 0. 22 μ m membrane filter, was added to the filtrate nalmefene hydrochloride 0. 1108g, after stirring for dissolution, after potting nitrogen to 0. 22 μ m membrane filter, 121 ° C heat sterilized for 20 minutes to obtain nalmefene hydrochloride injection.

[0055] 对本发明的盐酸纳美芬注射液进行了影响因素试验和过敏性、溶血性及局部刺激性等试验: [0055] The nalmefene hydrochloride injection according to the present invention and testing the allergic factors, hemolysis and local irritation, and other test:

[0056] 1、高温试验 [0056] 1, high-temperature test

[0057] 取实施例1〜4中制备的样品,置于恒温干燥箱内,调节温度为60°C,放置10天, 于第0天、5天、10天分别取样检测,结果如下: [0057] A sample was prepared in the embodiments 1 ~ 4, and placed in a constant temperature oven, the temperature is adjusted 60 ° C, for 10 days, on day 0, 5 days, 10 days were sampled, and the results are as follows:

[0058] [0058]

Figure CN101658489BD00061

[0059] 2、强光照射试验 [0059] 2, light irradiation test

[0060] 取实施例1〜4中制备的样品,于照度为45001x的可调光照箱中光照10天,于第0天、5天、10天分别取样检测,结果如下: [0060] A sample prepared in Example 1 ~ 4 in the embodiment, the illuminance of 45001x adjustable in the light of the light box for 10 days to 0 days, 5 days, 10 days were sampled, and the results are as follows:

[0061] [0061]

Figure CN101658489BD00062

[0062] [0062]

Figure CN101658489BD00071

[0063] 3、过敏性试验 [0063] 3, sensitization test

[0064] 3. 1受试药物:按实施例1、2、3制备的盐酸纳美芬注射液,批号:050502_1、 050502-2、050502-3,规格:1ml :0. Img。 [0064] The test drug was 3.1: Example of the preparation of 1,2,3 nalmefene hydrochloride injection, batch number: 050502_1, 050502-2,050502-3, specification: 1ml: 0 Img.. 氯化钠注射液,250ml/瓶,批号:D03051604,山东华 Sodium chloride injection, 250ml / bottle, batch number: D03051604, Shandong

鲁制药有限公司。 Lu Pharmaceutical Co., Ltd.

[0065] 3. 2阳性对照品:卵白蛋白,由联星生物有限公司提供,Sigma公司进口分装。 [0065] 3.2 positive control: ovalbumin, provided by the Star Biological Co., Sigma imported packaging. 以生理盐水配制成0. 4%浓度供试验用。 Saline concentration of 0.4% formulated for test.

[0066] 3. 3动物:白色豚鼠,雌雄各半,由山东米歇尔生物制品有限公司提供,许可证号: SCXK (鲁)20030011,购进后进行两周预饲养,用于试验时体重300〜400g左右。 [0066] 3.3 Animal: Albino Guinea Pigs, male and female, from Shandong Michel Biological Products Co., license number: SCXK when (Lu) 20030011, for two weeks after the purchase of pre-feeding, body weight for the test 300~400g around. 饲养条件:用金属兔笼单笼饲养,自由饮水,给予颗粒饲料,室温22〜25°C,湿度60%左右。 Feeding Conditions: metal single-caged rabbit cage, consisting of water, to give pellets, at room temperature 22~25 ° C, 60% humidity. 颗粒饲料由山东省实验动物中心提供,许可证号:鲁动饲字200001001。 Pellets provided by the Experimental Animal Center of Shandong Province, permit number: Lu move feeding word 200,001,001. 实验动物环境设施合格证号:鲁动环字H2004030507号。 Environmental Laboratory Animal Facilities Certificate of Conformity: Lu ring-word H2004030507.

[0067] 3. 4试验方法:取健康豚鼠Hartley种雄性豚鼠66只,按体重随机分为十一组(每组6只),分别为按实施例1、2、3制备的盐酸纳美芬注射液各三组、卵白蛋白阳性组及氯化钠注射液阴性对照组。 [0067] 3.4 Test Method: Male Hartley strain guinea pigs from healthy 66 guinea pigs, were randomly divided into eleven groups (six per group), nalmefene hydrochloride were prepared as described in Examples 1, 2 injection in all three groups, ovalbumin positive group and negative control group and sodium chloride injection. 各组动物按无菌操作隔日分别腹腔给予盐酸纳美芬注射液(0. Img/ ml)、0. 4%卵白蛋白和氯化钠注射液,0. 5ml/只,共三次致敏。 Groups of animals were intraperitoneally every other day by aseptic administered nalmefene hydrochloride injection (0. Img / ml), 0. 4% egg albumin and sodium chloride injection, 0. 5ml / only, a total of three sensitization. 将各组动物分为2批,每批3 只,一批于首次注射受试药后14天静脉注射受试药品Iml/只攻击,另一批于首次给药后第21天静脉注射受试品Iml/只攻击。 The animals were divided into 2 groups batches of 3, after the first injection to a group of test drug test drugs intravenously 14 days Iml / attack only, in another group on day 21 after the first dose intravenous injection test product Iml / attack only.

[0068] 3. 5试验结果:按实施例1、2、3制备的盐酸纳美芬注射液及氯化钠注射液阴性对照组动物两次攻击后,未见明显异常症状,试验结果均为阴性。 [0068] 3.5 Test Results: press nalmefene hydrochloride injection preparation of 2,3 Sodium Chloride Injection, and negative control animals two attacks embodiment, no abnormal symptoms, the test results are negative. 而阳性对照组可使受试动物出现抓鼻、竖毛、呼吸困难、痉挛、休克死亡等表现。 The positive control group of test animals can appear performance caught the nose, erect hair, difficulty breathing, convulsions, shock and death.

[0069] 4、溶血试验[0070] 4. 1受试药物:按实施例1、2、3制备的盐酸纳美芬注射液,批号分别为:050502_1、 050502-2、050502-3,规格:1ml :0. Imgo氯化钠注射液,250ml/瓶,山东华鲁制药有限公司, 批号:D03051604o [0069] 4, a hemolysis test [0070] 4.1 test drugs: nalmefene hydrochloride prepared according to Examples 1, 2 injection, respectively Lot: 050502_1, 050502-2,050502-3, specifications: 1ml:. 0 Imgo sodium chloride injection, 250ml / bottle, Shandong Lu pharmaceutical Co., Ltd., batch number: D03051604o

[0071] 4. 2动物及饲料:新西兰兔,雌雄兼用,由山东鲁抗医药集团有限公司提供,许可证号:SCXK(鲁)20030006。 [0071] 4.2 Animals and feed: New Zealand rabbits of either sex, Ltd. provided by Shandong Lukang Pharmaceutical Group, license number: SCXK (Lu) 20030006. 购进后预饲养两周,用于试验时体重2. 3〜2. ^ig。 After the purchase of pre-feeding for two weeks, when the test weight for 2. 3~2. ^ Ig. 饲养条件: 用金属兔笼单笼饲养,自由饮水,给予颗粒饲料,室温22〜25°C,湿度60%左右。 Feeding Conditions: metal single-caged rabbit cage, consisting of water, to give pellets, at room temperature 22~25 ° C, 60% humidity. 颗粒饲料由山东省实验动物中心提供,许可证号:鲁动饲字200001001。 Pellets provided by the Experimental Animal Center of Shandong Province, permit number: Lu move feeding word 200,001,001. 实验动物环境设施合格证号:鲁动环字H2004030507号。 Environmental Laboratory Animal Facilities Certificate of Conformity: Lu ring-word H2004030507.

[0072] 4. 3仪器:LXJ-II型离心沉淀机,上海医用分析仪器厂生产;HH-W21-600型恒温水 [0072] 4.3 Instrument: LXJ-II type centrifugation machine, Shanghai Medical Analysis Instrument Factory; HH-W21-600 thermostatic water

浴锅,上海医用设备常生产。 Bath pot, Shanghai medical equipment often produce.

[0073] 4. 4试验方法:取试管17支,分别加入不等量的按实施例1、2、3制备的盐酸纳美芬注射液(0. lmg/ml)0. 1,0. 2,0. 3、0. 4和0. 5ml,第16管不加受试品,作为空白对照,第17 管也不加受试品,用蒸馏水代替生理盐水,作为溶血阳性对照。 [0073] 4.4 Test method: Take the tube 17, were added to varying amounts of nalmefene hydrochloride in Example injection (0. lmg / ml) 1,2,3 1,0 0 2 prepared. , 0. 3,0. 4 and 0. 5ml, without first 16 test articles, as control, the test article 17 is not applied, instead of distilled water, physiological saline, hemolysis positive control. 将各管轻轻摇勻,在37°C水浴中保温4小时,观察各管有无溶血现象。 The tubes were gently shaken and incubated for 4 hours at 37 ° C water bath, to observe the presence or absence of hemolysis tube.

[0074] 4. 5试验结果:阳性对照管(17号管)加入蒸馏水后即刻出现溶血现象。 [0074] 4.5 Experimental results: positive control (No. 17) appears immediately after hemolysis by adding distilled water. 加入盐酸纳美芬注射液后,0. 25〜1小时,1〜16管红细胞开始下沉,上层液体无色澄明;2小时, 1〜16管上清液无色澄明,大量红细胞沉于管底;4小时,1〜16管溶液红细胞全部下沉, 上层液体无色澄明。 After the addition nalmefene hydrochloride injection, 25~1 0 hours, began to sink erythrocytes 1~16 tube, colorless and clear supernatant liquid; 2 hours, the supernatant was clear and colorless 1~16 pipe, a large number of red blood cells in the tube Shen bottom; 4 hours, the solution tube 1~16 all sink erythrocytes, the supernatant liquid is colorless transparent. 经振摇后可见红细胞均勻散开,证明无红细胞凝聚,显微镜检红细胞外形正常。 After shaking shows red blood cells spread evenly, without proof hemagglutination, microscopic examination of red blood cells normal shape.

[0075] 5、血管刺激试验 [0075] 5, Vascular stimulation test

[0076] 5. 1受试药物:按实施例1、2、3制备的盐酸纳美芬注射液,批号:050502_1、 050502-2、050502-3,规格:1ml :0. Imgo氯化钠注射液,250ml/瓶,山东华鲁制药有限公司, 批号:D03051604o [0076] The test drug was 5.1: nalmefene hydrochloride injection according to Preparation Examples 1, 2 embodiment, the batch number: 050502_1, 050502-2,050502-3, specification: 1ml:. 0 Imgo Sodium Chloride Injection liquid, 250ml / bottle, Shandong Lu Hua pharmaceutical Co., Ltd., batch number: D03051604o

[0077] 5. 2动物及饲料:新西兰兔,雌雄兼用,由山东鲁抗医药集团有限公司提供,许可证号:SCXK(鲁)20030006。 [0077] 5.2 Animals and feed: New Zealand rabbits of either sex, Ltd. provided by Shandong Lukang Pharmaceutical Group, license number: SCXK (Lu) 20030006. 购进后预饲养两周,用于试验时体重2. 3〜2. ^ig。 After the purchase of pre-feeding for two weeks, when the test weight for 2. 3~2. ^ Ig. 饲养条件: 用金属兔笼单笼饲养,自由饮水,给予颗粒饲料,室温22〜25°C,湿度60%左右。 Feeding Conditions: metal single-caged rabbit cage, consisting of water, to give pellets, at room temperature 22~25 ° C, 60% humidity. 颗粒饲料由山东省实验动物中心提供,许可证号:鲁动饲字200001001。 Pellets provided by the Experimental Animal Center of Shandong Province, permit number: Lu move feeding word 200,001,001. 实验动物环境设施合格证号:鲁动环字H2004030507号。 Environmental Laboratory Animal Facilities Certificate of Conformity: Lu ring-word H2004030507.

[0078] 5. 3试验方法:取健康、耳缘无损伤家兔12只,按体重随机分为四组,即按实施例1、2、3制备的盐酸纳美芬注射液试验组和氯化钠注射液对照组。 [0078] 5.3 Test Methods: The healthy, intact ear 12 rabbits were randomly divided into four groups, i.e., prepared according to Example 1, 2, nalmefene hydrochloride embodiment of the test group and the chlorine injection sodium injection control group. 本品临床成人一日静脉注射剂量为0. 5〜ang。 This product clinical adult day intravenous dose of 0. 5~ang. 按成人(60kg)临床用量ang/day计算,本试验设盐酸纳美芬注射液剂量为0. 038mg/kg/day,取原液(0. lmg/ml)配制成浓度为0. 09ang/ml,家兔左侧耳缘静脉推注给药,给药体积4. lml/kg,对照组给予等容积氯化钠注射液。 Clinical dosage ang / day calculated as adult (60kg), this test is satisfied provided nalmefene hydrochloride injection at a dose of 0. 038mg / kg / day, taking stock solution (0. lmg / ml) formulated at a concentration of 0. 09ang / ml, left rabbit ear vein bolus administration volume 4. lml / kg, control group received equal volume of sodium chloride injection. 每日给药一次,共七天。 Administered once daily for seven days.

[0079] 5. 4试验结果:与氯化钠注射液组相比,静脉滴注给予按实施例1、2、3制备的盐酸纳美芬注射液,给药期间及末次给药M小时后,兔耳血管纹路均清晰,周围组织无水肿。 Compared with the group of sodium chloride injection, administered by intravenous injection nalmefene hydrochloride Preparation of 1,2,3 embodiment, administration period and the last administration M h: [0079] 5.4 Test results , rabbit ear vascular lines are clear, the surrounding tissue without edema. 组织切片检查可见兔耳静脉血管规则,管壁薄,内壁平滑,腔内充满血液,管周无炎性渗出物。 Biopsy visible rabbit ear vein rule, thin wall, the inner wall of a smooth, cavity filled with blood, no perivascular inflammatory exudate. 表明本实验条件下盐酸纳美芬注射液对家兔耳缘静脉无明显刺激作用。 Nalmefene hydrochloride injection showed on rabbit ear vein had no stimulating effect under the present experimental conditions.

[0080] 以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。 [0080] The above are only preferred embodiments of the present invention, it should be noted that those of ordinary skill in the art, in the present invention without departing from the principles of the premise, can make various improvements and modifications, such modifications and modifications should also be regarded as the protection scope of the present invention.

Claims (9)

1. 一种盐酸纳美芬注射液,是由盐酸纳美芬和可用药用辅料溶于注射用水形成的溶液,可用药用辅料包括抗氧剂和渗透压调节剂,其特征在于盐酸纳美芬以纳美芬计与抗氧剂的重量比为1 : 0. 1〜1.0 ;所述的抗氧剂是叔丁基羟基茴香醚和2,6- 二叔丁基-4-甲基苯酚中一种或两种。 A nalmefene hydrochloride injection, a solution formed was dissolved in water for injection and nalmefene hydrochloride available from the pharmaceutical excipients, pharmaceutically acceptable excipients can be used include antioxidants and tonicity adjusting agent, wherein the sodium hydrochloride by in Finland nalmefene terms of the weight ratio of antioxidant to 1: 0. 1~1.0; said antioxidant is t-butylhydroxyanisole and 2,6-di-butyl-4-methylphenol one or both.
2.如权利要求1所述的盐酸纳美芬注射液,其特征在于:每ImL注射液中含盐酸纳美芬以纳美芬计为0. Img0 2. Nalmefene hydrochloride injection according to claim 1, characterized in that: each injection containing ImL nalmefene hydrochloride in terms of Nalmefene 0. Img0
3.如权利要求1或2所述的盐酸纳美芬注射液,其特征在于:所述的渗透压调节剂为氯化钠、氯化钾或葡萄糖。 Hydrochloric or claim 12 nalmefene injection claim, wherein: said tonicity modifier is sodium chloride, potassium chloride or dextrose.
4.如权利要求3所述的盐酸纳美芬注射液,其特征在于每ImL注射液含有盐酸纳美芬以纳美芬计为0. lmg、氯化钠9mg、叔丁基羟基茴香醚0. 015mg。 Nalmefene hydrochloride as claimed in claim 3 sodium chloride injection 9mg, t-butylhydroxyanisole in claim 0, characterized in that each injection containing ImL nalmefene to nalmefene hydrochloride in terms of 0. lmg, . 015mg.
5.如权利要求3所述的盐酸纳美芬注射液,其特征在于每ImL注射液含有盐酸纳美芬以纳美芬计为0. lmg、氯化钠9mg、2,6- 二叔丁基-4-甲基苯酚0. 06mg。 As claimed in claim 3 nalmefene hydrochloride injection of 2,6-di-t claim, characterized in that each injection containing ImL nalmefene to nalmefene hydrochloride in terms of 0. lmg, sodium chloride 9mg, yl-4-methylphenol 0. 06mg.
6.如权利要求3所述的盐酸纳美芬注射液,其特征在于每ImL注射液含有盐酸纳美芬以纳美芬计为0. lmg、氯化钠9mg、2,6-二叔丁基-4-甲基苯酚0. 06mg和叔丁基羟基茴香醚0. 015mgo As claimed in claim 3 nalmefene hydrochloride injection of 2,6-di-t claim, characterized in that each injection containing ImL nalmefene to nalmefene hydrochloride in terms of 0. lmg, sodium chloride 9mg, yl-4-methylphenol and 0. 06mg t-butylhydroxyanisole 0. 015mgo
7. —种权利要求1所述的盐酸纳美芬注射液的制备方法,其特征在于:首先取抗氧剂溶于注射用水中,加入渗透压调节剂,以盐酸调节pH至3. 5〜5. 5,补加注射用水至全量, 加入液体量0. 5〜3. Omg/mL的活性炭,搅拌脱色,脱色完毕后过滤,向滤液中加入盐酸纳美芬,搅拌溶解后,过滤,充氮灌封灭菌而成注射液。 7. - The method of claim 1 Preparation of nalmefene hydrochloride injection as claimed in claim species, wherein: firstly dissolved in water for injection to take antioxidants, tonicity adjusting agent is added, the pH was adjusted to 3 with hydrochloric acid -5 to 5.5, supplemented with water for injection to the total amount, the amount of liquid added 0. 5~3. Omg / mL activated carbon, stirred for bleaching, bleaching after completion of filtration, nalmefene hydrochloride was added to the filtrate, after dissolved under stirring, filtering, filling sterile potting from nitrogen injection.
8.如权利要求7所述的制备方法,其特征在于:所述注射用水总量按每ImL注射液中含盐酸纳美芬以纳美芬计为0. Img计算。 8. The production method according to claim 7, wherein: said total amount of water for injection containing per ImL injection nalmefene hydrochloride in terms of Nalmefene 0. Img calculated.
9.如权利要求7所述的制备方法,其特征在于:所述过滤是用0. 22 μ m滤膜过滤。 9. The method as recited in claim 7, wherein: said filter is a 0. 22 μ m membrane filter.
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