CN101658489B - Nalmefene hydrochloride injection and preparation method thereof - Google Patents
Nalmefene hydrochloride injection and preparation method thereof Download PDFInfo
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- CN101658489B CN101658489B CN200810146735XA CN200810146735A CN101658489B CN 101658489 B CN101658489 B CN 101658489B CN 200810146735X A CN200810146735X A CN 200810146735XA CN 200810146735 A CN200810146735 A CN 200810146735A CN 101658489 B CN101658489 B CN 101658489B
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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
Technical field
The present invention relates to a kind of pharmaceutical dosage form and preparation method thereof, particularly a kind of Nalmefene hydrochloride injection and preparation method thereof.
Background technology
Nalmefene hydrochloride is synthetic in 1975, is synthetic another new pure opiate receptor antagonist after naloxone (NAL) and naltrexone (NTX).It with opiate receptor μ, κ, δ all can in conjunction with, wherein the strongest with the effect of μ receptors bind.Nalmefene hydrochloride is the derivant of water solublity NTX, the chemical constitution of its 6 methylene makes it show long action time, route of administration is many, the bioavailability height, few side effects, physiologically active is stronger, the easier characteristics such as biomembrane that penetrate, to keeping breathing, circulation, digestion, endocrine and neural normal function in various degree effect is arranged all, be applied to the treatment of the treatment of antagonism, heart failure and shock of opioid analgesics respiration inhibition and alcoholism and addiction and fat-reducing etc. at present.
The chemical structural formula of nalmefene hydrochloride is:
The Nalmefene hydrochloride injection of Baxter Healthcare Corporat ion application went on the market in the U.S. through drugs approved by FDA in nineteen ninety-five, and disclosed prescription is in the description of its listing:
The name of material inventory
Nalmefene hydrochloride 0.1108g (being equivalent to nalmefene 0.1g)
Sodium chloride 9g
Hydrochloric acid is regulated pH to 3.9
Water for injection adds to 1000ml
Carry out study on the stability by this prescription trial production sample, found that the pH variation obviously (increases to about 5.6 by 3.9 in probation, be limited to 5.5 in the standard code), related substance changes also obviously (be increased to 1.7% by 0.4%, standard code is 1.5%).
Chinese patent literature CN1895251A also discloses " stable Nalmefene hydrochloride injection and preparation method ", its core is for adding sodium sulfite in the prescription, sodium sulfite, pyrosulfurous acid, inorganic antioxidant such as vitamin C, add a certain amount of antioxidant synergist disodiumedetate in addition again, but show by the stability test result that this prescription carries out, can't reach the stablizing effect of its description, related substance also has than obvious variation (being increased to 1.4% by 0.7%) in probation, pH changes also obviously (being increased to about 5.3 by 3.9), though the result does not all exceed standard, but also near the upper limit, the safety of medication, there is certain risk in effectiveness.
Researcher of the present invention is by a large amount of research and test, found that in the prescription add a certain amount of organic antioxidant as: butylhydroxy anisole (BHA), 2,6-di-tert-butyl-4-methy phenol (BHT) and Herba Rosmarini Officinalis etc. also can make the stability of injection achieve the goal.
Summary of the invention
The object of the present invention is to provide a kind of intravenous good stability, obvious results Nalmefene hydrochloride injection of being directly used in.
Another object of the present invention is to provide a kind of preparation method of Nalmefene hydrochloride injection.
For realizing first purpose of the present invention, adopt following technical scheme:
A kind of nalmefene hydrochloride injection, be to be dissolved in the solution that water for injection forms by nalmefene hydrochloride and available pharmaceutic adjuvant, pharmaceutically useful adjuvant comprises antioxidant and osmotic pressure regulator, it is characterized in that nalmefene hydrochloride is 1:0.1～1.0 in the weight ratio of nalmefene and antioxidant;
Described antioxidant is butylhydroxy anisole, 2,6-di-tert-butyl-4-methy phenol and Herba Rosmarini Officinalis one or more mixing.
Described osmotic pressure regulator is sodium chloride, potassium chloride or glucose etc., and its consumption in injection can be by existing injection standard.
Hydrochloric nalmefene can be 0.1mg in nalmefene in every 1ml injection.
The present invention also discloses a kind of preparation method of Nalmefene hydrochloride injection, at first get antioxidant and be dissolved in the water for injection, add osmotic pressure regulator, regulate pH to 3.5～5.5 with hydrochloric acid, benefit adds to the full amount of water for injection, the active carbon that adds amount of liquid 0.5～3.0mg/ml stirs decolouring, and the after-filtration that finishes decolours, in filtrate, add nalmefene hydrochloride, after the stirring and dissolving, filter, fill nitrogen embedding sterilization and form injection.
This Nalmefene hydrochloride injection of the present invention adopts specific organic antioxidant, and the stability of injection is improved, and has guaranteed the safety of medication.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment, to help understanding content of the present invention.
Embodiment 1: 1000 Nalmefene hydrochloride injections of present embodiment preparation (specification: 1ml:0.1mg),
Use following compositions:
The name of material inventory
Nalmefene hydrochloride 0.1108g (being equivalent to nalmefene 0.1g)
Sodium chloride 9g
Butylhydroxy anisole (BHA) 15mg
Water for injection adds to 1000ml
Processing step: get Butylated hydroxyanisole (BHA) 15mg and sodium chloride 9g and join in the water for injection, after the dissolving, regulate pH to 3.8, add water for injection to 1000ml with hydrochloric acid, add the 1.0g active carbon, room temperature decolouring 30 minutes, decolouring finish the back with 0.22 μ m membrane filtration, add nalmefene hydrochloride 0.1108g in filtrate, after the stirring and dissolving, filling the nitrogen embedding behind the 0.22 μ m membrane filtration, 121 ℃ of moist heat sterilizations 20 minutes obtain Nalmefene hydrochloride injection.
Embodiment 2: 1000 Nalmefene hydrochloride injections of present embodiment preparation (specification: 1ml:0.1mg),
Use following compositions:
The name of material inventory
Nalmefene hydrochloride 0.1108g (being equivalent to nalmefene 0.1g)
Sodium chloride 9g
2,6-di-t-butyl-4-hydroxyl-phenol (BHT) 60mg
Water for injection adds to 1000ml
Processing step: get 2,6-two tert-hydroxyl paracresol (BHT) 60mg and sodium chloride 9g join in the water for injection, after the dissolving, regulate pH to 3.8 with hydrochloric acid, add water for injection to 1000ml, add the 1.0g active carbon, room temperature decolouring 30 minutes, decolouring finishes the back with 0.22 μ m membrane filtration, in filtrate, add nalmefene hydrochloride 0.1108g, after the stirring and dissolving, to fill the nitrogen embedding behind the 0.22 μ m membrane filtration, 121 ℃ of moist heat sterilizations 20 minutes obtain Nalmefene hydrochloride injection.
Embodiment 3: 1000 Nalmefene hydrochloride injections of present embodiment preparation (specification: 1ml:0.1mg), use following compositions:
The name of material inventory
Nalmefene hydrochloride 0.1108g (being equivalent to nalmefene 0.1g)
Sodium chloride 9g
Herba Rosmarini Officinalis 20mg
Water for injection adds to 1000ml
Processing step: get Herba Rosmarini Officinalis 20mg and sodium chloride 9g joins in the water for injection, after the dissolving, regulate pH to 3.8, add water for injection to 1000ml with hydrochloric acid, add the 1.0g active carbon, room temperature decolouring 30 minutes, decolouring finish the back with 0.22 μ m membrane filtration, add nalmefene hydrochloride 0.1108g in filtrate, after the stirring and dissolving, filling the nitrogen embedding behind the 0.22 μ m membrane filtration, 121 ℃ of moist heat sterilizations 20 minutes obtain Nalmefene hydrochloride injection.
Embodiment 4: 1000 Nalmefene hydrochloride injections of present embodiment preparation (specification: 1ml:0.1mg), use following compositions:
The name of material inventory
Nalmefene hydrochloride 0.1108g (being equivalent to nalmefene 0.1g)
Sodium chloride 9g
2,6-di-t-butyl-4 methylphenol (BHT) 60mg
Butylhydroxy anisole (BHA) 15mg
Water for injection adds to 1000ml
Processing step: get 2,6-di-t-butyl-4 methylphenol (BHT) 60mg, butylhydroxy anisole (BHA) 15mg and sodium chloride 9g join in the water for injection, after the dissolving, regulate pH to 3.8 with hydrochloric acid, add water for injection to 1000ml, add the 1.0g active carbon, room temperature decolouring 30 minutes, decolouring finishes the back with 0.22 μ m membrane filtration, in filtrate, add nalmefene hydrochloride 0.1108g, after the stirring and dissolving, to fill the nitrogen embedding behind the 0.22 μ m membrane filtration, 121 ℃ of moist heat sterilizations 20 minutes obtain Nalmefene hydrochloride injection.
Nalmefene hydrochloride injection of the present invention has been carried out influence factor's test and tests such as anaphylaxis, hemolytic and local irritation:
1, hot test
Get the sample of preparation among the embodiment 1～4, place in the thermostatic drying chamber, attemperation is 60 ℃, places 10 days, and sampling detected respectively in the 0th day, 5 days, 10 days, and the result is as follows:
2, strong illumination test
Getting among the embodiment 1～4 sample of preparation, is illumination 10 days in the adjustable lighting box of 45001x in illumination, and sampling detected respectively in the 0th day, 5 days, 10 days, and the result is as follows:
3, sensitivity test
3.1 be subjected to the reagent thing: press the Nalmefene hydrochloride injection of embodiment 1,2,3 preparations, lot number: 050502-1,050502-2,050502-3, specification: 1ml:0.1mg.Sodium chloride injection, 250ml/ bottle, lot number: D03051604, Shangdong Hualu Pharmaceutical Co., Ltd..
3.2 positive reference substance: ovalbumin provides the import packing of Sigma company by the biological company limited of couple stars.Being mixed with 0.4% concentration with normal saline is for experiment.
3.3 animal: albino guinea-pig, male and female half and half provide credit number by Shandong Mi Xieer biological product company limited: SCXK (Shandong) 20030011, carry out pre-raising of two weeks, when being used to test about body weight 300～400g after buying.Raising condition: raise with metal rabbit-hutch list cage, freely drink water, give pellet, 22～25 ℃ of room temperatures, humidity about 60%.Pellet is provided by Shandong Province's Experimental Animal Center, credit number: the moving word 200001001 of raising in Shandong.The laboratory animal environmental facility quality certification number: Shandong rotating ring word H2004030507 number.
3.4 test method: get 66 of healthy guinea pig Hartley kind male guinea pigs, be divided into 11 groups (6 every group) at random by body weight, be respectively positive group of each three groups of Nalmefene hydrochloride injections, ovalbumin and sodium chloride injection negative control group by embodiment 1,2,3 preparations.Each treated animal by the sterile working next day respectively the abdominal cavity give Nalmefene hydrochloride injection (0.1mg/ml), 0.4% ovalbumin and sodium chloride injection, 0.5ml/ only, totally three sensitization.Each treated animal is divided into 2 batches, 3 every batch, a collection of in first the injection be subjected to reagent after intravenous injection in 14 days only attacked by reagent product 1ml/, another batch intravenous injection in the 21st day after first administration is only attacked by test product 1ml/.
3.5 result of the test: after pressing the Nalmefene hydrochloride injection and twice attack of sodium chloride injection negative control treated animal of embodiment 1,2,3 preparations, show no obvious abnormalities symptom, result of the test is all negative.And positive controls can make animal subject performances such as nose, perpendicular hair, dyspnea, spasm, shock death occur grabbing.
4, hemolytic test
4.1 be subjected to the reagent thing: press the Nalmefene hydrochloride injection of embodiment 1,2,3 preparations, lot number is respectively: 050502-1,050502-2,050502-3, specification: 1ml:0.1mg.Sodium chloride injection, 250ml/ bottle, Shangdong Hualu Pharmaceutical Co., Ltd., lot number: D03051604.
4.2 animal and feedstuff: new zealand rabbit, the male and female dual-purpose, anti-medical Group Co.,Ltd provides credit number by the Shandong, Shandong: SCXK (Shandong) 20030006.Buy pre-two weeks, the body weight 2.3～2.6kg when being used to test of raising in back.Raising condition: raise with metal rabbit-hutch list cage, freely drink water, give pellet, 22～25 ℃ of room temperatures, humidity about 60%.Pellet is provided by Shandong Province's Experimental Animal Center, credit number: the moving word 200001001 of raising in Shandong.The laboratory animal environmental facility quality certification number: Shandong rotating ring word H2004030507 number.
4.3 instrument: LXJ-II type centrifugal precipitation mechanism, medical analytical instrument factory in Shanghai produces; HH-W21-600 type thermostat water bath, the Shanghai medical equipment is often produced.
4.4 test method: get 17 in test tube, Nalmefene hydrochloride injection (0.1mg/ml) 0.1,0.2,0.3,0.4 and the 0.5ml that add inequality respectively by embodiment 1,2,3 preparations, the 16th pipe does not add and is subjected to test product, as blank, the 17th pipe does not add yet and is subjected to test product, replace normal saline with distilled water, as the haemolysis positive control.Each pipe is shaken up gently, and insulation is 4 hours in 37 ℃ of water-baths, observes each pipe and has or not haemolysis.
4.5 result of the test: occur haemolysis at once after positive control pipe (No. 17 pipes) adds distilled water.After adding Nalmefene hydrochloride injection, 0.25～1 hour, 1～16 pipe erythrocyte began to sink the supernatant liquid achromatism and clarity; 2 hours, 1～16 pipe supernatant achromatism and clarity, a large amount of erythrocyte are sunken to the pipe end; 4 hours, 1～16 pipe solution erythrocyte all sank the supernatant liquid achromatism and clarity.The visible red cell evenly scatters after jolting, proves no red blood cell condensation, and microscope inspection erythrocyte profile is normal.
5, vascular stimulation test
5.1 be subjected to the reagent thing: press the Nalmefene hydrochloride injection of embodiment 1,2,3 preparations, lot number: 050502-1,050502-2,050502-3, specification: 1ml:0.1mg.Sodium chloride injection, 250ml/ bottle, Shangdong Hualu Pharmaceutical Co., Ltd., lot number: D03051604.
5.2 animal and feedstuff: new zealand rabbit, the male and female dual-purpose, anti-medical Group Co.,Ltd provides credit number by the Shandong, Shandong: SCXK (Shandong) 20030006.Buy pre-two weeks, the body weight 2.3～2.6kg when being used to test of raising in back.Raising condition: raise with metal rabbit-hutch list cage, freely drink water, give pellet, 22～25 ℃ of room temperatures, humidity about 60%.Pellet is provided by Shandong Province's Experimental Animal Center, credit number: the moving word 200001001 of raising in Shandong.The laboratory animal environmental facility quality certification number: Shandong rotating ring word H2004030507 number.
5.3 test method: get 12 of health, ear edge not damaged rabbit, be divided into four groups at random, promptly press the Nalmefene hydrochloride injection test group and the sodium chloride injection matched group of embodiment 1,2,3 preparations by body weight.The clinical adult of this product intravenous injection dosage on the one is 0.5～2mg.Calculate by the clinical consumption 2mg/day of adult (60kg), it is 0.038mg/kg/day that Nalmefene hydrochloride injection dosage is established in this test, getting stock solution (0.1mg/ml), to be mixed with concentration be 0.092mg/ml, rabbit left side auricular vein is injected administration, administration volume 4.1ml/kg, matched group gives the isometric(al) sodium chloride injection.Be administered once every day, totally seven days.
5.4 result of the test: compare with the sodium chloride injection group, intravenous drip gives the Nalmefene hydrochloride injection by embodiment 1,2,3 preparations, reaches the last administration during the administration after 24 hours, and rabbit ear blood vessel lines is all clear, and surrounding tissue does not have edema.The visible rabbit ear vein blood vessel of tissue slice inspection rule, tube wall is thin, and inwall is level and smooth, and intracavity is full of blood, the Guan Zhouwu inflammatory exudate.Show that Nalmefene hydrochloride injection does not have the obvious stimulation effect to the rabbit auricular vein under this experiment condition.
The above only is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. Nalmefene hydrochloride injection, be to be dissolved in the solution that water for injection forms by nalmefene hydrochloride and available pharmaceutic adjuvant, available pharmaceutic adjuvant comprises antioxidant and osmotic pressure regulator, it is characterized in that nalmefene hydrochloride is 1: 0.1～1.0 in the weight ratio of nalmefene and antioxidant;
Described antioxidant is butylhydroxy anisole and 2, in the 6-di-tert-butyl-4-methy phenol one or both.
2. Nalmefene hydrochloride injection as claimed in claim 1 is characterized in that: hydrochloric nalmefene is counted 0.1mg with nalmefene in every 1mL injection.
3. Nalmefene hydrochloride injection as claimed in claim 1 or 2 is characterized in that: described osmotic pressure regulator is sodium chloride, potassium chloride or glucose.
4. Nalmefene hydrochloride injection as claimed in claim 3 is characterized in that every 1mL injection contains nalmefene hydrochloride and counts 0.1mg, sodium chloride 9mg, butylhydroxy anisole 0.015mg with nalmefene.
5. Nalmefene hydrochloride injection as claimed in claim 3 is characterized in that every 1mL injection contains nalmefene hydrochloride and counts 0.1mg, sodium chloride 9mg, 2 with nalmefene, 6-di-tert-butyl-4-methy phenol 0.06mg.
6. Nalmefene hydrochloride injection as claimed in claim 3 is characterized in that every 1mL injection contains nalmefene hydrochloride and counts 0.1mg, sodium chloride 9mg, 2 with nalmefene, 6-di-tert-butyl-4-methy phenol 0.06mg and butylhydroxy anisole 0.015mg.
7. the preparation method of the described Nalmefene hydrochloride injection of claim 1, it is characterized in that: at first get antioxidant and be dissolved in the water for injection, add osmotic pressure regulator, regulate pH to 3.5～5.5 with hydrochloric acid, benefit adds to the full amount of water for injection, the active carbon that adds amount of liquid 0.5～3.0mg/mL stirs decolouring, and the after-filtration that finishes decolours, in filtrate, add nalmefene hydrochloride, after the stirring and dissolving, filter, fill nitrogen embedding sterilization and form injection.
8. preparation method as claimed in claim 7 is characterized in that: described water for injection total amount is counted 0.1mg by hydrochloric nalmefene in every 1mL injection with nalmefene and is calculated.
9. preparation method as claimed in claim 7 is characterized in that: described filtration is with 0.22 μ m membrane filtration.
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| CN102415993B (en) * | 2011-12-03 | 2013-01-09 | 武汉同源药业有限公司 | Pharmaceutical composition containing nalmefene hydrochloride and preparation method of same |
| CN104922061B (en) * | 2015-05-26 | 2017-09-22 | 成都天台山制药有限公司 | Nalmefene hydrochloride injection pharmaceutical composition and preparation method |
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| CN1237106A (en) * | 1997-07-11 | 1999-12-01 | 东丽株式会社 | Stable medicinal compositions containing 4,5-epoxymorphinane derivatives |
| US6271240B1 (en) * | 1996-05-06 | 2001-08-07 | David Lew Simon | Methods for improved regulation of endogenous dopamine in prolonged treatment of opioid addicted individuals |
| CN1640986A (en) * | 2004-01-14 | 2005-07-20 | 云南玉溪瑞源生物化工有限责任公司 | Method for extracting natural antioxidant from rose mary |
| CN1652752A (en) * | 2002-03-14 | 2005-08-10 | 欧罗赛铁克股份有限公司 | Naltrexone hydrochloride compositions |
| CN1654616A (en) * | 2005-01-24 | 2005-08-17 | 中国林业科学研究院林产化学工业研究所 | combined extraction method for rosemary essential oil and rosemary antioxidant |
| CN1895251A (en) * | 2005-07-13 | 2007-01-17 | 汕头大学医学院 | Stabilized nalmefene hydrochloride injection and its preparation |
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2008
- 2008-08-27 CN CN200810146735XA patent/CN101658489B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6271240B1 (en) * | 1996-05-06 | 2001-08-07 | David Lew Simon | Methods for improved regulation of endogenous dopamine in prolonged treatment of opioid addicted individuals |
| CN1237106A (en) * | 1997-07-11 | 1999-12-01 | 东丽株式会社 | Stable medicinal compositions containing 4,5-epoxymorphinane derivatives |
| CN1652752A (en) * | 2002-03-14 | 2005-08-10 | 欧罗赛铁克股份有限公司 | Naltrexone hydrochloride compositions |
| CN1640986A (en) * | 2004-01-14 | 2005-07-20 | 云南玉溪瑞源生物化工有限责任公司 | Method for extracting natural antioxidant from rose mary |
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| CN1895251A (en) * | 2005-07-13 | 2007-01-17 | 汕头大学医学院 | Stabilized nalmefene hydrochloride injection and its preparation |
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Effective date of registration: 20220325 Address after: 101114 Beijing city Tongzhou District Zhangjiawan Town Qi Shanzhuang East Village Patentee after: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee after: Hainan four ring Pharmaceutical Co., Ltd. Address before: 570216 Haikou free trade zone a06-2, No. 168, Nanhai Avenue, Haikou City, Hainan Province Patentee before: Hainan Sihuan Cardiovascular Drug Research Institute Co.,Ltd. Patentee before: HAINAN SIHUAN PHARMACEUTICAL Co.,Ltd. Patentee before: BEIJING SIHUAN PHARMACEUTICAL Co.,Ltd. |