CN103637983B - A kind of pharmaceutical composition containing nalmefene hydrochloride and preparation method thereof - Google Patents
A kind of pharmaceutical composition containing nalmefene hydrochloride and preparation method thereof Download PDFInfo
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- CN103637983B CN103637983B CN201310690829.4A CN201310690829A CN103637983B CN 103637983 B CN103637983 B CN 103637983B CN 201310690829 A CN201310690829 A CN 201310690829A CN 103637983 B CN103637983 B CN 103637983B
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- nalmefene hydrochloride
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Abstract
Nalmefene hydrochloride pharmaceutical composition of the present invention is Nalmefene hydrochloride injection, it is characterised in that nalmefene hydrochloride counts the weight proportion with sodium dihydrogen phosphate as 1: 10~100 using nalmefene.Also disclose a kind of preparation method.The nalmefene hydrochloride pharmaceutical composition composition of the present invention is simple, and using sodium dihydrogen phosphate as specific pH stable agent, sample stability is good, it is ensured that the security and validity of medication.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparation method thereof, more particularly to a kind of medicine containing nalmefene hydrochloride
Composition and preparation method thereof, belongs to pharmaceutical technology field.
Background technology
Nalmefene hydrochloride (Nalmefene Hydrochloride) is a kind of opioid receptor antagonists, in 1975 by
The Miami drugmakers of Fla. develop, entitled (5 α) -17- cyclopropylmethylene -4, the 5- rings of its chemistry
Oxygen -6- methylene morphinan -3,14- diol hydrochlorides, chemical structural formula is：
Nalmefene hydrochloride injection (trade name：) inverse available for Post operation through U.S. FDA approval in nineteen ninety-five
Turn the effect of opioid drug, including respiration inhibition, drowsiness and low blood pressure.
Nalmefene hydrochloride injection be clinically widely used in Hemorrhagic shock, the treatment of Morphinoid drug acute poisoning and
Prevention, the anesthesia relapsed to drug rehabilitation patient is wakened in terms of i.e. rescue respiration inhibition and other CNS inhibition symptoms, with action
Hurry up, long action time, good effect, it is safe, can prevent may complication the advantage such as generation.
But, with the further investigation to Nalmefene hydrochloride injection, it is found that Nalmefene hydrochloride injection room temperature is put for a long time
Put, have significant nalmefene be oxidized nalmefene in pairs (Sataya S.Murthy etc., Stability of revex,
Nalmefene Hydrocholoride Injection in Injectable Solutions,
J.Pharm.Biomed.Anal.15 (1996)), in addition, Nalmefene hydrochloride injection pH value change in long-term placement process is bright
It is aobvious.Two above problem has had a strong impact on the security and validity that Nalmefene hydrochloride injection is clinically used.
For overcome disclosed in problem above, Chinese patent CN1895251 a kind of stabilization Nalmefene hydrochloride injection and
Its preparation method, its formulation core is addition antioxidant sodium hydrogensulfite and chelating agent disodium ethylene diamine tetraacetate in prescription, but
It is that the stability test result carried out by the prescription shows, it is impossible to reach the stablizing effect of its specification, it is steady at long-term 12 months
Relevant material has significantly change (increasing to 1.4% by 0.7%) in qualitative probation, and pH value change is also more apparent (by 3.9
Increase to 5.3 or so), there is certain risk in security, validity to medication.
A kind of Nalmefene hydrochloride injection of stabilization and preparation method thereof is disclosed in Chinese patent CN101658488, its
Formulation core is any formation buffering of addition sodium citrate, acetic acid and sodium acetate, citric acid and disodium hydrogen phosphate in prescription
System.But the influence factor result of the test carried out by prescription in the specification shows, adding above salt of weak acid in prescription can
To play the effect of stablizing solution pH value, but it is dissatisfied for the effect in reduction sample about content of material.Based on existing
The problem of with the presence of technology, this invention is intended to provide one kind can stablizing solution pH value, relevant material in sample can be reduced again and is contained
Pharmaceutical composition containing nalmefene hydrochloride of amount and preparation method thereof, to reach drug safety, effective purpose.
The content of the invention
To achieve the above object, the present invention is adopted the following technical scheme that：
A kind of Nalmefene hydrochloride injection, it is characterised in that contain nalmefene hydrochloride and pharmaceutical carrier, wherein pharmaceutical carrier
Include sodium dihydrogen phosphate.
Weight of the nalmefene hydrochloride in terms of nalmefene with sodium dihydrogen phosphate in Nalmefene hydrochloride injection of the present invention
Match as 1: 10~100；Wherein the pH value of parenteral solution is in the range of 3.5~4.5.
The preparation method of Nalmefene hydrochloride injection of the present invention, it is characterised in that comprise the following steps：Take appropriate
Water for injection, adds full dose nalmefene hydrochloride and sodium dihydrogen phosphate, is stirred to dissolve；The salt acid for adjusting pH value of debita spissitudo is extremely
3.5~4.5, activated carbon is added, stirring and adsorbing, filtering adds water for injection to full dose；Dispensed after filtering, inflated with nitrogen, sealing,
Sterilizing.
Nalmefene hydrochloride injection of the present invention, uses sodium dihydrogen phosphate for pH stable agent, pH value before and after sterilizing
Change is smaller, and production is easily controlled, and relevant material is smaller；Stability is good, influence factor experiment, accelerated test and long term test
Character, pH value, active constituent content and relevant material of 24 months samples etc. are without significant changes, it is ensured that the security of medication
And validity.
Brief description of the drawings
The weight proportion and pH value graph of a relation of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate in Fig. 1 samples
The weight proportion and total miscellaneous relation with contents figure of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate in Fig. 2 samples
Embodiment
With reference to embodiment, the invention will be further described with comparative example, and embodiment is only used for description originally with comparative example
Some specific embodiments of invention, rather than limit the scope of the invention.
Embodiment 1
The present embodiment prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium dihydrogen phosphate 1g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Embodiment 2
The present embodiment prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium dihydrogen phosphate 2g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Embodiment 3
The present embodiment prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium dihydrogen phosphate 5g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 15 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Embodiment 4
The present embodiment prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium dihydrogen phosphate 10g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Embodiment 5
The present embodiment prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 1.108g and sodium dihydrogen phosphate 20g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Comparative example 1
This comparative example prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and disodium hydrogen phosphate 5g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Comparative example 2
This comparative example prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium citrate 5g is added, stirring makes
Dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption is mixed, filters, adds water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Comparative example 3
This comparative example prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium dihydrogen phosphate 0.5g is added, stirs
Mixing makes dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Comparative example 4
This comparative example prepares 1000 Nalmefene hydrochloride injection (specifications：1ml:0.1mg)
Preparation process：(1) water for injection 900ml is taken, nalmefene hydrochloride 0.1108g and sodium dihydrogen phosphate 15g, stirring is added
Make dissolving；
(2) solution ph is adjusted to 3.5~4.5 with 0.5mol/L hydrochloric acid solutions, add 0.5% (w/v) medical charcoal, stir
Absorption 15 minutes is mixed, filtering is added water for injection to enough；
(3) dispensed after the filtering of 0.22 μm of filter, inflated with nitrogen, sealing, 121 DEG C of moist heat sterilizations 12 minutes obtain hydrochloric acid and received
U.S. sweet smell parenteral solution.
Stability compares：
1. influence factor is tested
By embodiment 1~5 and the sample of comparative example 1~4, respectively in illumination (illumination is 4500lx ± 500lx strong light) and
Placed 10 days under the conditions of high temperature (60 DEG C of baking ovens), and with 0 day results contrast, testing result is as follows：
Conclusion：The embodiment of the present invention 1~5 and the sample of comparative example 1~2 are under the conditions of illumination (4500lx) and high temperature (60 DEG C)
Place 10 days, its character, pH value and content Index for examination have no significant change.The relevant material of the sample of comparative example 1~2 is significantly greater than
The sample of embodiment 1~5, other single miscellaneous and other total miscellaneous contents are especially embodied in, sodium dihydrogen phosphate are pointed out compared with other weak acid
Salt, can substantially reduce impurity level, and ensure the stability of Nalmefene hydrochloride injection.
Weight proportion of the nalmefene hydrochloride in terms of nalmefene with sodium dihydrogen phosphate in embodiment 1~4, the sample of comparative example 3~4
Respectively 1: 10,1: 20,1: 50,1: 100,1: 5,1: 150, sample room character and content can reflect product without significant difference
Quality index is pH value and relevant material, wherein, the weight of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate in sample
Proportioning and pH value relation see in Fig. 1, sample the weight proportion of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate with it is total miscellaneous
Relation with contents is shown in Fig. 2.
As seen from Figure 1, Figure 2, the weight proportion of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate is less than 1 in sample
: 10, before and after sterilizing pH value change greatly, and placement 10 days, pH value and relevant under the conditions of illumination (4500lx) and high temperature (60 DEG C)
Material change is obvious；The weight proportion of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate is more than 1: 100 in sample, although
PH value is relatively stablized, but impurity level is significantly higher；The weight of nalmefene hydrochloride (in terms of nalmefene) and sodium dihydrogen phosphate in sample
Fit between 1: 10~100, pH stable and relevant material is smaller, quality is optimal.Accordingly, it is determined that nalmefene hydrochloride in sample
The weight of (in terms of nalmefene) and sodium dihydrogen phosphate is fitted between 1: 10~100.
2. accelerate and long term test
Further to investigate the stability of the sample of embodiment 1~5, the sample of embodiment 1~5 is pressed into commercially available back, temperature 40
DEG C ± 2 DEG C, placed 6 months under the conditions of the accelerated test of relative humidity 75% ± 5%, in 1st month, the 2nd month, the 3rd month,
The sampling detection of 6th the end of month, and with 0 month results contrast；By commercially available back, 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10%
Long term test under the conditions of place 24 months, in 3rd month, the 6th month, the 9th month, the 12nd month, the 18th month, the 24th
The end of month sampling detection, and with 0 month results contrast.
It is as follows that accelerated test investigates result：
It is as follows that long term test investigates result：
In accelerated test and experiment in long-term 24 months, the character of the sample of embodiment 1~5, pH value, active constituent content and relevant
Material etc. is without significant changes.
3. summarize
By the comparative study of embodiment 1~5 and comparative example 1~4, the sample of embodiment 1~5 is in process of production
Its superiority is shown, pH value change is smaller before and after being mainly manifested in sterilizing, and production is easily controlled, and relevant material is smaller；Surely
Character, pH value, active constituent content and relevant material of qualitative test sample etc. without significant changes, can make the storage of product
Phase reaches common 24 months.
Claims (3)
1. a kind of Nalmefene hydrochloride injection, containing nalmefene hydrochloride and pharmaceutical carrier, wherein pharmaceutical carrier includes biphosphate
Sodium, the nalmefene hydrochloride counts the weight proportion with the sodium dihydrogen phosphate as 1 using nalmefene:10~100.
2. parenteral solution according to claim 1, it is characterised in that scope of the pH value of the parenteral solution 3.5~4.5
It is interior.
3. the preparation method of the parenteral solution described in a kind of claim 1 or 2, it is characterised in that the described method comprises the following steps：
(1) appropriate water for injection is taken, full dose nalmefene hydrochloride and sodium dihydrogen phosphate is added, is stirred to dissolve；
(2) the salt acid for adjusting pH value of debita spissitudo adds activated carbon to 3.5~4.5, and stirring and adsorbing, filtering supplements water for injection
To full dose；
(3) dispense, inflated with nitrogen, seal after filtering, sterilizing.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101658488A (en) * | 2008-08-27 | 2010-03-03 | 海南四环心脑血管药物研究院有限公司 | Nalmefene hydrochloride injection and preparation method thereof |
| CN103202806A (en) * | 2013-04-10 | 2013-07-17 | 安徽恒星制药有限公司 | Method for preparing nalmefene hydrochloride injection and prepared nalmefene hydrochloride injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2447013A (en) * | 2007-03-01 | 2008-09-03 | Reckitt Benckiser Healthcare | Analgesic composition containing buprenorphone and nalmefene |
| CN101792444B (en) * | 2009-02-02 | 2011-10-12 | 天津康鸿医药科技发展有限公司 | Sodium levofolinate and preparation method and drug combination thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101658488A (en) * | 2008-08-27 | 2010-03-03 | 海南四环心脑血管药物研究院有限公司 | Nalmefene hydrochloride injection and preparation method thereof |
| CN103202806A (en) * | 2013-04-10 | 2013-07-17 | 安徽恒星制药有限公司 | Method for preparing nalmefene hydrochloride injection and prepared nalmefene hydrochloride injection |
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Effective date of registration: 20171121 Address after: 102627, No. 6, No. 6, No. 30, Venus Road, Daxing District, Beijing City, 101 Patentee after: Corbeille Park (Beijing) Medical Technology Co Ltd Address before: 100043 Beijing city Shijingshan District City Street No. 77 room 407 office building of Yunlong Patentee before: PHARMASEA (BEIJING) BIO-PHARMACEUTICAL CO., LTD. |