CN106619495A - Preparation method of nalmefene hydrochloride injection and nalmefene hydrochloride injection prepared with method - Google Patents
Preparation method of nalmefene hydrochloride injection and nalmefene hydrochloride injection prepared with method Download PDFInfo
- Publication number
- CN106619495A CN106619495A CN201611054165.2A CN201611054165A CN106619495A CN 106619495 A CN106619495 A CN 106619495A CN 201611054165 A CN201611054165 A CN 201611054165A CN 106619495 A CN106619495 A CN 106619495A
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- CN
- China
- Prior art keywords
- nalmefene hydrochloride
- preparation
- injection
- hydrochloride injection
- citric acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
Abstract
The invention discloses a preparation method of a nalmefene hydrochloride injection. When the nalmefene hydrochloride injection is prepared with a conventional method, a certain quantity of citric acid or citrate auxiliary material is added to the preparation, and 5-15 g of the citric acid or citrate auxiliary material is added in each liter of the injection. During preparation, the prescription quantity of the auxiliary material is dissolved in water for injection firstly, then activated carbon is added with stirring for adsorption, and filtration is performed for impurity removal; the prescription amount of nalmefene hydrochloride is added under the nitrogen protection, after full dissolution, the solution is metered to the designated volume with water, the pH value is adjusted to 3.5-4.5, and finally, the solution is filtered by a filter, sub-packaged, filled with nitrogen, sealed and sterilized. With the adoption of the method, the expiry date of the nalmefene hydrochloride injection can be obviously prolonged, the stability is good due to adoption of a specific citric acid pH value stabilizer, the sample appearance properties, pH value, effective ingredient content, related substances and the like are relatively stable, and the medication safety is guaranteed.
Description
Technical field
The present invention relates to a kind of pharmaceutical dosage form, the preparation method of more particularly to a kind of Nalmefene hydrochloride injection and its it is obtained
Nalmefene hydrochloride injection.
Background technology
Nalmefene hydrochloride synthesized in 1975, was that the pure opium of the another Dai Xin synthesized after naloxone and naltrexone is received
Body antagonist, to opiate receptor without agonism, and does not produce dependence, compares with naloxone with naltrexone, with during effect
Between long, oral administration biaavailability is high, dosage is little, safe range width the advantages of.
Chinese patent literature CN1813739 discloses a kind of nalmefene hydrochloride injection, wherein the salt in per unit dose
Sour nalmefene content range is 0.1～4.5mg；Pharmaceutical carrier can be mannitol, glucose, beta-schardinger dextrin, sodium chloride, dextrorotation
One or more in glucosides, fructose, sorbierite etc., preferred sweet dew alcohol and glucose, its content range in the formulation is 10
～100mg；The pH value of preparation is 5.0～7.0.
A kind of stable Nalmefene hydrochloride injection and preparation method thereof is disclosed in Chinese patent literature CN1895251,
Said preparation is made up of the nalmefene hydrochloride and appropriate pharmaceutical carrier of medicine effective quantity, and its core is to add bisulfite in prescription
The inorganic antioxidant such as sodium, sodium sulfite, pyrosulfurous acid, vitamin C, adds in addition a certain amount of antioxidant synergist ethylenediamine tetraacetic
Acetic acid disodium, but the stability experiment result carried out by the prescription shows, it is impossible to the stablizing effect in its specification is reached,
Relevant material also has significantly change in probation（Increase to 1.4% by 0.7%）, pH value changes also more apparent（Increased by 3.9
To 5.3）Although result is not exceeded, there is certain risk in the close upper limit, the security of medication, validity.
At present the term of validity of several Nalmefene hydrochloride injections of listing is 12～18 months, illustrates the stability of drug products not
Good, the Clinical practice and drug safety that product are so administered brings certain risk.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Nalmefene hydrochloride injection, hydrochloric acid prepared by the inventive method
More preferably, the term of validity is obviously prolonged Nalmefene injection stability.
To achieve these goals, the present invention is adopted the following technical scheme that：
A kind of preparation method of Nalmefene hydrochloride injection, it is characterised in that：Routinely method is preparing Nalmefene hydrochloride injection
When, a certain amount of citric acid or citrate are added in the formulation, its addition be its every liter parenteral solution in add citric acid 5～
5～15g of 15g or citrate.
The preparation method of described Nalmefene hydrochloride injection, it is characterised in that comprise the following steps：
（1）Sodium chloride, citric acid or the citrate of recipe quantity are taken, plus water for injection 500ml makes dissolving, plus 0.05%（W/V）It is living
Property charcoal stir 15 minutes, filtering decarbonization is cooled to room temperature；
（2）Under nitrogen protection, the nalmefene hydrochloride of recipe quantity is added, is stirred to dissolve, injected water at room temperature complete
Amount 1000ml, is well mixed, and pH value is adjusted to 3.5～4.5 with 1mol/L sodium hydroxide solutions or 1mol/L hydrochloric acid solutions；
（3）Under nitrogen protection, the nalmefene hydrochloride of recipe quantity is added, is stirred to dissolve, injected water at room temperature complete
Amount 1000ml, is well mixed, and pH value is adjusted to 3.5～4.5 with 1mol/L sodium hydroxide solutions or 1mol/L hydrochloric acid solutions；
（4）Dispense after being filtered with 0.45 μm and 0.22 μm of filter, nitrogen charging, sealing sterilizes for 116 DEG C/40 minutes.
The preparation method of described Nalmefene hydrochloride injection, it is characterised in that：Described Nalmefene hydrochloride injection, often
1000 Nalmefene hydrochloride injections are made up of following raw materials according component：99.53～121.65mg of nalmefene hydrochloride, sodium chloride 8～
10g, 5～15g of citric acid or citrate, balance of water.
The preparation method of described Nalmefene hydrochloride injection, it is characterised in that the system of the Nalmefene hydrochloride injection
Agent specification is 1ml parenteral solution 0.1mg containing nalmefene.
Nalmefene hydrochloride injection obtained in the preparation method of described Nalmefene hydrochloride injection.
Advantages of the present invention：The Nalmefene hydrochloride injection of the present invention, using specific citric acid or citrate pH value
Stabilizer, good stability, sample appearance proterties, pH value, active constituent content and relevant material etc. are more stable, it is ensured that medication
Security.The Nalmefene hydrochloride injection of citric acid or citrate is added, pH value is varied less before and after its sterilizing, in production
It is easily controlled, under influence factor hot conditions, stability is substantially better than the parenteral solution for being not added with citric acid or citrate, is adding
Under the conditions of fast June, long-term June, stability is also significantly better than the parenteral solution for being not added with citric acid or citrate, is mainly manifested in pH
In value, the index of double nalmefenes.
Specific embodiment
With reference to embodiment, the invention will be further described, and embodiment is only used for the present invention rather than limits this
Bright scope.
Embodiment 1
The present embodiment prepares 1000 Nalmefene hydrochloride injections（Specification：1ml ︰ 0.1mg）
Name of material inventory
Nalmefene hydrochloride 0.1108g（Equivalent to nalmefene 0.1g）
Sodium chloride 9g
Sodium chloride 9g
Water for injection adds to 1000ml,
Preparation process：
（1）The sodium chloride 9g of recipe quantity is taken, plus water for injection 500ml makes dissolving, plus 0.05%（W/V）Activated carbon is stirred 15 minutes,
Filtering decarbonization is cooled to room temperature；
（2）Under nitrogen protection, the nalmefene hydrochloride 0.1108g of recipe quantity is added（Equivalent to nalmefene 0.1g）, stirring makes molten
Solution, add to the full amount of water for injection at room temperature 1000ml, is well mixed, with 1mol/L hydrochloric acid solutions adjust pH value to 3.5～
4.5；
（3）Dispense after being filtered with 0.45 μm and 0.22 μm of filter, nitrogen charging, sealing, sterilize within 116 DEG C/40 minutes, obtain hydrochloric acid and receive U.S.
Fragrant parenteral solution.
Embodiment 2
The present embodiment prepares 1000 Nalmefene hydrochloride injections（Specification：1ml ︰ 0.1mg）
Preparation process：
（1）Sodium chloride 9g, the citric acid 10g of recipe quantity are taken, plus water for injection 500ml makes dissolving, plus 0.05%（W/V）Activated carbon
Stirring 15 minutes, filtering decarbonization is cooled to room temperature；
（2）Under nitrogen protection, the nalmefene hydrochloride 0.1108g of recipe quantity is added（Equivalent to nalmefene 0.1g）, stirring makes molten
Solution, add to the full amount of water for injection at room temperature 1000ml, is well mixed, and pH value is adjusted to 3.5 with 1mol/L sodium hydroxide solutions
～4.5；
（3）Dispense after being filtered with 0.45 μm and 0.22 μm of filter, nitrogen charging, sealing, sterilize within 116 DEG C/40 minutes, obtain hydrochloric acid and receive U.S.
Fragrant parenteral solution.
Embodiment 3
The present embodiment prepares 1000 Nalmefene hydrochloride injections（Specification：1ml ︰ 0.1mg）
Preparation process：
（1）Sodium chloride 9g, the sodium pyrosulfite 1g of recipe quantity are taken, plus water for injection 500ml makes dissolving, plus 0.05%（W/V）Activity
Charcoal is stirred 15 minutes, and filtering decarbonization is cooled to room temperature；
（2）Under nitrogen protection, the nalmefene hydrochloride 0.1108g of recipe quantity is added（Equivalent to nalmefene 0.1g）, stirring makes molten
Solution, add to the full amount of water for injection at room temperature 1000ml, is well mixed, with 1mol/L hydrochloric acid solutions adjust pH value to 3.5～
4.5；
（3）Dispense after being filtered with 0.45 μm and 0.22 μm of filter, nitrogen charging, sealing, sterilize within 116 DEG C/40 minutes, obtain hydrochloric acid and receive U.S.
Fragrant parenteral solution.
Claims (4)
1. a kind of preparation method of Nalmefene hydrochloride injection, it is characterised in that：Routinely method is preparing nalmefene hydrochloride injection
During liquid, a certain amount of citric acid or citrate auxiliary material are added in the formulation, its addition is to add citron in every liter of parenteral solution
Acid or 5～15g of citrate.
2. the preparation method of Nalmefene hydrochloride injection according to claim 1, it is characterised in that：Comprise the following steps：
（1）Sodium chloride, citric acid or the citrate of recipe quantity are taken, plus water for injection 500ml makes dissolving, plus 0.05%（W/V）It is living
Property charcoal stir 15 minutes, filtering decarbonization is cooled to room temperature；
（2）Under nitrogen protection, the nalmefene hydrochloride of recipe quantity is added, is stirred to dissolve, injected water at room temperature complete
Amount 1000ml, is well mixed, and pH value is adjusted to 3.5～4.5 with 1mol/L sodium hydroxide solutions or 1mol/L hydrochloric acid solutions；
（3）Dispense after being filtered with 0.45 μm and 0.22 μm of filter, nitrogen charging, sealing, 116 DEG C, sterilize within 40 minutes.
3. the preparation method of Nalmefene hydrochloride injection according to claim 1, it is characterised in that：Described hydrochloric acid receives U.S.
Fragrant parenteral solution, per 1000 Nalmefene hydrochloride injections（1ml/）It is made up of following raw materials according component：Nalmefene hydrochloride 99.53
～121.65mg, 8～10g of sodium chloride, 5～15g of citric acid or citrate, balance of water.
4. Nalmefene hydrochloride injection obtained in the preparation method of Nalmefene hydrochloride injection according to claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611054165.2A CN106619495A (en) | 2016-11-25 | 2016-11-25 | Preparation method of nalmefene hydrochloride injection and nalmefene hydrochloride injection prepared with method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611054165.2A CN106619495A (en) | 2016-11-25 | 2016-11-25 | Preparation method of nalmefene hydrochloride injection and nalmefene hydrochloride injection prepared with method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106619495A true CN106619495A (en) | 2017-05-10 |
Family
ID=58811972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611054165.2A Withdrawn CN106619495A (en) | 2016-11-25 | 2016-11-25 | Preparation method of nalmefene hydrochloride injection and nalmefene hydrochloride injection prepared with method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106619495A (en) |
-
2016
- 2016-11-25 CN CN201611054165.2A patent/CN106619495A/en not_active Withdrawn
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| PB01 | Publication | ||
| PB01 | Publication | ||
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| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20170510 |
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| WW01 | Invention patent application withdrawn after publication |