CN117257727B - Nalmefene hydrochloride injection pharmaceutical composition and preparation method thereof - Google Patents
Nalmefene hydrochloride injection pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN117257727B CN117257727B CN202310635966.1A CN202310635966A CN117257727B CN 117257727 B CN117257727 B CN 117257727B CN 202310635966 A CN202310635966 A CN 202310635966A CN 117257727 B CN117257727 B CN 117257727B
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- nalmefene hydrochloride
- lipoic acid
- nalmefene
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- GYWMRGWFQPSQLK-OPHZJPRHSA-N (4r,4as,7as,12bs)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;hydron;chloride Chemical compound Cl.N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 GYWMRGWFQPSQLK-OPHZJPRHSA-N 0.000 title claims abstract description 103
- 229960000677 nalmefene hydrochloride Drugs 0.000 title claims abstract description 101
- 238000002347 injection Methods 0.000 title claims abstract description 74
- 239000007924 injection Substances 0.000 title claims abstract description 74
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 47
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims abstract description 32
- 229960005297 nalmefene Drugs 0.000 claims abstract description 32
- 239000011780 sodium chloride Substances 0.000 claims abstract description 23
- NLDDIKRKFXEWBK-AWEZNQCLSA-N gingerol Chemical compound CCCCC[C@H](O)CC(=O)CCC1=CC=C(O)C(OC)=C1 NLDDIKRKFXEWBK-AWEZNQCLSA-N 0.000 claims abstract description 22
- JZLXEKNVCWMYHI-UHFFFAOYSA-N gingerol Natural products CCCCC(O)CC(=O)CCC1=CC=C(O)C(OC)=C1 JZLXEKNVCWMYHI-UHFFFAOYSA-N 0.000 claims abstract description 21
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical class [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 0.000 claims abstract 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 21
- 235000019136 lipoic acid Nutrition 0.000 claims description 19
- 229960002663 thioctic acid Drugs 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 13
- -1 lipoyl chloride Chemical compound 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 230000001954 sterilising effect Effects 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000004140 cleaning Methods 0.000 claims description 5
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003708 ampul Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 20
- 239000012535 impurity Substances 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 125000004430 oxygen atom Chemical group O* 0.000 abstract description 7
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 6
- 150000003254 radicals Chemical class 0.000 abstract description 6
- 230000003064 anti-oxidating effect Effects 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
- 230000021615 conjugation Effects 0.000 abstract description 3
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical class OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 51
- 230000000052 comparative effect Effects 0.000 description 22
- 238000002474 experimental method Methods 0.000 description 14
- 239000000126 substance Substances 0.000 description 9
- 238000005286 illumination Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical compound COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 2
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000003401 opiate antagonist Substances 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 241000218378 Magnolia Species 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000570 acute poisoning Toxicity 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 229940077239 chlorous acid Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 229940124636 opioid drug Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
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- 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
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Addiction (AREA)
- Toxicology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and relates to a nalmefene hydrochloride injection pharmaceutical composition and a preparation method thereof; comprises the following components in parts by weight: 0.1-1.0 part of nalmefene hydrochloride, 6-9 parts of sodium chloride and 0.04-0.1 part of lipoic acid derivative based on nalmefene. The lipoic acid derivative reserves a disulfide five-membered ring and a phenolic hydroxyl group on 6-gingerol, a single electron with unpaired oxygen atoms on the phenolic hydroxyl group can generate a conjugation effect with pi electron cloud on a benzene ring, the energy of free radicals is reduced, the disulfide five-membered ring has stronger electron affinity, can react with the oxygen atoms, the free radical content is reduced, the lipoic acid derivative has good antioxidation, the generation of the impurities of the bisnalmefene in the nalmefene hydrochloride injection can be effectively reduced, the stability of the product is improved, and the quality of the nalmefene hydrochloride injection is obviously improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a nalmefene hydrochloride injection pharmaceutical composition and a preparation method thereof.
Background
Nalmefene hydrochloride has the structural formula: The chemical name is 17-cyclopropylmethyl-4, 5 alpha-epoxy-6-methyl-iso-morphinan-3, 14-diol hydrochloride.
Nalmefene hydrochloride is a mu, kappa, alpha opioid receptor antagonist, especially with a strong affinity for the mu receptor. The injection is the only dosage form of the medicine on the market at present. Compared with the traditional opioid receptor antagonist, the nalmefene hydrochloride has the characteristics of stronger physiological activity and easier biological membrane penetration, is mainly used for reversing excessive actions of postoperative opioid drugs, including respiratory depression, somnolence and hypotension, is widely applied to the aspects of alcoholism treatment, acute poisoning treatment of morphine drugs, anesthesia and wakening, spinal cord injury treatment, whole brain protection treatment, relapse prevention treatment of drug-withdrawal patients and the like clinically, and has the advantages of short acting time, long effect duration, no opioid agonistic activity, high safety, no drug resistance, no dependence, small side effect, economy and the like.
Because phenolic hydroxyl exists in the nalmefene hydrochloride structure, the nalmefene hydrochloride is easily oxidized in aqueous solution by illumination, ultraviolet irradiation or under high temperature condition, and degradation impurities, mainly dimer nalmefene hydrochloride-bisnalmefene, can be generated by oxidation after long-term storage at normal temperature. The generation of the diclofenac can cause the injection to change color and deteriorate, and seriously affects the clinical medication safety and effectiveness of the nalmefene hydrochloride injection. Therefore, the national drug standard YBH07072010 clearly indicates that the content of the degradation impurity of the nalmefene hydrochloride (the bisnalmefene) in the nalmefene hydrochloride injection cannot exceed 1.0 percent, and the total content of other impurities except the bisnalmefene cannot exceed 1.0 percent.
The prior art mainly has the following problems:
The nalmefene hydrochloride injection is easy to oxidize in the storage process, and the impurities of the bisnalmefene are generated, so that the effectiveness of the nalmefene hydrochloride injection is reduced, and the safety is influenced.
Therefore, it is necessary to find a preparation method which can reduce the content of impurities of the bisnalmefene produced in the storage process of the nalmefene hydrochloride injection and stabilize the active ingredients.
Disclosure of Invention
Aiming at the situation, in order to overcome the defects in the prior art, the invention provides a nalmefene hydrochloride injection pharmaceutical composition. In order to solve the problem that the nalmefene hydrochloride injection generates the impurities of the binamefene after long-term storage, the invention provides a method for adding the lipoic acid derivative into the phase injection, thereby realizing the reduction of the impurity content of the nalmefene hydrochloride injection and further realizing the technical effect of improving the quality of the product after long-term storage of the nalmefene hydrochloride injection.
In order to achieve the above purpose, the invention provides a nalmefene hydrochloride injection pharmaceutical composition, wherein every 1000 compositions comprise the following components in parts by weight: 0.1 to 1.0 part of nalmefene hydrochloride (calculated by nalmefene), 6 to 9 parts of sodium chloride and 0.04 to 0.1 part of lipoic acid derivative, wherein the concentration of the injection of the nalmefene hydrochloride (calculated by nalmefene) is 0.1mg/mL, 0.5mg/mL or 1mg/mL, and the dosage of the injection water is limited according to the concentration.
Preferably, the lipoic acid derivative is a compound obtained by reacting 6-gingerol with lipoic acid.
Preferably, the preparation method of the lipoic acid derivative specifically comprises the following steps:
(1) Dissolving 6-gingerol, potassium carbonate and DMC (dimethyl phosphate) in DMSO (dimethyl sulfoxide), stirring for reaction, cooling, adding water, stirring, extracting, cleaning with solution, and recrystallizing to obtain 6-gingerol intermediate;
(2) Dissolving lipoic acid, SOCl 2 and 4-Dimethylaminopyridine (DMAP) in CH 2Cl2, stirring and reacting to generate lipoyl chloride;
(3) Dissolving the obtained lipoyl chloride, the 6-gingerol intermediate and Tetrahydrofuran (THF) in CH 2Cl2, and stirring to generate lipoic acid intermediate;
(4) Dissolving the lipoic acid intermediate in CH 2Cl2, dripping BBr 3, stirring, reacting, adding water, extracting a water layer, drying by using anhydrous Na 2SO4, and purifying to obtain the lipoic acid derivative.
Preferably, in the step (1), the molar ratio of 6-gingerol to potassium carbonate is 1:4, the molar ratio of potassium carbonate to DMC is 1:1, the molar ratio of DMSO to 6-Jiang Fenma is 5:1, the reaction temperature is 150 ℃, the reaction time is 16 hours, water is added and stirred for 0.5 hour, dichloromethane is adopted for extraction, the volume ratio of dichloromethane to DMSO is 3:1, naOH solution with the concentration of 1mol/L is adopted for cleaning, and the volume ratio of NaOH solution to dichloromethane is 1:5;
Preferably, in the step (2), the volume ratio of SOCl 2 to CH 2Cl2 is 1:10, the mole ratio of SOCl 2 to lipoic acid is 1:1, the mole ratio of SOCl 2 to 4-dimethylaminopyridine is 1:2, the concentration of 4-dimethylaminopyridine is 5mol/L, the reaction temperature is-10 ℃, the reaction time is 3 hours, and the yield is 84%;
Preferably, in the step (3), the molar ratio of the lipoyl chloride to the 6-gingerol intermediate is 1:1, the volume ratio of the lipoyl chloride to the CH 2Cl2 is 1:6, the stirring time is 48 hours, the lipoic acid derivative is yellow oily matter, and the yield is 58%;
Preferably, in the step (4), the volume ratio of the lipoic acid intermediate to the CH 2Cl2 is 1:4, the reaction is stirred for 4 hours in an ice-water bath at the temperature of 0 ℃, water is added at the temperature of 0 ℃, the volume ratio of water to the CH 2Cl2 is 1:3, and the mixture is extracted for 3 times by using the chlorous acid.
The invention also provides a preparation method of the nalmefene hydrochloride injection pharmaceutical composition, which specifically comprises the following steps:
S1, adding water for injection into a liquid preparation tank, sequentially adding sodium chloride and lipoic acid derivatives according to parts by weight, stirring to dissolve, adjusting pH with hydrochloric acid solution, adding nalmefene hydrochloride, and stirring to dissolve;
S2, adding active carbon, preserving heat, stirring, adsorbing, rough filtering and decarbonizing;
s3, sterilizing and filtering by using a sterilizing filter;
s4, adding water for injection to the full amount, finely filtering the obtained solution, filling the solution into an ampoule bottle, and sealing;
S5, sterilizing to obtain the nalmefene hydrochloride injection pharmaceutical composition;
preferably, in S1, the ratio of the adding amount of the water for injection to the volume of the injection is 3:5, and the pH is regulated to 3.9 by adopting a hydrochloric acid solution with the concentration of 0.5 mol/L;
Preferably, in S2, the mass-volume ratio of the activated carbon to the water for injection is 1:6, the activated carbon is activated for 2 hours at 120 ℃, the heat preservation temperature is 80 ℃, and the time is 0.5 hour;
Preferably, in S3, the cartridge of the sterilizing filter is 0.22 μmpes;
Preferably, in S5, sterilization is performed at 121 ℃ for 15min.
The beneficial effects obtained by the invention are as follows:
(1) After the nalmefene hydrochloride injection prepared by the invention is stored for a long time, the content of impurities in the nalmefene hydrochloride is low, the nalmefene hydrochloride meets the national drug standard specification, the content of the main ingredient nalmefene hydrochloride is high, the stability of the product is enhanced, and the quality of the product is obviously improved;
(2) The lipoic acid derivative prepared by the invention reserves a disulfide five-membered ring and a phenolic hydroxyl group on 6-gingerol, and the unpaired single electron of an oxygen atom on the phenolic hydroxyl group can generate a conjugation effect with pi electron cloud on a benzene ring, so that the energy of free radicals is reduced, and an antioxidation effect is achieved; the disulfide five-membered ring has stronger electron affinity, can react with oxygen atoms, reduces the content of free radicals, plays an antioxidant role, reduces the generation of the impurities of the diclofenac in the nalmefene hydrochloride injection, and ensures that the nalmefene hydrochloride injection is kept stable in the long-time storage process;
(3) According to the invention, chelating agents such as disodium ethylenediamine tetraacetate are not added, so that adverse effects caused by the chelating agents are reduced.
Drawings
FIG. 1 is a flow chart of a lipoic acid derivative synthesis process;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the attached tables in the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments; all other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present application. The preferred methods and materials described herein are illustrative only and should not be construed as limiting the application.
The experimental methods in the following examples are all conventional methods unless otherwise specified; the test materials used in the examples described below, unless otherwise specified, were purchased from commercial sources.
The sources of the materials used in the invention are as follows:
nalmefene hydrochloride CasNo:58895-64-0, available from Shanghai Milin Biochemical technology Co., ltd., product number N855700-250 mg;
sodium chloride CasNo:7647-14-5, commercially available from Beijing enokie technologies Co., ltd., product number A63214;
Sodium hydroxide CasNo:1310-73-2, available from Beijing Inocai technologies Co., ltd., product number A53741;
6-gingerol CasNo:23513-14-6, available from Shanghai Michelia Biochemical technology Co., ltd., product number G810517-20mg;
4-Dimethylaminopyridine (DMAP) CasNo:1122-58-3, commercially available from Beijing enokikai technologies Co., ltd., product number A11182;
DMCCasNo:108481-44-3, available from Shanghai Michlin Biochemical technologies Co., ltd., product number D874750-50mg;
DMSOCasNo:67-68-5, available from Beijing Inocai technologies Co., ltd., product number D3851;
BBr 3 CasNo:10294-33-4, available from Beijing Inoca technologies Co., ltd., product number A26365;
Anhydrous Na 2SO4 CasNo:7757-82-6, available from Beijing Inocover technologies Inc., cat# A19940;
Dichloromethane CasNo:75-09-2, available from Beijing Inocai technologies Co., ltd., product number G00001;
SOCl 2 CasNo:7719-09-7, available from Beijing InocKai technologies Co., ltd., product number A04564;
CH 2Cl2 CasNo:75-09-2, available from Beijing Inocover technologies, inc., cat# G00001;
lipoic acid CasNo:62-46-4, available from Shanghai Michlin Biochemical technology Co., ltd., product No. A800612-20mg;
Tetrahydrofuran (THF) CasNo:109-99-9, available from Beijing Inocover technologies Inc., cat# G00007;
Potassium carbonate CasNo:584-08-7, commercially available from Beijing Inoca technologies Co., ltd., product number A67982;
Water for injection CasNo:7732-18-5, available from Shanghai Milin Biochemical technology Co., ltd., product number W915679-100ml;
The chlorine is purchased from Shanghai Biyun biotechnology limited company, cat# 429021000;
hydrochloric acid CasNo:7647-01-0, available from Shanghai Micin Biochemical technology Co., ltd., product number A18256;
activated carbon CasNo:7440-44-0, available from Beijing enokie technologies Co., ltd., product number I11113;
0.22 mu mPESCasNo:24937-78-8, available from Shanghai Biyun biotechnology Co., ltd., product number FVF021-1pc.
The preparation methods of the nalmefene hydrochloride injection pharmaceutical compositions of the embodiments 1-12 and the comparative examples 1-2 are the same, and specifically comprise the following steps:
S1, adding water for injection into a liquid preparation tank, wherein the volume ratio of the water for injection to the injection is 3:5, sequentially adding sodium chloride and lipoic acid derivatives according to parts by weight, stirring to dissolve the sodium chloride and lipoic acid derivatives, adopting hydrochloric acid solution with the concentration of 0.5mol/L to adjust the pH value to 3.9, adding nalmefene hydrochloride, and stirring to dissolve the nalmefene hydrochloride;
s2, adding active carbon, wherein the mass-volume ratio of the active carbon to the water for injection is 1:6, activating for 2 hours at 120 ℃, preserving heat for 0.5 hour at 80 ℃, stirring, adsorbing, rough filtering and decarbonizing;
S3, performing sterilization filtration by using a 0.22 mu mPES sterilization filter;
s4, adding water for injection to the full amount, finely filtering the obtained solution, filling the solution into an ampoule bottle, and sealing;
s5, sterilizing for 15min at 121 ℃ to obtain the nalmefene hydrochloride injection pharmaceutical composition;
Example 1
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
Nalmefene hydrochloride (calculated as nalmefene) 0.1 parts, sodium chloride 6 parts, lipoic acid derivative 0.04 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:10.
The preparation method of the lipoic acid derivative specifically comprises the following steps:
1. Dissolving 6-gingerol, potassium carbonate and DMC (dimethyl phosphate) in DMSO (dimethyl sulfoxide), wherein the molar ratio of the 6-gingerol to the potassium carbonate is 1:4, the molar ratio of the potassium carbonate to the DMC is 1:1, the molar ratio of the DMSO to the 6-Jiang Fenma is 5:1, stirring, reacting for 16 hours at 150 ℃, cooling, adding water, stirring for 0.5 hour, extracting by using methylene dichloride, the volume ratio of the methylene dichloride to the DMSO is 3:1, cleaning by using NaOH solution with the concentration of 1mol/L, the volume ratio of the NaOH solution to the methylene dichloride is 1:5, and recrystallizing to obtain a 6-gingerol intermediate;
2. Dissolving lipoic acid, SOCl 2 and 4-Dimethylaminopyridine (DMAP) in CH 2Cl2, wherein the volume ratio of SOCl 2 to CH 2Cl2 is 1:10, the mole ratio of SOCl 2 to lipoic acid is 1:1, the mole ratio of SOCl 2 to 4-dimethylaminopyridine is 1:2, the concentration of 4-dimethylaminopyridine is 5mol/L, stirring, and reacting for 3 hours at the temperature of minus 10 ℃ to generate lipoyl chloride;
3. Dissolving the obtained lipoyl chloride, the 6-gingerol intermediate and Tetrahydrofuran (THF) in CH 2Cl2, wherein the mol ratio of the lipoyl chloride to the 6-gingerol intermediate is 1:1, the volume ratio of the lipoyl chloride to the CH 2Cl2 is 1:6, and stirring for 48 hours to generate a lipoic acid intermediate;
4. Dissolving lipoic acid intermediate in CH 2Cl2, dropwise adding BBr 3, stirring, reacting in ice-water bath at 0deg.C for 4h, adding water at 0deg.C, extracting water layer with chlorine for 3 times, drying with anhydrous Na 2SO4, and purifying to obtain lipoic acid derivative.
Example 2
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
Nalmefene hydrochloride (calculated as nalmefene) 0.1 parts, sodium chloride 9 parts, lipoic acid derivative 0.04 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:10.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 3
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
Nalmefene hydrochloride (calculated as nalmefene) 0.1 parts, sodium chloride 9 parts, lipoic acid derivative 0.07 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:10.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 4
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
Nalmefene hydrochloride (calculated as nalmefene) 0.1 parts, sodium chloride 9 parts, lipoic acid derivative 0.1 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:10.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 5
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
nalmefene hydrochloride (calculated as nalmefene) 0.5 parts, sodium chloride 6 parts, lipoic acid derivative 0.04 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:2.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 6
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
nalmefene hydrochloride (calculated as nalmefene) 0.5 parts, sodium chloride 9 parts, lipoic acid derivative 0.04 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:2.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 7
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
Nalmefene hydrochloride (calculated as nalmefene) 0.5 parts, sodium chloride 9 parts, lipoic acid derivative 0.07 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:2.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 8
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
Nalmefene hydrochloride (calculated as nalmefene) 0.5 parts, sodium chloride 9 parts, lipoic acid derivative 0.1 parts, nalmefene hydrochloride (calculated as nalmefene) injection concentration (mg/mL) 1:2.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 9
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
1.0 part of nalmefene hydrochloride (calculated as nalmefene), 6 parts of sodium chloride, 0.04 part of lipoic acid derivative and the concentration (mg/mL) of the injection of nalmefene hydrochloride (calculated as nalmefene) is 1:1.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 10
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
1.0 part of nalmefene hydrochloride (calculated as nalmefene), 9 parts of sodium chloride, 0.04 part of lipoic acid derivative and the concentration (mg/mL) of the injection of nalmefene hydrochloride (calculated as nalmefene) is 1:1.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 11
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
1.0 part of nalmefene hydrochloride (calculated as nalmefene), 9 parts of sodium chloride, 0.07 part of lipoic acid derivative and the concentration (mg/mL) of the injection of nalmefene hydrochloride (calculated as nalmefene) is 1:1.
The lipoic acid derivative was prepared in the same manner as in example 1.
Example 12
The nalmefene hydrochloride injection medicine composition specifically comprises the following components:
1.0 part of nalmefene hydrochloride (calculated as nalmefene), 9 parts of sodium chloride, 0.1 part of lipoic acid derivative and the concentration (mg/mL) of the injection of nalmefene hydrochloride (calculated as nalmefene) is 1:1.
The lipoic acid derivative was prepared in the same manner as in example 1.
Comparative example 1
The comparative example provides a nalmefene hydrochloride injection pharmaceutical composition, which comprises the following components in parts by weight:
6.0 parts of sodium chloride, pH3.9, 0.1 part of nalmefene hydrochloride and the concentration (mg/mL) of the injection of nalmefene hydrochloride (calculated as nalmefene) are 1:10.
Comparative example 2
The comparative example provides a nalmefene hydrochloride injection pharmaceutical composition, which comprises the following components in parts by weight:
9.0 parts of sodium chloride, pH3.9, 0.1 part of nalmefene hydrochloride, and the concentration (mg/mL) of the injection of nalmefene hydrochloride (calculated by nalmefene) is 1:10;
table 2 shows the results of the components of examples 1-12 and comparative examples 1-2 of the present invention;
TABLE 2
The experimental methods in the following examples are conventional methods unless otherwise specified.
1. Accelerated experiments at 40 DEG C
Samples prepared in examples 1-12 and comparative examples 1-2 were taken, placed in an environment at 40℃and sampled and tested after 6 months of standing.
Table 3 shows the results of 40℃acceleration experiments for examples 1-12 and comparative examples 1-2 of the present invention;
TABLE 3 Table 3
2. Normal temperature placing experiment
Samples prepared in examples 1-12 and comparative examples 1-2 were taken, placed in an environment at 20℃and sampled and tested after 24 months of standing.
Table 4 shows the results of the room temperature standing experiments of examples 1 to 12 and comparative examples 1 to 2 of the present invention;
TABLE 4 Table 4
3. High temperature experiments
Samples prepared in examples 1 to 12 and comparative examples 1 to 2 were taken, placed in a constant temperature oven at a temperature of 60℃for 10 days, and sampled and examined on days 0, 5 and 10, respectively.
4. Experiment of intense light irradiation
Samples prepared in examples 1-12 and comparative examples 1-2 were taken and sampled and tested after 10 days of illumination in an adjustable illumination box with an illumination of 4500 lx.
Table 5 shows the results of the high temperature experiments and the strong light irradiation experiments of examples 1 to 12 and comparative examples 1 to 2 of the present invention;
TABLE 5
Analysis of results:
Table 3 shows the results of the accelerated experiments of nalmefene hydrochloride injections prepared in examples 1-12 and comparative examples 1-2 at 40deg.C, wherein the solutions of the samples in examples 1-12 are colorless after being placed at 40deg.C for 6 months, the pH value and nalmefene hydrochloride content are not changed significantly, and the content of related substances is increased; after the samples of comparative examples 1-2 were left for 6 months under the same conditions, the color of the solution was colorless, the pH value of the solution was greatly changed, the content of the related substances was increased, and the samples of examples 1-12 were significantly superfluous.
Table 4 shows the results of the experiment of the nalmefene hydrochloride injection prepared in examples 1-12 and comparative examples 1-2 at normal temperature, as shown in the figure, the solutions of the samples in examples 1-12 are colorless, the pH value is stable, the nalmefene hydrochloride content is maintained above 90%, the content of related substances is increased, and the content of related substances is less than the national drug standard specification and meets the requirements; after comparative examples 1-2 were left for 24 months under the same conditions, the sample solution was pale yellow, the pH value was greatly changed, the content of the related substances was significantly increased, which was far greater than that of examples 1-12 under the same conditions, and the content of the bisnalmefene was greater than 1.0%, which was not in compliance with the national pharmaceutical standards.
Table 5 shows the results of high temperature experiments and strong light irradiation experiments of nalmefene hydrochloride injection prepared in examples 1-12 and comparative examples 1-2, as shown in the figures, after the nalmefene hydrochloride injection is placed for 10 days at a high temperature of 60 ℃ and under light of 4500lx, the solution properties, pH values, contents and related substances of the samples in examples 1-12 are not obviously changed; the samples of comparative examples 1-2 were allowed to stand at a high temperature of 60℃for 10 days, the pH value was changed, the solution was colorless, the content of the relevant substances was increased, and the solution was colorless under the condition of 4500lx of light, the pH value and the content of the relevant substances were remarkably increased.
The experimental results show that the quality of the samples of the embodiments 1-12 of the invention is obviously better than that of the samples of the comparative examples 1-2, and the lipoic acid derivatives can effectively prevent the generation of impurities such as the bisnalmefene; as can be seen from example 1, comparative example 1 and comparative example 2, the lipoic acid derivative has good antioxidation, the lipoic acid derivative retains the disulfide five-membered ring and the phenolic hydroxyl group on the 6-gingerol, the unpaired single electron of the oxygen atom on the phenolic hydroxyl group can generate conjugation effect with pi electron cloud on the benzene ring, the electron density of the pi electron cloud can be improved, the paired electrons are not fixed on the oxygen atom, but are distributed on the benzene ring partially, the energy of free radical is reduced, and the antioxidation is achieved; the disulfide five-membered ring has stronger electron affinity, can react with oxygen atoms, reduces the content of free radicals, plays an antioxidant role, and the lipoic acid derivative can effectively reduce the generation of the impurities of the nalmefene in the nalmefene hydrochloride injection, while the increase of the content of sodium chloride can not reduce the generation of the impurities of the nalmefene hydrochloride.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
The invention and its embodiments have been described above with no limitation, and the invention is illustrated in the figures of the accompanying drawings as one of its embodiments, without limitation in practice. In summary, those skilled in the art, having benefit of this disclosure, will appreciate that the invention can be practiced without the specific details disclosed herein.
Claims (9)
1. The nalmefene hydrochloride injection pharmaceutical composition is characterized in that: every 1000 compositions comprise the following components in parts by weight: 0.1-1.0 part of nalmefene hydrochloride, 6-9 parts of sodium chloride and 0.04-0.1 part of lipoic acid derivative, wherein the lipoic acid derivative is a compound obtained by reacting 6-gingerol with lipoic acid;
the preparation method of the lipoic acid derivative specifically comprises the following steps:
(1) Dissolving 6-gingerol, potassium carbonate and DMC in DMSO, stirring for reaction, cooling, adding water for stirring, extracting, adopting solution for cleaning, and recrystallizing to obtain a 6-gingerol intermediate;
(2) Dissolving lipoic acid, SOCl 2 and 4-dimethylaminopyridine in CH 2Cl2, stirring and reacting to generate lipoyl chloride;
(3) Dissolving the obtained lipoyl chloride, the 6-gingerol intermediate and tetrahydrofuran in CH 2Cl2, and stirring to generate lipoic acid intermediate;
(4) Dissolving the lipoic acid intermediate in CH 2Cl2, dripping BBr 3, stirring, reacting, adding water, extracting a water layer, drying by using anhydrous Na 2SO4, and purifying to obtain the lipoic acid derivative.
2. The nalmefene hydrochloride injection pharmaceutical composition according to claim 1, characterized in that: the mass concentration of the nalmefene hydrochloride injection calculated by nalmefene is 0.1mg/mL, 0.5mg/mL or 1mg/mL.
3. The nalmefene hydrochloride injection pharmaceutical composition according to claim 2, characterized in that: in the step (1), the molar ratio of 6-gingerol to potassium carbonate is 1:4, the molar ratio of potassium carbonate to DMC is 1:1, the molar ratio of DMSO to 6-Jiang Fenma is 5:1, the reaction temperature is 150 ℃, the reaction time is 16 hours, water is added and stirred for 0.5 hour, dichloromethane is adopted for extraction, the volume ratio of dichloromethane to DMSO is 3:1, naOH solution with the concentration of 1mol/L is adopted for cleaning, and the volume ratio of NaOH solution to dichloromethane is 1:5.
4. A nalmefene hydrochloride injectable pharmaceutical composition according to claim 3, characterized in that: in the step (2), the volume ratio of SOCl 2 to CH 2Cl2 is 1:10, the mole ratio of SOCl 2 to lipoic acid is 1:1, the mole ratio of SOCl 2 to 4-dimethylaminopyridine is 1:2, the concentration of 4-dimethylaminopyridine is 5mol/L, the reaction temperature is-10 ℃, and the reaction time is 3 hours.
5. The nalmefene hydrochloride injection pharmaceutical composition according to claim 4, wherein: in the step (3), the mol ratio of the lipoyl chloride to the 6-gingerol intermediate is 1:1, the volume ratio of the lipoyl chloride to the CH 2Cl2 is 1:6, and the stirring time is 48 hours.
6. The nalmefene hydrochloride injection pharmaceutical composition according to claim 5, wherein: in the step (4), the volume ratio of the lipoic acid intermediate to CH 2Cl2 is 1:4, the reaction condition is that the lipoic acid intermediate and CH 2Cl2 are in an ice-water bath at 0 ℃, the reaction is stirred for 4 hours, water is added at 0 ℃, the volume ratio of the water to CH 2Cl2 is 1:3, and the lipoic acid intermediate and CH 2Cl2 are extracted for 3 times by using the chlorine.
7. The method for preparing the nalmefene hydrochloride injection pharmaceutical composition according to any one of claims 1-6, wherein the method comprises the following steps: the method specifically comprises the following steps:
S1, adding water for injection into a liquid preparation tank, sequentially adding sodium chloride and lipoic acid derivatives according to parts by weight, stirring to dissolve, adjusting pH with hydrochloric acid solution, adding nalmefene hydrochloride, and stirring to dissolve;
S2, adding active carbon, preserving heat, stirring, adsorbing, rough filtering and decarbonizing;
s3, sterilizing and filtering by using a sterilizing filter;
s4, adding water for injection to the full amount, finely filtering the obtained solution, filling the solution into an ampoule bottle, and sealing;
s5, sterilizing to obtain the nalmefene hydrochloride injection pharmaceutical composition.
8. The method for preparing the nalmefene hydrochloride injection pharmaceutical composition according to claim 7, which is characterized in that: in S1, the ratio of the adding amount of water for injection to the volume of injection is 3:5, and the pH is regulated to 3.9 by adopting hydrochloric acid solution with the concentration of 0.5 mol/L; in S2, the mass-volume ratio of the activated carbon to the water for injection is 1:6, the activated carbon is activated for 2 hours at 120 ℃, the heat preservation temperature is 80 ℃, and the time is 0.5 hour.
9. The method for preparing the nalmefene hydrochloride injection pharmaceutical composition according to claim 8, which is characterized in that: in S3, the filter element of the sterilizing filter is 0.22 mu mPES; in S5, the mixture is sterilized at 121℃for 15min.
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| CN101406474A (en) * | 2008-02-28 | 2009-04-15 | 云南绿野生物医药有限公司 | Nalmefene 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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| 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 |
| CN106727293A (en) * | 2016-12-12 | 2017-05-31 | 河南润弘制药股份有限公司 | A kind of Nalmefene hydrochloride injection and preparation method thereof |
| US20210401827A1 (en) * | 2018-11-07 | 2021-12-30 | Opiant Pharmaceuticals, Inc. | Methods, parenteral pharmaceutical formulations, and devices for the prevention of opioid overdose |
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| CN101406474A (en) * | 2008-02-28 | 2009-04-15 | 云南绿野生物医药有限公司 | Nalmefene 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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