CN1895251A - Stabilized nalmefene hydrochloride injection and its preparation - Google Patents
Stabilized nalmefene hydrochloride injection and its preparation Download PDFInfo
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- CN1895251A CN1895251A CN 200510083046 CN200510083046A CN1895251A CN 1895251 A CN1895251 A CN 1895251A CN 200510083046 CN200510083046 CN 200510083046 CN 200510083046 A CN200510083046 A CN 200510083046A CN 1895251 A CN1895251 A CN 1895251A
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- injection
- acid
- nalmefene hydrochloride
- sodium chloride
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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 40
- 229960000677 nalmefene hydrochloride Drugs 0.000 title claims abstract description 40
- 238000002347 injection Methods 0.000 title claims abstract description 34
- 239000007924 injection Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 40
- 239000011780 sodium chloride Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 6
- 239000008103 glucose Substances 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims abstract description 6
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims abstract description 3
- 229920002307 Dextran Polymers 0.000 claims abstract description 3
- 239000000600 sorbitol Substances 0.000 claims abstract description 3
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 235000010265 sodium sulphite Nutrition 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 9
- 229940087511 calcium disodium versenate Drugs 0.000 claims description 9
- 238000005516 engineering process Methods 0.000 claims description 9
- 230000001954 sterilising effect Effects 0.000 claims description 9
- 238000012856 packing Methods 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 235000006708 antioxidants Nutrition 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 230000003204 osmotic effect Effects 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 235000019154 vitamin C Nutrition 0.000 claims description 2
- 239000011718 vitamin C Substances 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 abstract 1
- 239000001116 FEMA 4028 Substances 0.000 abstract 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 abstract 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 abstract 1
- 229960004853 betadex Drugs 0.000 abstract 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 abstract 1
- -1 pectose Chemical compound 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 29
- 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 description 20
- 229960005297 nalmefene Drugs 0.000 description 19
- 239000007788 liquid Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 239000003708 ampul Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 7
- 229960004127 naloxone Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229960003086 naltrexone Drugs 0.000 description 5
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 5
- 239000011521 glass Substances 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 208000007848 Alcoholism Diseases 0.000 description 3
- 150000001875 compounds Chemical group 0.000 description 3
- 239000003401 opiate antagonist Substances 0.000 description 3
- 229940124636 opioid drug Drugs 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000030990 Impulse-control disease Diseases 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000026331 Disruptive, Impulse Control, and Conduct disease Diseases 0.000 description 1
- 208000001613 Gambling Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 206010034158 Pathological gambling Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000005267 amalgamation Methods 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- UDELQFFXWHYONT-UHFFFAOYSA-L disodium hydrogen sulfite chloride Chemical compound [Na+].[Na+].[Cl-].OS([O-])=O UDELQFFXWHYONT-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 229940024844 naloxone injection Drugs 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229940116238 revex Drugs 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- VWHAEAMVKOWNBA-UHFFFAOYSA-N sulfur dioxide sulfurous acid Chemical compound O=S=O.OS(O)=O VWHAEAMVKOWNBA-UHFFFAOYSA-N 0.000 description 1
- 235000010269 sulphur dioxide Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
Abstract
A high-stability nalmefene hydrochloride injection is prepared from nalmefene hydrochloride (0.005-0.2 W/v %) and the medicinal carrier chosen from sodium chloride, glucose, beta-cyclodextrin, dextran, pectose, sorbitol, etc. Its preparing process is also disclosed.
Description
Technical field:
The present invention relates to a kind of Nalmefene injection and preparation method thereof, belong to technical field of medicaments.
Technical background:
Nalmefene hydrochloride is in the process of last century the seventies further investigation naloxone and naltrexone, transforming and optimizing on the basis of parent compound structure, at the deficiency that existing opiate receptor antagonist exists, the new compound of designing and developing.Nalmefene hydrochloride has kept the characteristics of naloxone, naltrexone pure antagonist fully, opiate receptor is not had agonism, and does not produce dependency.Compare with naloxone, naltrexone and to have a long action time, oral administration biaavailability height, dosage little, advantages such as safety range is wide, therefore, nalmefene hydrochloride has characteristics of high efficiency and low toxicity, becomes the kind that development potentiality is arranged in the opiate receptor antagonist of new generation most.
As opiate receptor antagonist of new generation, nalmefene hydrochloride in April nineteen ninety-five at U.S.'s official listing.Nalmefene hydrochloride is the effect that can be used for all or part of upset opioid drug through the indication of FDA approval, comprises the respiration inhibition effect that natural and synthetic opioid drug causes.And opioid drug that can be used for making a definite diagnosis or doubtful is excessive.
March calendar year 2001, the U.S. caused the market short supply of naloxone injection because of output reduces, and FDA special authorization Canada Sabex company promptly supplies to separate the matter of great urgency, and simultaneously, United States Hospital pharmacist community (ASHP) recommends nalmefene to substitute the naloxone of shortage to society.This shows that nalmefene is the very ideal succedaneum of naloxone.
Nalmefene is the same with naloxone, all belongs to the opiate receptor pure antagonist, in the presence of no opioid, does not produce other any side effect, belongs to the higher kind of safety in chemical medicine.Compare with naloxone, the alternative route of administration of nalmefene is more extensively and more convenient.The oral solid formulation of nalmefene is more suitable for the treatment of non-emergency case.The ContrAlPharma of Finland (with the BioTie company amalgamation) company is in January, 2002, begin the three phases clinical research of nalmefene sheet simultaneously in Finland and Britain, the new indication of exploitation is the treatment of chronic alcoholism and alcohol dependence, estimates that the second quarter in 2003 can get PRELIMINARY RESULTS.The alleviating alcohol addiction effect of early stage clinical trial proof nalmefene is better than naltrexone, especially is fit to have the alcoholic of family history, and does not see the liver toxicity side effect that naltrexone occurs when heavy dose.It is clinical that the treatment that nalmefene is used for impulse control disorder (Impulse controldisorders) has entered the second phase in the U.S., and study subject is the pathological gambling patient, the first half of the year in 2003 is expected to obtain PRELIMINARY RESULTS.Nalmefene also has the quick withdrawal of opium dependent patient at the indication of test among a small circle.
In the process of the 0.1mol/L of nalmefene hydrochloride sodium hydroxide solution and hydrogen peroxide failure test, influence factor's test and stability study, it is the chromatographic peak that relative retention time is about 2 times of principal agents that the catabolite of finding Nalmefene hydrochloride injection has over half, according to the result of study of LC-MS as can be known this degradation material be the promptly two nalmefene of dimer of nalmefene.Commodity Revex by name among the FDA
The Nalmefene hydrochloride injection prescription information, except that active medicine, only added pH regulator agent hydrochloric acid and isoosmotic adjusting agent sodium chloride in the prescription, produce to adopt and to fill nitrogen technology.
Application number is 200410022782.5 the denomination of invention Chinese patent for " Nalmefene powder injection preparation and preparation method thereof ", has described a kind of Nalmefene powder injection, and said preparation is to be crude drug with the nalmefene, is filler with mannitol, and lyophilizing forms.Though freeze-dried powder can improve stability of formulation, but the freeze-drying process surplus in the of 30 hour has improved production cost greatly, and nalmefene is mainly used in first aid, and injectable powder can use also need add the dissolving of injection water in clinical use after, makes clinical use more loaded down with trivial details.
The present invention uses suitable additives, the Nalmefene hydrochloride injection steady quality of producing, strong illumination and high temperature were placed back 10 days and 6 months every indexs of injection appearance character, pH value, content and related substance of accelerated test have no significant change, and production process is easy to control.
Summary of the invention:
The object of the invention is to provide a kind of evident in efficacy and stay-in-grade Nalmefene injection and preparation method thereof, and Nalmefene injection provided by the invention can improve stability of drug, makes it safer and more effective.Can solve the problem that prior art exists.
Nalmefene hydrochloride injection of the present invention is made up of nalmefene hydrochloride for the treatment of effective dose and an amount of pharmaceutical carrier basically.
Nalmefene hydrochloride injection of the present invention, wherein the concentration of nalmefene hydrochloride in weight/volume, can be 0.001%～2.0%, is preferably 0.005%～1.0%, more preferably 0.01%～0.1%.
Nalmefene hydrochloride injection of the present invention, the pharmaceutical carrier that is contained is not particularly limited, so long as the carrier that can be used in the injection preparation is just passable, for example osmotic pressure regulator can be selected from one or more in sodium chloride, glucose, beta-schardinger dextrin-, dextran, fructose, the sorbitol etc., is preferably sodium chloride and/or glucose.The PH regulator can be selected from hydrochloric acid, acetic acid, phosphoric acid, malic acid, citric acid, maleic acid, succinic acid etc., is preferably hydrochloric acid.Antioxidant can be selected from sulfurous acid, sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin C, cysteine etc., is preferably sodium sulfite.Stabilizing agent (chelating agen) is preferably Calcium Disodium Versenate.The content of pharmaceutical carrier in preparation also is not particularly limited, and can at random use pharmaceutical carrier in the scope of harmless effect of the present invention.
Because injection normally is divided in the easy cut ampule, with the unit dosage form administration, therefore Nalmefene hydrochloride injection of the present invention, per unit dosage, promptly containing nalmefene hydrochloride in every injection can be 0.1mg～4mg; Pharmaceutical carrier for example sodium chloride can be 4.5mg～90mg, and perhaps glucose can be 25mg～400mg; Sodium sulfite can be 0.005mg～0.5mg; Calcium Disodium Versenate can be 0.001mg～0.5mg; Hydrochloric acid or acetic acid are an amount of, and the pH value of regulating the preceding solution of this product packing is 3.5～5.5.
Nalmefene hydrochloride injection of the present invention contains sodium chloride in the preparation of per unit dosage, is preferably 7mg～60mg, more preferably, contains sodium chloride 9mg～36mg in the preparation of per unit dosage; Containing sodium sulfite in the preparation of per unit dosage and preferably can be 0.01mg～0.1mg, more preferably is 0.02mg～0.05mg; Containing Calcium Disodium Versenate in the preparation of per unit dosage and be preferably 0.002mg～0.25mg, optimally is 0.004mg～0.1mg.
Nalmefene hydrochloride injection of the present invention, pH value is 3.5～5.5, is preferably 4.0～5.0.
Nalmefene hydrochloride injection sterilising conditions of the present invention can be 105 ℃ of sterilization 45min or 115 ℃ of following pressure sterilizing 20min or 121 ℃ of following pressure sterilizing 15min.Be preferably 115 ℃ of following pressure sterilizing 20min.
Technical scheme of the present invention is achieved in that it adds injection water and an amount of antioxidant and stabilizing agent with nalmefene hydrochloride and makes.Specifically, by weight calculating: with 0.1～4g nalmefene, 0.0005～0.05% sodium sulfite, sodium sulfite or sulfur dioxide (sulfurous acid), 0.0001～0.05% Calcium Disodium Versenate, 0.9% sodium chloride adds sterile water for injection and is prepared to 2000ml.Described preparation is an injection; The preparation method of Nalmefene hydrochloride injection: adopt in the whole process of preparation and fill nitrogen technology.Get the water for injection that nalmefene hydrochloride adds full dose 60%, be stirred to dissolving fully; Sodium sulfite, sodium sulfite or sulfur dioxide and 0.0001～0.05% Calcium Disodium Versenate of adding 0.0005～0.05% stir and make dissolving, add the 1.0mol/L hydrochloric acid solution and regulate pH to 3.7～4.1; Other adds the active carbon through 115～120 ℃ of activation 2h of recipe quantity 0.05% (w/v), and at 80 ℃ of insulated and stirred absorption 30min, coarse filtration is taken off charcoal; Extremely clear and bright with the compound membrane filtration that 0.45 μ m and 0.22 μ m form, packing under 100 grades of environment of clean level.115 ℃ of following pressure sterilizing 20min.
Its clinical administration method of Nalmefene hydrochloride injection of the present invention is: intravenous injection or intramuscular injection.When being used for partial switching opioid effect after surgery, use accumulated dose to be no more than 1.0 μ g/kg body weight, the excessive treatment using dosage of opioid is no more than 20 μ g/kg body weight, and surpassing this dosage can not increase therapeutic effect.
Nalmefene hydrochloride injection reasonable recipe of the present invention, technology is simple, good stability.Factors influencing under high temperature, high humidity and strong illumination condition 10 days and 40 ℃ of accelerated tests 6 months, sample appearance character, pH, active constituent content and related substance etc. have no significant change.
The specific embodiment:
Further specify the present invention by the following examples, but these embodiment do not limit the present invention in any way.
Embodiment 1
Prescription:
Nalmefene hydrochloride 0.1g
Sodium chloride 9g
Hydrochloric acid is in right amount to pH3.6
Technology: 1) get 1000ml water for injection and put in the dosing cylinder, add the sodium chloride of prescription full dose, be stirred to dissolving; 2) nalmefene hydrochloride of adding recipe quantity is stirred to dissolving; The microporous filter membrane fine straining of reuse 0.22 μ m is to clear and bright; 3) embedding (fill 1ml liquid in the glass ampule of 2ml volume) in glass ampule; 4) sealing by fusing.5) 115 ℃ of sterilization 20min.5) gland is labelled, and packing gets product after the assay was approved.Sterilization back pH value: get 10 of this product, merge, measure (two appendix VIH of Chinese Pharmacopoeia version in 2000) in accordance with the law, pH value is 3.9.
Embodiment 2
Prescription:
Nalmefene hydrochloride 1g
Sodium chloride 9g
Hydrochloric acid is in right amount to pH3.8
Technology: with embodiment 1.Adopt the 2ml glass ampule to carry out packing, the packing volume is 2ml.
PH value: assay method is got 5 solution in the ampoule and is merged with embodiment 1, and the result who measures pH value is 3.9.
Embodiment 3
Prescription:
Nalmefene hydrochloride 1g
Sodium chloride 9g
Hydrochloric acid is in right amount to pH 3.8
Technology: with embodiment 1.Adopt the 5ml glass ampule to carry out packing, the packing volume is 4ml.
PH value: assay method is got 3 solution in the ampoule and is merged with embodiment 1, and the result who measures pH value is 3.9.
Embodiment 4
Prescription:
Nalmefene hydrochloride 0.1g
Sodium chloride 9g
Sodium sulfite 0.02g
Hydrochloric acid is in right amount to pH3.8
Technology: 1) get 1000ml water for injection and put in the dosing cylinder, add the sodium chloride and the sodium sulfite of prescription full dose, be stirred to dissolving; Other steps are with embodiment 1.
PH value: assay method is with embodiment 1, and pH value is 3.9.
Embodiment 5
Prescription:
Nalmefene hydrochloride 0.1g
Sodium chloride 9g
Sodium sulfite 0.02g
Calcium Disodium Versenate 0.005g
Hydrochloric acid is in right amount to pH3.8
Technology: 1) get 1000ml water for injection and put in the dosing cylinder, add the prescription full dose sodium chloride sodium sulfite and Calcium Disodium Versenate, be stirred to dissolving; Other steps are with embodiment 1.
PH value: assay method is with embodiment 1, and pH value is 3.9.
To the injection of embodiment 5 preparation carry out that the influence factor tested 10 days and 40 ℃ ± 2 ℃ conditions under accelerated test 6 months, influence factor's test the results are shown in Table 1, accelerated test the results are shown in Table 2:
The measurement result of table 1 Nalmefene hydrochloride injection influence factor after 5,10 days
| Time (my god) | The placement condition | The investigation project | ||||
| Appearance character | Clarity | PH value | Content (%) | Assorted peak area (%) | ||
| 0 | - | Colourless clear liquid | Qualified | 3.9 | 100.0 | 0.25 |
| 5 days | High light | Colourless clear liquid | Qualified | 3.9 | 99.3 | 0.36 |
| High temperature | Colourless clear liquid | Qualified | 3.9 | 98.7 | 0.32 | |
| 10 days | High light | Colourless clear liquid | Qualified | 3.9 | 98.6 | 0.41 |
| High temperature | Colourless clear liquid | Qualified | 3.9 | 98.1 | 0.38 | |
Strong illumination, hot conditions are transferred postpone appearance character no change, still keep colourless clear liquid.PH value no change after the illumination.The amount of content and related substance is no change almost also.The prescription of determining embodiment 5 is all more stable to high light and high temperature.
Accelerated test result under 40 ℃ ± 2 ℃ conditions of table 2 Nalmefene hydrochloride injection
| Time/moon | Outward appearance, character | Clarity | PH value | Content/% | Related substance/% |
| 0 | Colourless clear liquid | Qualified | 3.9 | 99.1 | 0.32 |
| 1 | Colourless clear liquid | Qualified | 3.9 | 98.9 | 0.34 |
| 2 | Colourless clear liquid | Qualified | 3.9 | 98.9 | 0.28 |
| 3 | Colourless clear liquid | Qualified | 3.9 | 98.6 | 0.40 |
| 6 | Colourless clear liquid | Qualified | 3.9 | 98.3 | 0.46 |
Sample result of 6 months of accelerated test under 40 ℃ ± 2 ℃ conditions shows that its related substances does not have significant change, and all less than 2.0%, the content of nalmefene hydrochloride and pH value are stable, and aseptic, endotoxin and clarity test result are also up to specification.Integrate, the high spot reviews project all meets the quality standard regulation.
Claims (10)
1. a Nalmefene hydrochloride injection is characterized in that containing nalmefene hydrochloride and pharmaceutical carrier.
2. according to the preparation of claim 1, wherein the concentration of nalmefene hydrochloride counts 0.001%～2.0% with concentration in the preparation, and pharmaceutical carrier comprises one or more in osmotic pressure regulator, pH regulator agent, antioxidant and the chelating agen.
3. according to the preparation of claim 2, wherein osmotic pressure regulator is selected from one or more in sodium chloride, glucose, beta-schardinger dextrin-, dextran, fructose, the sorbitol etc., is preferably sodium chloride or glucose, more preferably sodium chloride.
4. according to the preparation of claim 2, wherein the pH regulator agent is selected from hydrochloric acid, acetic acid, phosphoric acid, malic acid, citric acid, maleic acid, succinic acid etc., is preferably hydrochloric acid.
5. according to the preparation of claim 2, wherein antioxidant is sulfurous acid, sodium sulfite, sodium sulfite, sodium pyrosulfite, vitamin C, cysteine etc., is preferably sodium sulfite.
6. according to the preparation of claim 2, wherein chelating agen is preferably Calcium Disodium Versenate.Containing Calcium Disodium Versenate in the preparation of per unit dosage and be preferably 0.002mg～0.25mg, optimally is 0.004mg～0.1mg.
7. according to the preparation of claim 3, wherein every dosage unit amount of sodium chloride is preferably 7mg～60mg in 4.5mg～90mg scope, more preferably, contains sodium chloride 9mg～36mg in the preparation of per unit dosage.
8. according to the preparation of claim 4, wherein the consumption of hydrochloric acid is an amount of, and the solution pH value to the injection packing is 3.5～5.5, is preferably 4.0～5.0.
9. according to the preparation of claim 2, wherein the every dosage unit of the consumption of antioxidant sodium sulfite can be 0.005mg～0.5mg, is preferably 0.001mg～0.1mg, more preferably is 0.02mg～0.05mg.
10. the requirement according to claim 2 prepares injection, and preparation process is used and filled nitrogen technology; Sterilization process can be selected from 105 ℃ ± 2 ℃ 45min, 115 ℃ ± 2 ℃ 20min, or 120 ℃ ± 2 ℃ 15min, is preferably 115 ℃ ± 2 ℃ 20min.
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