CN103705448B - Pharmaceutical composition containing nalmefene hydrochloride for injection - Google Patents
Pharmaceutical composition containing nalmefene hydrochloride for injection Download PDFInfo
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- CN103705448B CN103705448B CN201310734116.3A CN201310734116A CN103705448B CN 103705448 B CN103705448 B CN 103705448B CN 201310734116 A CN201310734116 A CN 201310734116A CN 103705448 B CN103705448 B CN 103705448B
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- nalmefene
- hydrochloride
- water
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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 179
- 229960000677 nalmefene hydrochloride Drugs 0.000 title claims abstract description 179
- 238000002347 injection Methods 0.000 title claims abstract description 92
- 239000007924 injection Substances 0.000 title claims abstract description 92
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 174
- 239000000243 solution Substances 0.000 claims abstract description 116
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 110
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 95
- 239000011780 sodium chloride Substances 0.000 claims abstract description 85
- 239000002253 acid Substances 0.000 claims abstract description 61
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 47
- 230000001105 regulatory effect Effects 0.000 claims abstract description 39
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 165
- 239000008215 water for injection Substances 0.000 claims description 160
- 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 description 111
- 229960005297 nalmefene Drugs 0.000 claims description 110
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 96
- KWTQSFXGGICVPE-UHFFFAOYSA-N 2-amino-5-(diaminomethylideneamino)pentanoic acid;hydron;chloride Chemical group Cl.OC(=O)C(N)CCCN=C(N)N KWTQSFXGGICVPE-UHFFFAOYSA-N 0.000 claims description 91
- 238000003756 stirring Methods 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 58
- 239000007788 liquid Substances 0.000 claims description 55
- 150000003839 salts Chemical class 0.000 claims description 55
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
- 230000001954 sterilising effect Effects 0.000 claims description 44
- 239000012528 membrane Substances 0.000 claims description 35
- 238000005261 decarburization Methods 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 239000003963 antioxidant agent Substances 0.000 claims description 23
- 230000003078 antioxidant effect Effects 0.000 claims description 22
- 238000000034 method Methods 0.000 abstract description 58
- 230000003204 osmotic effect Effects 0.000 abstract description 15
- 230000008569 process Effects 0.000 abstract description 15
- 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 abstract description 14
- 239000008103 glucose Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 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 abstract description 4
- -1 preferably Chemical compound 0.000 abstract description 3
- 239000002738 chelating agent Substances 0.000 abstract 1
- 239000003937 drug carrier Substances 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 38
- 238000003860 storage Methods 0.000 description 37
- 238000001179 sorption measurement Methods 0.000 description 27
- 239000003814 drug Substances 0.000 description 23
- 238000007689 inspection Methods 0.000 description 20
- 238000005516 engineering process Methods 0.000 description 19
- 229940079593 drug Drugs 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 16
- 235000006708 antioxidants Nutrition 0.000 description 15
- 230000015556 catabolic process Effects 0.000 description 15
- 238000006731 degradation reaction Methods 0.000 description 15
- 238000001914 filtration Methods 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 12
- 238000004659 sterilization and disinfection Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 10
- 238000005374 membrane filtration Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000011265 semifinished product Substances 0.000 description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 230000033228 biological regulation Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000007774 longterm Effects 0.000 description 8
- 239000001509 sodium citrate Substances 0.000 description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 238000004806 packaging method and process Methods 0.000 description 7
- 239000002526 disodium citrate Substances 0.000 description 6
- 235000019262 disodium citrate Nutrition 0.000 description 6
- 229940079896 disodium hydrogen citrate Drugs 0.000 description 6
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 6
- 239000006174 pH buffer Substances 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 235000010265 sodium sulphite Nutrition 0.000 description 6
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 6
- 229940038773 trisodium citrate Drugs 0.000 description 6
- 229940087511 calcium disodium versenate Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 4
- 229930003268 Vitamin C Natural products 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000019154 vitamin C Nutrition 0.000 description 4
- 239000011718 vitamin C Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- JHECKPXUCKQCSH-UHFFFAOYSA-J calcium;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O JHECKPXUCKQCSH-UHFFFAOYSA-J 0.000 description 3
- 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 3
- 229960004127 naloxone Drugs 0.000 description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 229960003086 naltrexone Drugs 0.000 description 2
- 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 2
- 239000000049 pigment Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000003698 Heroin Dependence Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000009413 insulation Methods 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
- 238000011835 investigation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000001935 peptisation Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- DOIRQSBPFJWKBE-UHFFFAOYSA-N phthalic acid di-n-butyl ester Natural products CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 1
- NHOXRBDMOTVJBL-UHFFFAOYSA-M potassium;dihydrogen phosphate;methanol Chemical compound [K+].OC.OP(O)([O-])=O NHOXRBDMOTVJBL-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012475 sodium chloride buffer Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a formula of a pharmaceutical composition containing nalmefene hydrochloride for injection. The pharmaceutical composition is characterized in that an injection does not contain a chelating agent, and comprises effective dose of nalmefene hydrochloride and a defined amount of pharmaceutical carrier, wherein the concentration of the nalmefene hydrochloride in the injection can be 0.01-0.2 percent (w/v), the content of the nalmefene hydrochloride in each unit of injection is 0.1-2.0mg; an osmotic pressure regulator can be sodium chloride or glucose, preferably, sodium chloride, the content of the osmotic pressure regulator in each unit of injection is 4.5-22.5mg; the pH value of the injection is regulated to be 3.2-4.5 by using hydrochloric acid. The invention further discloses a preparation method of the formula of the injection. The preparation method comprises the steps of in a blending process, regulating the pH value of a solution to be 6.0-9.0 by using alkaline in first time, and after adsorbing by using active carbon, regulating the pH value of the solution to be 3.2-4.5 by using acid in second time. The formula of the injection containing the nalmefene hydrochloride is simple, and is stable in quality; the preparation method is simple in process, simple and convenient to operate, and more suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical formulating art, particularly pharmaceutical composition and preparation method thereof containing nalmefene hydrochloride of a kind of injection.
Background technology
Nalmefene hydrochloride is the pure opiate receptor antagonist of new generation synthesized after naloxone and naltrexone, is researched and developed by American I vax/Ohmeda company, and in nineteen ninety-five first by U.S. FDA approval listing, listing dosage form is injection.At present, nalmefene hydrochloride has become the succedaneum of naloxone, compares with naltrexone with naloxone, has the advantages such as long action time, oral administration biaavailability is high, dosage is little, safety range is wide.Nalmefene hydrochloride clinical application is extensive, the symptoms such as the respiration inhibition caused for antagonism opioid analgesics, calmness and hypotension, and is applied to the treatment of alcoholism and heroin dependence etc.
But up to now, the nalmefene hydrochloride gone on the market is injection, belong to injection liquid drugs injection, owing to containing phenolic hydroxyl group in nalmefene structure, it is in aqueous through illumination, ultraviolet radiation or be easy to oxidized under the high temperature conditions, generate degradation impurity, also can there is autoxidation and degrade in long storage periods even at normal temperatures.Research proves, the two nalmefene of its dimer hydrochloric acid is very easily degraded to after nalmefene hydrochloride long storage periods, make injection generation variable color, go bad, have a strong impact on drug safety, for this reason, explicitly pointing out the two nalmefene content of degradation impurity hydrochloric acid in nalmefene hydrochloride injection in national drug standards YBH07072010 must not more than 1.0%, and other content of impurities except two nalmefene can not more than 1.0%.But, commercially available nalmefene hydrochloride injection usual effect duration is 12 ~ 18 months, there is the prescription of the longest effect duration, namely nalmefene hydrochloride, antioxidant sodium sulfite, chelating agen Calcium Disodium Versenate, osmotic pressure regulator sodium chloride, hydrochloric acid and water for injection is comprised, its keeping life is also only 24 months, and the main cause causing keeping life short is exactly that the two nalmefene of degradation impurity produces in a large number in long term storage.As everyone knows, expiration date of drug is one of important indicator weighing drug quality of the same race.Expiration date of drug is too short, and can not ensure that medicine is up-to-standard in " production-wholesale-retail-patient's medication " whole longer operating cycle, this will certainly have a strong impact on drug safety; And expiration date of drug is too short, discarded medicine increases, and can not make the best use of everything, thus can cause the serious waste of medicine resource.As can be seen here, find one can avoid to greatest extent generating the two nalmefene of impurity, effect duration is long, and Nalmefene hydrochloride injection meeting the national drug standards and preparation method thereof is significantly.
The prescription of the nalmefene hydrochloride injection of current report is varied, and the prescription of Yuan Yan company is the simplest, only containing principal agent nalmefene hydrochloride, adjuvant sodium chloride and water for injection, then uses salt acid for adjusting pH value to 3.9.Present invention applicant grinds a collection of product of formula preparation according to former, finds that the two nalmefene content of degradation impurity is 0.2% 0 day time; Under this product holding conditions, i.e. lucifuge, under being no more than 20 DEG C of temperature, storage is after 12 months, two nalmefene content is increased to 0.54%, but places after 24 months, and two nalmefene content is rapidly increased to more than 1.0%, be 1.68%, do not met the restriction of pharmacopeia to impurity content; And after storing 30 months, two nalmefene content is up to 2.44%.In order to extend the period of storage of injection, technique is had to attempt at the former adjuvants such as adding antioxidant, pH buffer agent or chelating agen again that grinds in prescription.As Chinese patent CN103040733A adds reducing agent vitamin C, chelating agen EDTA calcium and pH value buffer agent DisodiumHydrogen Citrate and trisodium citrate in Nalmefene hydrochloride injection, to strengthening the stability of injection.During a collection of finished product that result present invention applicant adopts method disclosed in CN103040733A to produce 0 day, two nalmefene content is 0.42%; In lucifuge, under being no more than 20 DEG C of temperature, storage is after 12 months, and two nalmefene content is 0.78%; Place after 24 months, the two nalmefene content of degradation impurity just exceedes and is rapidly increased to 1.66%, does not meet States Pharmacopoeia specifications.
In addition, existing preparation technology also adopts active carbon adsorption process medicinal liquid usually, to remove the insoluble matter in supplementary material medicinal liquid, and the impurity that oxidation, degraded etc. produce, or pigment in medicinal liquid and thermal source etc., in long storage periods, generate degradation impurity to reducing product as far as possible.Chinese patent CN103202806A reports a kind of preparation technology of nalmefene hydrochloride, namely first use 0.05%(W/V) the adjuvant of activated carbon adsorption recipe quantity, comprise sodium chloride and pH buffer agent citric acid or citrate, filter decarburization, add nalmefene hydrochloride again after cooling, then use 1mol/L hydrochloric acid solution adjust ph to 3.5 ~ 4.5.When present invention applicant found through experiments the finished product 0 day that this preparation method produces, the two nalmefene content of impurity is 0.56%; But store after 12 months, two nalmefene content increases to 1.89% rapidly; And place 24 months rear impurity content up to 3.21%, considerably beyond the content range of States Pharmacopoeia specifications.
Adopt nalmefene hydrochloride in patent CN100536848C, antioxidant sodium sulfite, after osmotic pressure regulator sodium chloride is prepared into solution together with the supplementary materials such as chelating agen Calcium Disodium Versenate, with 1mol/L hydrochloric acid solution adjust ph to 3.7 ~ 4.1, use amount of liquid 0.05%(W/V again) active carbon at 115 DEG C ~ 120 DEG C temperature, activate 2 hours, 80 DEG C of insulation absorption 30min, fructufy issues after examination and approval Nalmefene hydrochloride injection prepared by this technique existing in lucifuge, under being no more than 20 DEG C of temperature, storage is after 24 months, two nalmefene content is 0.94%, still States Pharmacopoeia specifications is met, but store after 30 months, two nalmefene content is rapidly increased to 2.15%, does not still meet States Pharmacopoeia specifications.And the Chinese patent of Authorization Notice No. CN101406474B is pointed out in the introduction: the Nalmefene injection prepared with reference to technical scheme disclosed in CN100536848C description, can produce new impurity after sterilizing.
Then use butylhydroxy anisole as antioxidant in Nalmefene hydrochloride injection disclosed in patent CN101658489B, pH to 3.5 ~ 5.5 are regulated after adding osmotic pressure regulator, again with the activated carbon adsorption decolouring of amount of liquid 0.5mg/ml ~ 3.0mg/ml, finally add nalmefene hydrochloride again, when result present invention applicant tests the Nalmefene hydrochloride injection 0 day finding to produce, two nalmefene content is only 0.31%; In lucifuge, to be no more than storage 12 months impurity contents at 20 DEG C of temperature be 0.59%; After 24 months, two nalmefene reaches 1.45%; But place after 30 months, two nalmefene content is increased to 2.33% rapidly.In Chinese patent CN101406474B, antioxidant tertiary butyl BHA tryptophan in CN101658489B is substituted, add nalmefene hydrochloride and chelating agen, osmotic pressure regulator, pH to 3.7 ~ 4.1 are reconciled after dissolving, and then at 115 DEG C ~ 120 DEG C temperature, activate 2 hours with the active carbon of 0.05% (W/V), after the Nalmefene hydrochloride injection that present invention applicant adopts said method to obtain stores 24 months, two nalmefene content exceedes States Pharmacopoeia specifications; After 30 months, content reaches 2.45%, does not also meet States Pharmacopoeia specifications.
Find to the investigation of the two nalmefene of degradation impurity, the adjuvants such as specific antioxidant, chelating agen or pH buffer agent are added in nalmefene hydrochloride injection, really the long term storage stability of injection finished product can be improved, although two nalmefene content is all lower than 1.0% during the product produced of above-mentioned prior art prescription 0 day, but along with the increase of period of storage, impurity content increases, after especially storage reaches 30 months, two nalmefene content, all more than 2.0%, does not all meet States Pharmacopoeia specifications.As can be seen here, finding one can prevent Nalmefene hydrochloride injection from degrading after long storage periods to greatest extent, obtain that two nalmefene impurity content is low, long shelf-life, and prescription is simple, technological process is simple, easy and simple to handle, the Nalmefene hydrochloride injection and the preparation technology thereof that are applicable to Chinese Industrialization production are now very important.
Summary of the invention
After the long storage periods that the nalmefene hydrochloride injection produced to overcome prior art exists, the two nalmefene content of degradation impurity is high, effect duration is short, and existing prescription is more complicated, thus cause the problems such as production cost is high, industrial applications value is low, impurity content is low, long shelf-life to provide one to obtain, and prescription is simple, technological process simple, be applicable to Nalmefene hydrochloride injection and the preparation technology thereof of large-scale industrial production, the invention provides following technical scheme:
The invention provides a kind of nalmefene hydrochloride injection: not containing chelating agen.
The present invention further provides a kind of nalmefene hydrochloride injection: in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 0.1g ~ 2.0g(is in nalmefene)
Osmotic pressure regulator 4.5g ~ 22.5g
Antioxidant 0.5g ~ 4.5g
Salt acid for adjusting pH to 3.2 ~ 4.5
Water for injection adds to 1000ml.
The present invention provides again a kind of nalmefene hydrochloride injection: in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 0.8g ~ 1.5g(is in nalmefene)
Osmotic pressure regulator 7.2g ~ 12.5g
Antioxidant 1.0g ~ 2.1g
Salt acid for adjusting pH to 3.5 ~ 4.0
Water for injection adds to 1000ml.
The present invention further provides a kind of nalmefene hydrochloride injection: in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Osmotic pressure regulator 9.0g
Antioxidant 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
The present invention also provides a kind of nalmefene hydrochloride injection: in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Osmotic pressure regulator 9.0g
Antioxidant 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Osmotic pressure regulator of the present invention is selected from the one in sodium chloride, glucose, is preferably sodium chloride; Described antioxidant is L-arginine hydrochloride.
The present invention also provides a kind of preparation method of nalmefene hydrochloride injection: in dosing process, first regulates pH value of solution to be 6.0 ~ 9.0, after activated carbon adsorption with alkali first time, then regulates pH value of solution to be 3.2 ~ 4.5 by acid second time.
The present invention further provides a kind of preparation method of nalmefene hydrochloride injection: in dosing process, first regulate pH value of solution to be 7.5 ~ 8.5, after activated carbon adsorption with alkali first time, then regulate pH value of solution to be 3.2 ~ 4.5 by acid second time.
Alkali of the present invention is sodium hydroxide solution, and acid is hydrochloric acid solution.
The preparation method of nalmefene hydrochloride injection of the present invention, comprises the following steps:
(1) nalmefene hydrochloride and the osmotic pressure regulator of getting prescription full dose are placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH value of solution is regulated with sodium hydroxide solution first time, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add active carbon, stirring and adsorbing, filter decarburization and be cooled to room temperature;
(2) the medicinal liquid hydrochloric acid solution obtained through (1) second time is regulated pH, add to the full amount of water for injection in dilute preparing tank, with microporous filter membrane fine straining to clear and bright, fill nitrogen embedding sterilizing and form injection.
Present invention applicant is found by test: preparing in nalmefene hydrochloride injection process, grind on prescription basis former, adds a large amount of generations that specific antioxidant, chelating agen or pH buffer agent can prevent the two nalmefene of degradation impurity really.Therefore first present invention applicant attempts grinding on prescription basis former, add injection again and commonly use adjuvant: be selected from butylhydroxy anisole, 2, 6-di-t-butyl-4-methyl-phenol, Herba Rosmarini Officinalis, tryptophan, thioglycolic, sodium thiosulfate, thiourea, TGA, cysteine, sulfurous acid, sodium sulfite, sodium pyrosulfite, sodium sulfite, vitamin C, cysteine, sodium citrate, one or more antioxidant in disodium edetate, and/or be selected from citric acid and sodium citrate, acetic acid and sodium acetate, citric acid and sodium hydrogen phosphate, one or more pH buffer agent in DisodiumHydrogen Citrate and trisodium citrate, and/or be selected from Calcium Disodium Versenate, one or more chelating agen in EDTA, when fructufy issues after examination and approval the nalmefene hydrochloride injection 0 day that existing said method produces, two nalmefene content is all lower than 1.0%, in lucifuge, be no more than at 20 DEG C of temperature that storage is after 24 months, two nalmefene content is increased between 0.94% ~ 3.08%, and period of storage is when reaching 30 months, two nalmefene content all higher than 2.0%, considerably beyond the regulation of standard YBH07072010.
Present invention applicant has attempted the conventional adjuvant of current industrial production injection, and through lot of experiments, finally surprisingly find: the nalmefene hydrochloride injection containing special antioxidants L-arginine hydrochloride, in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 0.1g ~ 2.0g(is in nalmefene)
Osmotic pressure regulator 4.5g ~ 22.5g
L-arginine hydrochloride 0.5g ~ 4.5g
Salt acid for adjusting pH to 3.2 ~ 4.5
Water for injection adds to 1000ml.
The nalmefene hydrochloride injection produced of prescription of the present invention lucifuge, be no more than 20 DEG C of temperature under, even if period of storage reaches 30 months, the two nalmefene content of its degradation impurity still meets national drug standards YBH07072010 regulation, all lower than 1.0%, and other impurity contents also conformance with standard regulation, its long term storage stability is considerably beyond prior art prescription.
Further, the nalmefene hydrochloride injection storage of samples time lengthening that above-mentioned prescription is produced by present invention applicant was by 36 months, and result unfortunately finds that its pair of nalmefene content is still increased to more than 1.0%.In order to extend the shelf-life of nalmefene hydrochloride injection further, make its effect duration can more than 30 months, present invention applicant attempts again adsorbing medicinal liquid with active carbon in dosing process, to remove impurity, precipitation, pigment or thermal source etc., improves nalmefene hydrochloride long term storage stability.First present invention applicant attempts the sodium chloride of recipe quantity and L-arginine hydrochloride to add in dense preparing tank, dissolve with water for injection, mix homogeneously, add hydrochloric acid solution adjust ph to 3.0 ~ 4.5, the active carbon of 0.01% ~ 0.10% (W/V) is used to adsorb 20min ~ 60min again at 50 DEG C ~ 100 DEG C temperature, removal activity charcoal, cool to room temperature after filtering, then in dilute preparing tank, add the nalmefene hydrochloride of recipe quantity.Present invention applicant by the nalmefene hydrochloride injection of preparation in lucifuge, to be no more than at 20 DEG C of temperature storage 36 months, the two nalmefene content of degradation impurity still exceedes 1.0% of pharmacopoeia limit.Present invention applicant attempts again the addition sequence changing active carbon, adopt and first use activated carbon adsorption medicinal liquid, use hydrochloric acid conditioning solution pH more afterwards, namely in dense preparing tank, add the nalmefene hydrochloride of recipe quantity, sodium chloride and L-arginine hydrochloride, dissolve with water for injection, mix homogeneously, at 50 DEG C ~ 100 DEG C temperature, 20min ~ 60min is adsorbed with the active carbon of 0.01% ~ 0.10% (W/V), removal activity charcoal, hydrochloric acid solution adjust ph to 3.0 ~ 4.5 are added after filtration, cool to room temperature, then at dilute preparing tank standardize solution.The Nalmefene hydrochloride injection prepared of the method after 36 months two nalmefene content still higher than 1.5%.
Present invention applicant finds through above-mentioned experiment, and no matter the operating sequence of technique is: the mixed solution one of nalmefene hydrochloride, sodium chloride and L-arginine hydrochloride reinstates activated carbon adsorption, or first uses activated carbon adsorption adjuvant solution, then adds nalmefene hydrochloride; Or change the order of activated carbon adsorption operation: first regulate pH to 3.0 ~ 4.5, then with activated carbon adsorption or first use activated carbon adsorption, then regulating pH value of solution to 3.0 ~ 4.5, after period of storage reaches 36 months, the two nalmefene content of degradation impurity is still without obviously reduction.
Present invention applicant is through a large amount of trials, finally find uncannily between accidentally: in dosing process, first pH value of solution is regulated to be 6.0 ~ 9.0 with sodium hydroxide solution first time, after activated carbon adsorption, regulate pH value of solution to be 3.2 ~ 4.5 by hydrochloric acid solution second time again, and in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 0.1g ~ 2.0g(is in nalmefene)
Osmotic pressure regulator 4.5g ~ 22.5g
L-arginine hydrochloride 0.5g ~ 4.5g
Salt acid for adjusting pH to 3.2 ~ 4.5
Water for injection adds to 1000ml.
This prescription composition and preparation technology can realize Nalmefene hydrochloride injection in lucifuge, be no more than at 20 DEG C of temperature that storage is after 30 months, degradation impurity pair nalmefene content is lower than 0.6%; Period of storage reaches the content of two nalmefene after 36 months also surprisingly also below 1.0%, and other impurity contents all meet national drug standards YBH07072010 regulation.
The interior packaging material of nalmefene hydrochloride injection of the present invention is not particularly limited, and is normally divided in Pyrex ampulla.
Nalmefene hydrochloride injection specification of the present invention is also not particularly limited.
Microporous filter membrane of the present invention is selected from the one in the composite microporous filter film of 0.22 μm of microporous filter membrane, 0.45 μm and 0.22 μm composition; Be preferably 0.22 μm of microporous filter membrane.
The consumption of active carbon of the present invention is not particularly limited, and is generally 0.05% (W/V).
Activated carbon adsorption temperature of the present invention is generally 80 DEG C ~ 100 DEG C.
The activated carbon adsorption time of the present invention is generally 20min ~ 40min.
The clinical administration of nalmefene hydrochloride injection of the present invention is intravenous injection or intramuscular injection.
Present invention applicant, in order to further extend the shelf-life of nalmefene hydrochloride injection, attempts again the pH value changing activated carbon adsorption.A lot of result of study finds, active carbon is better to the adsorption effect of injection under slightly acidic condition, as Xiao Sui etc. (
practical medical technologies magazine, 2005,12 (6): 1446-1447) in disclose active carbon may produce " peptization ", De contamination effect in alkaline solution, absorption affinity is strong in an acidic solution, and should control medicinal liquid pH value is faintly acid.But, present invention applicant surprisingly finds in further experiment, on the contrary under weak basic condition, the adsorption effect of active carbon is better, namely, in dosing process, first pH value of solution is regulated to be 7.5 ~ 8.5, with activated carbon adsorption with sodium hydroxide solution first time, regulate pH value of solution to be 3.2 ~ 4.5 by hydrochloric acid solution second time again, and in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride 0.1g ~ 2.0g(is in nalmefene)
Osmotic pressure regulator 4.5g ~ 22.5g
L-arginine hydrochloride 0.5g ~ 4.5g
Salt acid for adjusting pH to 3.2 ~ 4.5
Water for injection adds to 1000ml.
This prescription composition and preparation technology can realize Nalmefene hydrochloride injection lucifuge, be no more than and store 30 months at 20 DEG C of temperature after, the two nalmefene content of degradation impurity hydrochloric acid is lower than 0.5%, period of storage reaches the content of two nalmefene after 36 months surprisingly below 0.6%, and other impurity contents also meet national drug standards YBH07072010 regulation, have extraordinary long term storage stability.
The advantage of the present invention compared with existing similar technique is: nalmefene hydrochloride injection prescription of the present invention is simple, and period of storage more than 30 months after, impurity content conforms with the regulations, long shelf-life, can ensure that medicine is up-to-standard in " production-wholesale-retail-patient's medication " operating cycle, drug safety is good; Long shelf-life also reduces discarded medicine simultaneously, saves medicine resource.In addition, present invention process flow process is simple, easy and simple to handle, is the nalmefene hydrochloride injection product being applicable to Chinese Industrialization production now.
comparative example
comparative example 1
Prescription is ground according to former:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
Water for injection adds to 1000ml
Preparation technology: the sodium chloride getting prescription full dose is placed in dosing cylinder, adds water for injection, stirs and makes it dissolve, pH is regulated with the hydrochloric acid solution of 0.2mol/L, make pH in 3.8 ~ 4.0 scopes, then add the nalmefene hydrochloride of prescription full dose, be stirred to dissolve, mend again and add to the full amount of water for injection, after coarse filtration, then use 0.22 μm of microporous filter membrane fine straining to clear and bright, carry out the inspection of semifinished product, controlling content is 0.095mg/ml ~ 0.105mg/ml, pH=3.9.After the inspection of semifinished product is qualified, fill under inflated with nitrogen protection, in 115 DEG C of steam sterilization 30min, leak detection, lamp inspection, labels, packs, and obtains nalmefene hydrochloride injection.Make 1000, sample.
comparative example 2
Prescription according to Chinese patent CN101658489B embodiment 1:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
Butylhydroxy anisole 0.015g
Water for injection adds to 1000ml
Preparation technology: get prescription full dose butylhydroxy anisole and sodium chloride joins in water for injection, after dissolving, with salt acid for adjusting pH to 3.8, benefit injects water to 1000ml, adds 1.0g active carbon, room temperature decolouring 30min, with 0.22 μm of membrane filtration after decolouring, in filtrate, add nalmefene hydrochloride 0.1108g, after stirring and dissolving, to fill nitrogen embedding after 0.22 μm of membrane filtration, 121 DEG C of moist heat sterilization 20min, leak detection, lamp inspection, label, pack, obtain nalmefene hydrochloride injection.Make 1000, sample.
comparative example 3
Prescription according to Chinese patent CN100536848C embodiment 5:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
Sodium sulfite 0.02g
Calcium Disodium Versenate 0.005g
Hydrochloric acid regulates pH to 3.8 in right amount
Water for injection adds to 1000ml
Preparation technology: get 1000ml water for injection and be placed in dosing cylinder, add the sodium chloride of prescription full dose, sodium sulfite and Calcium Disodium Versenate, be stirred to dissolving; Add the nalmefene hydrochloride of recipe quantity, be stirred to dissolving; Use the microporous filter membrane fine straining of 0.22 μm to clear and bright again; Embedding is in glass ampoule, and sealing by fusing, 115 DEG C of sterilizing 20min, gland, labels, and packaging, gets product after the assay was approved.Make 1000, sample.
comparative example 4
Prescription according to patent CN103040733A embodiment 1:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Tween 80 1g
EDTA calcium 2g
Vitamin C 1.5g
Water for injection adds to 1000ml
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 500ml of 1:4
Wherein, the collocation method of DisodiumHydrogen Citrate and trisodium citrate buffer is as follows: take DisodiumHydrogen Citrate 13g, and trisodium citrate 60g is dissolved in 1000ml water for injection and obtains the buffer solution that pH value is 7.0.
Preparation technology: first configure DisodiumHydrogen Citrate and trisodium citrate buffer 500ml, then the nalmefene hydrochloride of above-mentioned amount is got, Tween 80, EDTA calcium, vitamin C adding citric acid buffer solution, then use water for injection standardize solution to 1000ml, the filter membrane of via hole diameter molecular cut off 20000 filters, after clarity is qualified, fill, packaging, obtains nalmefene hydrochloride injection.Make 1000, sample.
comparative example 5
According to prescription of the present invention:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Preparation method: get the sodium chloride of prescription full dose, L-arginine hydrochloride is placed in dosing cylinder, add water for injection, stir and make it dissolve, regulate pH with the hydrochloric acid solution of 0.2mol/L, make pH in 3.8 ~ 4.0 scopes, add the nalmefene hydrochloride of prescription full dose again, be stirred to dissolve, then benefit adds to the full amount of water for injection, after coarse filtration, use 0.22 μm of microporous filter membrane fine straining to clear and bright again, carry out the inspection of semifinished product, control content is 0.95mg/ml ~ 1.05mg/ml; PH value is 3.9.After the inspection of semifinished product is qualified, fill under inflated with nitrogen protection, in 115 DEG C of steam sterilization 30min, leak detection, lamp inspection, labels, packs, and obtains nalmefene hydrochloride injection.Make 1000, sample.
comparative example 6
According to prescription of the present invention:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
According to patent CN100536848C preparation technology: get recipe quantity nalmefene hydrochloride and add water for injection, be stirred to and dissolve completely, add sodium chloride and the L-arginine hydrochloride of prescription full dose, be stirred to dissolving, mix homogeneously, regulates pH value of solution to 3.7 ~ 4.1 with the hydrochloric acid solution of 1.0mol/L; Separately add the active carbon activating 2 hours through 115 DEG C of amount of liquid 0.05% (W/V), at 80 DEG C of insulated and stirred absorption 30min, coarse filtration, decarburization; With the filtering with microporous membrane of 0.22 μm to clear and bright, regulate pH value of solution to 3.9, pressure sterilizing 20min at 115 DEG C.Make 1000, sample.
comparative example 7
According to prescription of the present invention:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
According to patent CN101658489B preparation technology: L-arginine hydrochloride and the sodium chloride of getting recipe quantity join in water for injection, after dissolving, with salt acid for adjusting pH to 3.9, mend and inject water to 1000ml, add 1.0g active carbon, room temperature decolouring 30min, with 0.22 μm of membrane filtration after decolouring, adds nalmefene hydrochloride 1.0g in filtrate, after stirring and dissolving, to fill nitrogen embedding after 0.22 μm of membrane filtration, 121 DEG C of moist heat sterilization 20min, obtain nalmefene hydrochloride injection.Make 1000, sample.
comparative example 8
According to prescription of the present invention:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Preparation technology according to patent CN103202806A: get the sodium chloride of recipe quantity, L-arginine hydrochloride, add water for injection and make dissolving, adds 0.05% (W/V) active carbon stirring and adsorbing 15min, filters decarburization and is cooled to room temperature; Under nitrogen protection, add the nalmefene hydrochloride of recipe quantity, be stirred to dissolve, at room temperature add to the full amount of water for injection 1000ml, mix homogeneously, by 1.0mol/L sodium hydroxide solution or 1.0mol/L hydrochloric acid solution adjust ph to 3.9; With subpackage after 0.45 μm and 0.22 μm of frit, fill nitrogen, sealing, 116 DEG C/40min sterilizing, obtains nalmefene hydrochloride injection.Make 1000, sample.
comparative example 9
According to prescription of the present invention:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
According to preparation technology of the present invention:
(1) prescription full dose nalmefene hydrochloride is got and recipe quantity sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 6.5 with sodium hydroxide solution first time, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 30min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the medicinal liquid hydrochloric acid solution second time obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 30min at 115 DEG C.Make 1000, sample.
Dirt content test: get this product, as need testing solution; Precision measures need testing solution 1mL, is placed in 100mL measuring bottle, adds mobile phase and is diluted to scale, shake up, in contrast solution.Another precision takes the two nalmefene reference substance (C of hydrochloric acid
42h
48n
2o
62HCl) appropriate, add mobile phase and dissolve and make in every 1mL containing two nalmefene (C
42h
48n
2o
6) solution of 1.0 μ g, as the two nalmefene reference substance solution of hydrochloric acid.According to the chromatographic condition under assay item, precision measures contrast solution 200 μ L injection liquid chromatography, regulates detection sensitivity, makes the peak height of main constituent be about 20% ~ 25% of monitor full scale; Precision measures the two each 200 μ L of nalmefene reference substance solution of need testing solution, contrast solution and hydrochloric acid again, respectively injection liquid chromatography, and the chromatogram of record need testing solution is to 4 times of main peak retention time.If any impurity peaks in the chromatogram of need testing solution, contain two nalmefene according to external standard method with calculated by peak area, must not more than 1.0%.
Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Be mobile phase with 0.02mol/L potassium dihydrogen phosphate-methanol (60:40, containing 0.1% triethylamine, phosphorate acid for adjusting pH value to 4.6); Determined wavelength is 284nm.Number of theoretical plate calculates should be not less than 2000 according to nalmefene hydrochloride peak.
Computing formula:
In formula:
Ai is two nalmefene peak area in test sample;
C
0for two nalmefene reference substance concentration;
A
0for nalmefene peak area two in two nalmefene reference substance;
C
mtest sample nalmefene labelled amount concentration.
To obtained 9 batch samples of comparative example 1 ~ 9 respectively at 0 day, lucifuge, to be no more than at 20 DEG C of temperature storage 12,24,30 and after 36 months, working sample impurity content, testing result is as follows:
By comparative example 1 ~ 4, adopt the prescription of prior art, specific antioxidant, pH buffer agent or chelating agen is added in nalmefene hydrochloride injection, the sample of preparation in lucifuge, be no more than at 20 DEG C of temperature that storage is within 12 months, the two nalmefene content of its degradation impurity is all in the scope of States Pharmacopoeia specifications; But when long storage periods reaches 30 months, the two nalmefene content of impurity is all more than 2.0%, and its long term storage stability is poor as seen.
Found out by comparative example 5, use prescription of the present invention, even if do not use activated carbon adsorption in preparation technology, sample 0 day two nalmefene content of production is only 0.30%; In lucifuge, be no more than at 20 DEG C of temperature that storage is after 12 months, impurity content is 0.36%; And after storing 24 months, two nalmefene content is also only increased to 0.65%, even reach 30 months standing time, two nalmefene content is only 0.85%, and other impurity contents also meet national drug standards YBH07072010 regulation, compared with prior art, show better long term storage stability, but detect after 36 months, its pair of nalmefene content also exceedes 1.0% of restriction.
From comparative example 6 ~ 8, use prescription of the present invention, and use activated carbon adsorption in preparation technology, but adopt the absorbing process of prior art, no matter the operating sequence of technique is: the mixed solution one of nalmefene hydrochloride, sodium chloride and L-arginine hydrochloride reinstates activated carbon adsorption, or first use activated carbon adsorption adjuvant solution, then add nalmefene hydrochloride; Or change the order of activated carbon adsorption operation: first regulate pH to 3.2 ~ 4.5, again with activated carbon adsorption or first use activated carbon adsorption, regulate pH value of solution again, prescription of the present invention is adopted with comparative example 5, but do not use activated carbon adsorption to compare in preparation technology, the nalmefene hydrochloride injection of preparation 0 day, in lucifuge, to be no more than at 20 DEG C of temperature storage 12 months, 24 months, 30 months and 36 months, the two nalmefene content of its impurity there is no obvious reduction.
From comparative example 9, only have and both use prescription of the present invention, adopt again preparation method of the present invention, namely in dosing process, first pH value of solution is regulated to be 6.0 ~ 9.0 with sodium hydroxide solution first time, with activated carbon adsorption, pH value of solution is regulated to be 3.2 ~ 4.5 by hydrochloric acid solution second time again, even if the nalmefene hydrochloride injection period of storage of preparation reaches 36 months, also the two nalmefene content of impurity can be kept to meet national drug standards YBH07072010 regulation, visible use prescription of the present invention and preparation method thereof can produce the nalmefene hydrochloride injection with extraordinary long term storage stability.
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
embodiment 1
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 4.5g
L-arginine hydrochloride 0.5g
Salt acid for adjusting pH to 3.2
Water for injection adds to 1000ml.
Technique: the sodium chloride getting prescription full dose, L-arginine hydrochloride is placed in dosing cylinder, add water for injection, stirring makes it dissolve, pH to 3.2 ~ 3.5 are regulated with the hydrochloric acid solution of 0.2mol/L, add the nalmefene hydrochloride of prescription full dose again, be stirred to dissolve, mend again and add to the full amount of water for injection, after coarse filtration, with 0.22 μm of microporous filter membrane fine straining to clear and bright, carry out the inspection of semifinished product, control content is 0.45mg/ml ~ 0.55mg/ml, pH=3.2, after the assay was approved, fill under inflated with nitrogen protection, in 115 DEG C of steam sterilization 30min, leak detection, lamp inspection, label, packaging, make 1000, sample.
embodiment 2
Prescription:
Nalmefene hydrochloride 2.0g(is in nalmefene)
Sodium chloride 22.5g
L-arginine hydrochloride 4.5g
Salt acid for adjusting pH to 4.5
Water for injection adds to 1000ml.
Technique: the sodium chloride getting prescription full dose, L-arginine hydrochloride is placed in dosing cylinder, add water for injection, stirring makes it dissolve, pH to 4.5 ~ 4.8 are regulated with the hydrochloric acid solution of 0.1mol/L, add the nalmefene hydrochloride of prescription full dose again, be stirred to dissolve, mend again and add to the full amount of water for injection, after coarse filtration, with 0.22 μm of microporous filter membrane fine straining to clear and bright, carry out the inspection of semifinished product, control content is 2.45mg/ml ~ 2.55mg/ml, pH=4.5, after the assay was approved, fill under inflated with nitrogen protection, in 120 DEG C of steam sterilization 15min, leak detection, lamp inspection, label, packaging, make 500, sample.
embodiment 3
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 22.5g
L-arginine hydrochloride 0.5g
Salt acid for adjusting pH to 3.2
Water for injection adds to 1000ml.
Technique: get prescription full dose L-arginine hydrochloride and sodium chloride joins in water for injection, after dissolving, with salt acid for adjusting pH to 3.2, benefit injects water to 1000ml, adds 1.0g active carbon, room temperature decolouring 30min, with 0.22 μm of membrane filtration after decolouring, in filtrate, add the nalmefene hydrochloride of prescription full dose, after stirring and dissolving, to fill nitrogen embedding after 0.22 μm of membrane filtration, 121 DEG C of moist heat sterilization 12min, leak detection, lamp inspection, label, pack, make 1000, sample.
embodiment 4
Prescription:
Nalmefene hydrochloride 2.0g(is in nalmefene)
Sodium chloride 4.5g
L-arginine hydrochloride 4.5g
Salt acid for adjusting pH to 4.5
Water for injection adds to 1000ml.
Technique: get recipe quantity nalmefene hydrochloride and add water for injection, be stirred to and dissolve completely, adds sodium chloride and the L-arginine hydrochloride of prescription full dose, is stirred to dissolving, mix homogeneously, regulates pH value of solution to 4.5 with the hydrochloric acid solution of 1.0mol/L; Separately add the active carbon activating 2 hours through 115 DEG C of amount of liquid 0.05% (W/V), at 80 DEG C of insulated and stirred absorption 30min, coarse filtration, decarburization; With the filtering with microporous membrane of 0.22 μm to clear and bright, regulate pH value of solution to 4.5, pressure sterilizing 45min at 105 DEG C.Make 500, sample.
embodiment 5
Prescription:
Nalmefene hydrochloride 2.0g(is in nalmefene)
Glucose 22.5g
L-arginine hydrochloride 0.5g
Salt acid for adjusting pH to 4.5
Water for injection adds to 1000ml.
Technique: get the glucose of recipe quantity, L-arginine hydrochloride, add water for injection and make dissolving, adds 0.05% (W/V) active carbon stirring and adsorbing 15min, filters decarburization and is cooled to room temperature; Under nitrogen protection, add the nalmefene hydrochloride of recipe quantity, be stirred to dissolve, at room temperature add to the full amount of water for injection 1000ml, mix homogeneously, by 1.0mol/L sodium hydroxide solution or 1.0mol/L hydrochloric acid solution adjust ph to 4.5; With subpackage after 0.45 μm and 0.22 μm of frit, fill nitrogen, sealing, 116 DEG C/40min sterilizing.Make 1000, sample.
embodiment 6
Prescription:
Nalmefene hydrochloride 1.5g(is in nalmefene)
Sodium chloride 12.5g
L-arginine hydrochloride 2.1g
Salt acid for adjusting pH to 4.0
Water for injection adds to 1000ml.
Technique: get the sodium chloride of recipe quantity, L-arginine hydrochloride, add water for injection and make dissolving, adds 0.05% (W/V) active carbon stirring and adsorbing 20min, filters decarburization and is cooled to room temperature; Under nitrogen protection, add the nalmefene hydrochloride of recipe quantity, be stirred to dissolve, at room temperature add to the full amount of water for injection 1000ml, mix homogeneously, by 1.0mol/L sodium hydroxide solution or 1.0mol/L hydrochloric acid solution adjust ph to 4.0; With subpackage after 0.45 μm and 0.22 μm of frit, fill nitrogen, sealing, 116 DEG C/40min sterilizing.Make 500, sample.
embodiment 7
Prescription:
Nalmefene hydrochloride 0.8g(is in nalmefene)
Sodium chloride 7.2g
L-arginine hydrochloride 1.0g
Salt acid for adjusting pH to 3.5
Water for injection adds to 1000ml.
Technique: the sodium chloride getting prescription full dose, L-arginine hydrochloride is placed in dosing cylinder, add water for injection, stirring makes it dissolve, pH to 3.5 ~ 3.8 are regulated with the hydrochloric acid solution of 0.1mol/L, add the nalmefene hydrochloride of prescription full dose again, be stirred to dissolve, mend again and add to the full amount of water for injection, after coarse filtration, with 0.22 μm of microporous filter membrane fine straining to clear and bright, carry out the inspection of semifinished product, control content is 0.75mg/ml ~ 0.85mg/ml, pH=3.5, after the assay was approved, fill under inflated with nitrogen protection, in 120 DEG C of steam sterilization 20min, leak detection, lamp inspection, label, packaging, make 500, sample.
embodiment 8
Prescription:
Nalmefene hydrochloride 0.8g(is in nalmefene)
Glucose 12.5g
L-arginine hydrochloride 2.1g
Salt acid for adjusting pH to 3.5
Water for injection adds to 1000ml.
Technique: get prescription full dose L-arginine hydrochloride and glucose joins in water for injection, after dissolving, with salt acid for adjusting pH to 3.5, benefit injects water to 1000ml, adds 1.0g active carbon, room temperature decolouring 30min, with 0.22 μm of membrane filtration after decolouring, in filtrate, add the nalmefene hydrochloride of prescription full dose, after stirring and dissolving, to fill nitrogen embedding after 0.22 μm of membrane filtration, 121 DEG C of moist heat sterilization 20min, leak detection, lamp inspection, label, pack, make 1000, sample.
embodiment 9
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique: the sodium chloride getting prescription full dose, L-arginine hydrochloride is placed in dosing cylinder, add water for injection, stirring makes it dissolve, pH to 3.9 ~ 4.0 are regulated with the hydrochloric acid solution of 0.2mol/L, add the nalmefene hydrochloride of prescription full dose again, be stirred to dissolve, mend again and add to the full amount of water for injection, after coarse filtration, with 0.22 μm of microporous filter membrane fine straining to clear and bright, carry out the inspection of semifinished product, control content is 0.95mg/ml ~ 1.05mg/ml, pH=3.9, after the assay was approved, fill under inflated with nitrogen protection, in 115 DEG C of steam sterilization 30min, leak detection, lamp inspection, label, packaging, make 500, sample.
embodiment 10
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique: get the sodium chloride of recipe quantity, L-arginine hydrochloride, add water for injection and make dissolving, adds 0.05% (W/V) active carbon stirring and adsorbing 15min, filters decarburization and is cooled to room temperature; Under nitrogen protection, add the nalmefene hydrochloride of recipe quantity, be stirred to dissolve, at room temperature add to the full amount of water for injection 1000ml, mix homogeneously, by 1.0mol/L sodium hydroxide solution or 1.0mol/L hydrochloric acid solution adjust ph to 3.9; With subpackage after 0.45 μm and 0.22 μm of frit, fill nitrogen, sealing, 116 DEG C/40min sterilizing.Make 500, sample.
embodiment 11
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Glucose 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique: get prescription full dose L-arginine hydrochloride and glucose joins in water for injection, after dissolving, with salt acid for adjusting pH to 3.9, benefit injects water to 1000ml, adds 1.0g active carbon, room temperature decolouring 30min, with 0.22 μm of membrane filtration after decolouring, in filtrate, add the nalmefene hydrochloride of prescription full dose, after stirring and dissolving, to fill nitrogen embedding after 0.22 μm of membrane filtration, 121 DEG C of moist heat sterilization 20min, leak detection, lamp inspection, label, pack, make 500, sample.
embodiment 12
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique: get the sodium chloride of recipe quantity, L-arginine hydrochloride, add water for injection and make dissolving, adds 0.05% (W/V) active carbon stirring and adsorbing 20min, filters decarburization and is cooled to room temperature; Under nitrogen protection, add the nalmefene hydrochloride of recipe quantity, be stirred to dissolve, at room temperature add to the full amount of water for injection 1000ml, mix homogeneously, by 2.0mol/L sodium hydroxide solution or 1.0mol/L hydrochloric acid solution adjust ph to 3.9; With subpackage after 0.45 μm and 0.22 μm of frit, fill nitrogen, sealing, 116 DEG C/40min sterilizing.Make 1000, sample.
embodiment 13
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique: the sodium chloride getting prescription full dose, L-arginine hydrochloride is placed in dosing cylinder, add water for injection, stirring makes it dissolve, pH to 3.9 ~ 4.0 are regulated with the hydrochloric acid solution of 0.2mol/L, add the nalmefene hydrochloride of prescription full dose again, be stirred to dissolve, mend again and add to the full amount of water for injection, after coarse filtration, with 0.22 μm of microporous filter membrane fine straining to clear and bright, carry out the inspection of semifinished product, control content is 0.095mg/ml ~ 0.105mg/ml, pH=3.9, after the assay was approved, fill under inflated with nitrogen protection, in 120 DEG C of steam sterilization 15min, leak detection, lamp inspection, label, packaging, make 1000, sample.
embodiment 14
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 4.5g
L-arginine hydrochloride 0.5g
Salt acid for adjusting pH to 3.2
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 6.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 30min at 90 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.2 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 1000, sample.
embodiment 15
Prescription:
Nalmefene hydrochloride 2.0g(is in nalmefene)
Sodium chloride 22.5g
L-arginine hydrochloride 4.5g
Salt acid for adjusting pH to 4.5
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 9.0 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 4.5 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 20min at 115 DEG C.Make 500, sample.
embodiment 16
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Glucose 22.5g
L-arginine hydrochloride 0.5g
Salt acid for adjusting pH to 3.2
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and glucose is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 9.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 30min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.2 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 12min at 121 DEG C.Make 1000, sample.
embodiment 17
Prescription:
Nalmefene hydrochloride 0.8g(is in nalmefene)
Sodium chloride 7.2g
L-arginine hydrochloride 1.0g
Salt acid for adjusting pH to 3.5
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 6.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.5 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 500, sample.
embodiment 18
Prescription:
Nalmefene hydrochloride 1.5g(is in nalmefene)
Sodium chloride 12.5g
L-arginine hydrochloride 2.1g
Salt acid for adjusting pH to 4.0
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 9.0 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 30min at 90 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 4.0 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 20min at 115 DEG C.Make 500, sample.
embodiment 19
Prescription:
Nalmefene hydrochloride 0.8g(is in nalmefene)
Glucose 12.5g
L-arginine hydrochloride 2.1g
Salt acid for adjusting pH to 3.5
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 6.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.5 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 12min at 121 DEG C.Make 500, sample.
embodiment 20
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 6.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.06% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 500, sample.
embodiment 21
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 9.0 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.06% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 20min at 115 DEG C.Make 500, sample.
embodiment 22
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 6.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.06% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 1000, sample.
embodiment 23
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 9.0 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.06% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 20min at 115 DEG C.Make 1000, sample.
embodiment 24
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 4.5g
L-arginine hydrochloride 0.5g
Salt acid for adjusting pH to 3.2
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 7.5 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.2 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 1000, sample.
embodiment 25
Prescription:
Nalmefene hydrochloride 2.0g(is in nalmefene)
Glucose 22.5g
L-arginine hydrochloride 4.5g
Salt acid for adjusting pH to 4.5
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 8.5 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 4.5 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 12min at 121 DEG C.Make 1000, sample.
embodiment 26
Prescription:
Nalmefene hydrochloride 0.8g(is in nalmefene)
Sodium chloride 7.2g
L-arginine hydrochloride 1.0g
Salt acid for adjusting pH to 3.5
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 7.5 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.5 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 500, sample.
embodiment 27
Prescription:
Nalmefene hydrochloride 1.5g(is in nalmefene)
Sodium chloride 12.5g
L-arginine hydrochloride 2.1g
Salt acid for adjusting pH to 4.0
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and recipe quantity sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 8.5 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 4.0 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 12min at 121 DEG C.Make 500, sample.
embodiment 28
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 7.5 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 500, sample.
embodiment 29
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 8.5 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 90 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 30min at 115 DEG C.Make 500, sample.
embodiment 30
Prescription:
Nalmefene hydrochloride 1.0g(is in nalmefene)
Glucose 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 8.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 12min at 121 DEG C.Make 500, sample.
embodiment 31
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 7.5 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 80 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 45min at 105 DEG C.Make 1000, sample.
embodiment 32
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Sodium chloride 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 8.5 with the sodium hydroxide solution first time of 0.2mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 40min at 90 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.1mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 30min at 115 DEG C.Make 1000, sample.
embodiment 33
Prescription:
Nalmefene hydrochloride 0.1g(is in nalmefene)
Glucose 9.0g
L-arginine hydrochloride 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml.
Technique:
(1) prescription full dose nalmefene hydrochloride is got and sodium chloride is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH is regulated to be 8.0 with the sodium hydroxide solution first time of 0.1mol/L, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add amount of liquid 0.05% (W/V) active carbon, stirring and adsorbing 20min at 100 DEG C of temperature, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.9 the hydrochloric acid solution second time of the medicinal liquid 0.2mol/L obtained through (1), add to the full amount of water for injection, with 0.22 μm of microporous filter membrane fine straining to clear and bright, pressure sterilizing 12min at 121 DEG C.Make 1000, sample.
To obtained 33 batch samples of embodiment 1 ~ 33 respectively 0 day, lucifuge, to be no more than at 20 DEG C of temperature storage 12,24,30 and after 36 months, detect its related substances in sample, testing result is as follows:
Claims (2)
1. a nalmefene hydrochloride injection, is characterized in that in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride is in nalmefene 0.1g ~ 2.0g
Sodium chloride 4.5g ~ 22.5g
Antioxidant 0.5g ~ 4.5g
Salt acid for adjusting pH to 3.2 ~ 4.5
Water for injection adds to 1000ml,
Described antioxidant is L-arginine hydrochloride.
2. nalmefene hydrochloride injection according to claim 1, is characterized in that in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride is in nalmefene 0.8g ~ 1.5g
Sodium chloride 7.2g ~ 12.5g
Antioxidant 1.0g ~ 2.1g
Salt acid for adjusting pH to 3.5 ~ 4.0
Water for injection adds to 1000ml,
Described antioxidant is L-arginine hydrochloride.
3. nalmefene hydrochloride injection according to claim 1, is characterized in that in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride is in nalmefene 1.0g
Sodium chloride 9.0g
Antioxidant 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml,
Described antioxidant is L-arginine hydrochloride.
4. nalmefene hydrochloride injection according to claim 1, is characterized in that in every 1000ml injection, each component is composed as follows:
Nalmefene hydrochloride is in nalmefene 0.1g
Sodium chloride 9.0g
Antioxidant 1.5g
Salt acid for adjusting pH to 3.9
Water for injection adds to 1000ml,
Described antioxidant is L-arginine hydrochloride.
5. the preparation method of nalmefene hydrochloride injection according to Claims 1 to 4 any one, is characterized in that comprising the following steps:
(1) sodium chloride of the nalmefene hydrochloride and recipe quantity of getting prescription full dose is placed in dosing cylinder, add water for injection, stir and make it dissolve completely, after mix homogeneously, pH value of solution is regulated to be 6.0 ~ 9.0 with sodium hydroxide solution first time, and then drop into the L-arginine hydrochloride of recipe quantity, add water for injection, be stirred to dissolve, after mix homogeneously, add active carbon, stirring and adsorbing, filter decarburization and be cooled to room temperature;
(2) regulate pH to be 3.2 ~ 4.5 the medicinal liquid hydrochloric acid solution second time obtained through (1), add to the full amount of water for injection in dilute preparing tank, with microporous filter membrane fine straining to clear and bright, fill nitrogen embedding sterilizing and form injection.
6. the preparation method of nalmefene hydrochloride injection according to claim 5, it is characterized in that first time regulates pH value of solution to be 7.5 ~ 8.5, second time regulates pH value of solution to be 3.2 ~ 4.5.
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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 |
| CN106474054A (en) * | 2015-08-31 | 2017-03-08 | 成都国弘医药有限公司 | A kind of injection containing nalmefene hydrochloride |
| CN106177903B (en) * | 2016-07-25 | 2018-02-23 | 成都国为生物医药有限公司 | The pharmaceutical composition of two kinds of effective components of nalmefene hydrochloride and reduced glutathione |
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| EP3876938A4 (en) * | 2018-11-06 | 2022-08-10 | Purdue Pharma L.P. | Compositions and methods for opioid antagonist delivery |
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