CN101732243A - Stable methyl naltrexone injection and preparation method thereof - Google Patents
Stable methyl naltrexone injection and preparation method thereof Download PDFInfo
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- CN101732243A CN101732243A CN200810233125A CN200810233125A CN101732243A CN 101732243 A CN101732243 A CN 101732243A CN 200810233125 A CN200810233125 A CN 200810233125A CN 200810233125 A CN200810233125 A CN 200810233125A CN 101732243 A CN101732243 A CN 101732243A
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- Prior art keywords
- injection
- methyl naltrexone
- valine
- cysteine
- antioxidant
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Links
- 229940026048 methylnaltrexone injection Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 46
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 36
- JVLBPIPGETUEET-WIXLDOGYSA-O (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one Chemical compound C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 JVLBPIPGETUEET-WIXLDOGYSA-O 0.000 claims abstract description 29
- 229960002921 methylnaltrexone Drugs 0.000 claims abstract description 29
- 229940090044 injection Drugs 0.000 claims abstract description 28
- 238000002347 injection Methods 0.000 claims abstract description 28
- 239000007924 injection Substances 0.000 claims abstract description 28
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229960004295 valine Drugs 0.000 claims abstract description 24
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 22
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 13
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 13
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims abstract description 12
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960002433 cysteine Drugs 0.000 claims abstract description 12
- 239000004474 valine Substances 0.000 claims abstract description 12
- 235000014393 valine Nutrition 0.000 claims abstract description 12
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000018417 cysteine Nutrition 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000000654 additive Substances 0.000 claims abstract description 10
- 239000000337 buffer salt Substances 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 32
- 229960002834 methylnaltrexone bromide Drugs 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 19
- 239000007979 citrate buffer Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 10
- 239000008215 water for injection Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000011082 depyrogenation Methods 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- 238000005303 weighing Methods 0.000 claims description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 238000005262 decarbonization Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 3
- 239000003708 ampul Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000011521 glass Substances 0.000 claims description 2
- IFGIYSGOEZJNBE-LHJYHSJWSA-N (3s,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one;bromide Chemical compound [Br-].C([N@@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 IFGIYSGOEZJNBE-LHJYHSJWSA-N 0.000 claims 3
- 230000003204 osmotic effect Effects 0.000 claims 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract 2
- 230000000996 additive effect Effects 0.000 abstract 2
- 229960003966 nicotinamide Drugs 0.000 abstract 1
- 235000005152 nicotinamide Nutrition 0.000 abstract 1
- 239000011570 nicotinamide Substances 0.000 abstract 1
- IFGIYSGOEZJNBE-NQMNLMSRSA-N (3r,4r,4as,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-3-ium-7-one;bromide Chemical compound [Br-].C([N@+]1(C)[C@@H]2CC=3C4=C(C(=CC=3)O)O[C@@H]3[C@]4([C@@]2(O)CCC3=O)CC1)C1CC1 IFGIYSGOEZJNBE-NQMNLMSRSA-N 0.000 description 24
- 235000006708 antioxidants Nutrition 0.000 description 16
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- 239000000872 buffer Substances 0.000 description 7
- 239000001509 sodium citrate Substances 0.000 description 7
- 239000007951 isotonicity adjuster Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 229940038773 trisodium citrate Drugs 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- 239000008896 Opium Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960001027 opium Drugs 0.000 description 3
- 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 3
- 238000012360 testing method Methods 0.000 description 3
- 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 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 229940105899 relistor Drugs 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 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
- 206010010774 Constipation Diseases 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 240000006927 Foeniculum vulgare Species 0.000 description 1
- 235000004204 Foeniculum vulgare Nutrition 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- HHCCNQLNWSZWDH-UHFFFAOYSA-N n-hydroxymethanimine oxide Chemical compound O[N+]([O-])=C HHCCNQLNWSZWDH-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229940079358 peripheral opioid receptor antagonist Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 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
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a stable methyl naltrexone injection or a pharmaceutical salt injection thereof and a preparation method thereof. The injection comprises methyl naltrexone or pharmaceutical salt thereof and additive, wherein the additive is citric acid buffer salt and antioxidant, and the antioxidant is one or more chosen from thiourea, cysteine, L-cysteine, valine, L-valine and nicotinamide. The prescription of the methyl naltrexone injection of the invention uses no EDTA or derivative thereof in the prescription of a foreign market methyl naltrexone injection but has higher stability than the foreign market methyl naltrexone injection. The preparation method of the stable methyl naltrexone injection of the invention has simple process and is applied to mass production.
Description
Technical field:
The present invention relates to a kind of stable medicaments injection and preparation method thereof, be specifically related to a kind of methyl naltrexone or its officinal salt, and with citric acid buffer salt and one or more antioxidant of being selected from thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide as additives, especially methylnaltrexone bromide becomes the injection of effective ingredient.
Background technology:
The chemical structural formula of methylnaltrexone bromide (methylnaltrexone bromide) is:
Chemical name is that 17-encircles third methyl-4,5-epoxy-3, and 14-dihydroxy-17-methyl-6-oxygen-, bromide (5a)
Methylnaltrexone bromide is white or off-white color crystalline powder, and is water-soluble, no hygroscopicity, and fusing point is 251 ℃, and pH is approximately 4.6, and octanol/water partition coefficient (logP) is-1.12.
The methylnaltrexone bromide injection is colourless or almost colourless clear and bright solution.
Methylnaltrexone bromide is by Wyeth Pharmaceuticals company and Progenics Pharmaceuticals, Inc. the peripheral opioid receptor antagonist developed jointly of company, FDA ratifies its injection, and (specification: trade name 12mg/0.6ml) is RELISTOR, is mainly used in the constipation that treatment is caused by the opium treatment clinically.
WO02098422 discloses a kind of with the method for methyl naltrexone treatment because of the inductive immunosuppressant disease of opium (as HIV), in the description of this patent, mention the injection of methyl naltrexone, its active substance consumption is 0.05-0.5mg/kg, buffer is acetate buffer (1-2%W/V), citrate buffer solution (1-3%W/V), and antiseptic is selected from Acetochlorone, nipalgin is first-class.
World patent WO2008019115 discloses the injection of methyl naltrexone or its officinal salt, comprises calcium salt and chelating agen as stabilizing agent, and the also available chelating agen of calcium salt that contains is as stabilizing agent.This patent also discloses the preparation method of methyl naltrexone injection: preparation earlier contains the solution of methyl naltrexone or its officinal salt, isoosmotic adjusting agent and calcium salt chelating agen; This solution and divide of sterilizing is filled in one or more sealed containers.
The Chinese patent CN1767831 of Progenics Pharm Inc.'s application discloses the pharmaceutical preparation of the solution that comprises methyl naltrexone or its salt, and principal character is that the degraded concentration of methyl naltrexone is no more than 2% through placing 6 months behind the autoclaving or under the room temperature.Its dependent claims limits said preparation respectively and contains chelating agen (EDTA etc.), and buffer (Acidum Citricum etc.), pH value are 2-6, antioxidant, isotonic agent, cryoprotector (polyhydric alcohol) or opium material, and methyl naltrexone concentration is 0.1-100mg/ml.Wherein, antioxidant is selected from ascorbic acid derivates, fourth hydroxyl fennel ether, butylated hydroxytoluene, alkyl gallates, sodium pyrosulfite, sodium sulfite, sodium dithionite, sodium thioglycollate, rongalite, tocopherol and derivant, thioglycerol and sodium sulfite.
The inventor is unexpected the discovery in development methylnaltrexone bromide injection process, in pH3～4 scopes, with citric acid, trisodium citrate (or citrate buffer) as buffer agent, with sodium chloride as isoosmotic adjusting agent, with one or more materials that are selected from thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide as antioxidant, under the situation that does not have chelating agen to exist, the stability of the methylnaltrexone bromide injection that makes is better than the sample that the prescription by listing RELISTOR prepares.And we prove that by pharmacological testing the injection that this prescription makes does not have hemolytic, blood vessel irritation and anaphylaxis.Owing to contain phenolic hydroxyl group in the methylnaltrexone bromide chemical structural formula; oxidized easily; so we are except adding in prescription the antioxidant; also in preparation technology, carry out nitrogen filled protection; itself and oxygen are further isolated; this technology has not only improved the stability of this product, and also simple possible is easy to suitability for industrialized production.
Summary of the invention:
Of the present inventionly supplied a kind of stable methyl naltrexone injection, contained methyl naltrexone or its officinal salt and additives, it is characterized in that: additives comprise (a) citrate buffer and (b) one or more antioxidant.Wherein, the officinal salt of said methyl naltrexone is an inorganic salt, and example hydrochloric acid salt, hydrobromate, sulfate and other acylate are preferably hydrobromate, i.e. methylnaltrexone bromide.
Methyl naltrexone injection of the present invention, wherein the concentration of methyl naltrexone is 1.0～50.0mg/ml, is preferably 10～30mg/ml, more preferably 20mg/ml.
Methyl naltrexone injection of the present invention, its pH scope is 3.0～4.0.
Methyl naltrexone injection of the present invention, the concentration range of its citrate buffer is: 0.5mg/ml～10mg/ml.
Methyl naltrexone injection of the present invention, its described antioxidant is selected from one or more in the following reagent: thiourea, half Guang nitronic acid, L-cysteine, valine, L-valine, nicotiamide, its concentration range is: 0.01～5mg/ml.
In one embodiment, methyl naltrexone injection of the present invention, contain methyl naltrexone or its officinal salt, its concentration is 1.0～50.0mg/ml, concentration is the antioxidant that the citrate buffer of 0.5mg/ml～10mg/ml and one or more are selected from one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide.The wherein preferred 10-30mg/ml of the concentration of methyl naltrexone, more preferably 20mg/ml.Also further comprise isotonic agent sodium chloride in this embodiment.The PH of the injection of this embodiment is 3.0-4.0.
In another embodiment, methyl naltrexone injection of the present invention, contain methyl naltrexone or its officinal salt, its concentration is 1.0～50.0mg/ml, concentration is the citrate buffer of 0.5mg/ml～10mg/ml, with one or more antioxidant that is selected from one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, its concentration range is: 0.01～5mg/ml, the PH of this injection are 3.0～4.0.Wherein, the preferred 10-30mg/ml of the concentration of methyl naltrexone, more preferably 20mg/ml.PH usable acid or alkali are regulated, example hydrochloric acid, hydrobromic acid, citric acid or its buffer, sodium hydroxide solution etc.Also further comprise isotonic agent sodium chloride in this embodiment.
In another specific embodiments, methyl naltrexone injection of the present invention, contain methyl naltrexone or its officinal salt, its concentration is 1.0～50.0mg/ml, preferred 10-30mg/ml, citrate buffer, and its concentration is 0.5mg/ml～10mg/ml, one or more are selected from the antioxidant of one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, its concentration is the isotonic agent of 0.01～5mg/ml and a kind of sodium chloride, and the PH of this injection is 3.0～4.0.Wherein, the preferred 10-30mg/ml of the concentration of methyl naltrexone, more preferably 20mg/ml.PH usable acid or alkali are regulated, example hydrochloric acid, hydrobromic acid, citric acid or its buffer, sodium hydroxide solution etc., preferred hydrochloric acid or sodium hydroxide solution.
In a specific embodiments again, methyl naltrexone injection of the present invention, by methyl naltrexone or its officinal salt, its concentration is 1.0～50.0mg/ml, preferred 10-30mg/ml, citrate buffer, its concentration are 0.5mg/ml～10mg/ml, and one or more are selected from the antioxidant of one group of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide, its concentration is 0.01～5mg/ml, and a kind of isotonic agent of sodium chloride and water for injection are formed.Wherein, the PH of this injection is 3.0～4.0, and PH usable acid or alkali are regulated, example hydrochloric acid, hydrobromic acid, citric acid or its buffer, sodium hydroxide solution etc., preferred hydrochloric acid or sodium hydroxide solution; The concentration of methyl naltrexone is 20mg/ml more preferably.
In above-mentioned all specific embodiments, the officinal salt of said methyl naltrexone is an inorganic salt, and example hydrochloric acid salt, hydrobromate, sulfate, and other acylate are preferably hydrobromate, i.e. methylnaltrexone bromide; Sodium chloride is as isoosmotic adjusting agent, and its concentration is that scope is 1mg/ml～20mg/ml, preferred 5mg/ml～10mg/ml.
In above-mentioned all specific embodiments, wherein, the preferred 1mg/ml～5mg/ml of the concentration of citrate buffer (in citric acid and trisodium citrate weight sum).Citrate buffer can make by citric acid and sodium hydroxide reaction; Also can make by sodium citrate and hydrochloric acid reaction; Can also get by the citric acid and the sodium citrate mixing of constant weight proportioning, wherein, the weight ratio scope of citric acid and sodium citrate is 1: 10 to 10: 1, preferred 1: 1.5 to 1.5: 1, by densitometer, the concentration range of the two all can be 0.5mg/ml～5mg/ml, preferred 1mg/ml～1.5mg/ml.The conventional preparation method preparation of the available buffer of the preparation of citrate buffer.
The present invention also provides a kind of preparation method of stable methylnaltrexone bromide injection, this preparation method is that injection additives such as methyl naltrexone and sodium chloride, antioxidant and citric acid buffer salt are dissolved in an amount of water for injection, be mixed with solution, depyrogenation, available in case of necessity hydrochloric acid or sodium hydrate regulator solution pH value to 3.0～4.0, fine straining, fill, fill nitrogen, seal, sterilize finished product.The gained injection is that 0.6ml contains bromination methyl naltrexone 12mg.
Concrete preparation method is: the methylnaltrexone bromide that takes by weighing recipe quantity respectively, sodium chloride, be selected from thiourea, cysteine, the L-cysteine, valine, the antioxidant that L-valine and nicotiamide are one group, citric acid and trisodium citrate, with an amount of water for injection dissolving, add an amount of needle-use activated carbon, stir depyrogenation, filtering decarbonization, obtain filtrate just, measure pH value, water for injection is added to amount of preparation in pH to 3.0～4.0 of available in case of necessity hydrochloric acid or sodium hydroxide solution regulator solution, gained solution mixed cellulose ester microporous membrane fine straining, fill, fill nitrogen, seal, sterilization gets product.
In one embodiment, the kind of the present invention method for preparing methyl naltrexone injection comprises following process:
A) take by weighing methylnaltrexone bromide, citric acid buffer salt, one or more antioxidant, with an amount of water for injection dissolving;
B) add proper amount of active carbon in last step solution, stir depyrogenation, filtering decarbonization obtains filtrate;
C) measure pH value of filtrate, regulate pH to 3.0～4.0 with hydrochloric acid or sodium hydroxide in case of necessity, add the injection water to configuration amount;
D) will go up step gained solution fine straining, get filtrate, irritate in ampoule bottle or glass tube vial, and charge into aseptic nitrogen and protect, seal; Then,
E) use flowing steam sterilization, obtain methylnaltrexone bromide injection finished product.
In said method, described methyl naltrexone injection, comprise methyl naltrexone or its officinal salt and additives, it is characterized in that: additives comprise (a) citrate buffer, (b) one or more antioxidant, wherein, its officinal salt of methyl naltrexone is hydrobromate, i.e. methylnaltrexone bromide.
In said method, also can add isoosmotic adjusting agent sodium chloride in step a), antioxidant is selected from one or more of thiourea, cysteine, L-cysteine, valine, L-valine and nicotiamide.
Specific embodiment
Further illustrate the present invention by the following examples, but be not limited to scope of embodiments.
Embodiment 1
Methylnaltrexone bromide injection prescription (prescription) sees Table 1.
The tabulation of table 1 methylnaltrexone bromide injection formula
| Prescription | 1 | 2 | 3 | 4 | 5 | 6 (commercially available prescriptions) |
| Methylnaltrexone bromide | 0.72g | 0.48g | 0.48g | 0.48g | 0.24g | 0.48g |
| NaCl | 0.168g | 0.12g | 0.12g | 0.12g | 0.12g | 0.156g |
| Citric acid | 0.036g | 0.03g | 0.03g | 0.03g | 0.03g | - |
| Trisodium citrate | 0.026g | 0.024g | 0.024g | 0.024g | 0.024g | - |
| Thiourea | 0.020g | 0.012g | - | - | - | - |
| The L-cysteine | - | - | 0.12g | - | - | - |
| L-a word used in person's names propylhomoserin | - | - | - | 0.072g | - | - |
| Nicotiamide | - | - | - | - | 0.024g | - |
| Glycine | - | - | - | - | - | 0.0072g |
| EDTA-2Na | - | - | - | - | - | 0.0096g |
| Water for injection | 24ml | 24ml | 24ml | 24ml | 24ml | 24ml |
| PH value | 3.20 | 3.59 | 3.48 | 3.57 | 3.45 | 3.36 |
Preparation technology:
1, the supplementary material that takes by weighing recipe quantity adds the water for injection of recipe quantity, stirring and dissolving in beaker.
2, the needle-use activated carbon of adding 0.05% stirs 30min;
3, filter, measure pH value, regulate pH value with HCl or NaOH in case of necessity;
4, use the mixed cellulose ester microporous membrane fine straining of 0.22u;
5, be sub-packed in the 3ml lyophilizing bottle every bottle of 0.6ml;
6, fill nitrogen, tamponade;
7, use flowing steam sterilization, obtain the methylnaltrexone bromide injection.
Embodiment 2
Stability test: sample is carried out influence factor's test, survey the 10th day related substance.
The sample of the methylnaltrexone bromide injection that above-mentioned 6 prescriptions are made places respectively in illumination, 40 ℃ and 60 ℃ of influence factor's proof boxs and investigates 10 days, measures its related substance situation of change, and with compared in 0 day, concrete data see Table 2.
10 days influence factor's result of the tests of table 2
Conclusion: the sample that adopts prepared injection liquid samples of the present invention and external commercially available prod to write out a prescription carries out stability test under the same conditions, the result shows that the stability of methylnaltrexone bromide injection of the present invention is better than the stability of sample by external commercially available prescription, and does not add chelating agen in the prescription of the present invention.
Claims (10)
1. a stable methyl naltrexone injection contains methyl naltrexone or its officinal salt and additives, it is characterized in that: additives comprise (a) citrate buffer and (b) one or more antioxidant.
2. methyl naltrexone officinal salt according to claim 1 is inorganic salt example hydrochloric acid salt, hydrobromate, sulfate and other acylate, is preferably methylnaltrexone bromide.
3. according to the described arbitrary methyl naltrexone injection of claim 1-2, wherein the concentration of methyl naltrexone is 1.0～50.0mg/ml.
4. methyl naltrexone injection according to claim 3, wherein the concentration of methyl naltrexone is 20mg/ml.
5. according to the described arbitrary methyl naltrexone injection of claim 1-2, it is characterized in that the pH scope is 3.0～4.0.
6. according to the described arbitrary methyl naltrexone injection of claim 1-2, the concentration range of its described citrate buffer is: 0.5mg/ml～10mg/ml.
7. methyl naltrexone injection according to claim 1, its described antioxidant is selected from one or more in the following reagent: thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide.
8. methyl naltrexone injection according to claim 1 also further comprises a kind of isoosmotic adjusting agent sodium chloride.
9. method for preparing methyl naltrexone injection according to claim 1 is characterized in that this method comprises following process:
A) take by weighing methylnaltrexone bromide, citric acid buffer salt, one or more antioxidant, osmotic pressure regulator, with an amount of water for injection dissolving;
B) add proper amount of active carbon, stir depyrogenation, filtering decarbonization obtains filtrate;
C) pH value of mensuration solution is regulated pH to 3.0～4.0 with hydrochloric acid or sodium hydroxide in case of necessity, adds the injection water to configuration amount;
D) with gained solution fine straining, get filtrate, irritate in ampoule bottle or glass tube vial, charge into aseptic nitrogen and protect, seal;
E) use flowing steam sterilization, obtain methylnaltrexone bromide injection finished product.
10. method according to claim 9, antioxidant are selected from one or more of thiourea, cysteine, L-cysteine, valine, L-valine, nicotiamide.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102166185A (en) * | 2011-03-30 | 2011-08-31 | 重庆健能医药开发有限公司 | Isotonic naloxone injection and preparation method thereof |
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| CN105769755A (en) * | 2014-12-23 | 2016-07-20 | 北大方正集团有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
| CN110960486A (en) * | 2018-09-29 | 2020-04-07 | 北京凯因科技股份有限公司 | Methylnaltrexone bromide injection composition |
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Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AR057035A1 (en) * | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SYNTHESIS OF (R) -N-METHYLNTREXONE, PHARMACEUTICAL COMPOSITIONS AND USES |
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| CN102166185A (en) * | 2011-03-30 | 2011-08-31 | 重庆健能医药开发有限公司 | Isotonic naloxone injection and preparation method thereof |
| CN103385889A (en) * | 2013-07-22 | 2013-11-13 | 珠海经济特区生物化学制药厂 | Carbohydrate and electrolyte mixed injection and preparation method thereof |
| CN104116707A (en) * | 2014-08-03 | 2014-10-29 | 张星一 | Pharmaceutical composition containing methyhaaltrexone bromide |
| CN104116707B (en) * | 2014-08-03 | 2016-11-23 | 张星一 | A kind of pharmaceutical composition containing methylnaltrexone bromide |
| CN105769755A (en) * | 2014-12-23 | 2016-07-20 | 北大方正集团有限公司 | Methyhaaltrexone bromide injection and preparation method thereof |
| CN110960486A (en) * | 2018-09-29 | 2020-04-07 | 北京凯因科技股份有限公司 | Methylnaltrexone bromide injection composition |
| CN110960486B (en) * | 2018-09-29 | 2022-05-13 | 北京凯因科技股份有限公司 | Methylnaltrexone bromide injection composition |
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