CN115702878B - Dronedarone hydrochloride injection composition, preparation method and application thereof - Google Patents
Dronedarone hydrochloride injection composition, preparation method and application thereof Download PDFInfo
- Publication number
- CN115702878B CN115702878B CN202210438565.2A CN202210438565A CN115702878B CN 115702878 B CN115702878 B CN 115702878B CN 202210438565 A CN202210438565 A CN 202210438565A CN 115702878 B CN115702878 B CN 115702878B
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- CN
- China
- Prior art keywords
- dronedarone hydrochloride
- injection composition
- cyclodextrin
- dronedarone
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- CPKOXUVSOOKUDA-UHFFFAOYSA-N 1-bromo-5-fluoro-2-iodo-4-methylbenzene Chemical compound CC1=CC(I)=C(Br)C=C1F CPKOXUVSOOKUDA-UHFFFAOYSA-N 0.000 title claims abstract description 165
- 229960002919 dronedarone hydrochloride Drugs 0.000 title claims abstract description 165
- 239000007924 injection Substances 0.000 title claims abstract description 93
- 238000002347 injection Methods 0.000 title claims abstract description 93
- 239000000203 mixture Substances 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 45
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 25
- 229960004853 betadex Drugs 0.000 claims abstract description 25
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 20
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 14
- 239000008215 water for injection Substances 0.000 claims abstract description 11
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 9
- 229960002084 dronedarone Drugs 0.000 claims abstract description 8
- ZQTNQVWKHCQYLQ-UHFFFAOYSA-N dronedarone Chemical compound C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 ZQTNQVWKHCQYLQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 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 description 51
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 28
- 235000006708 antioxidants Nutrition 0.000 claims description 19
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 239000001509 sodium citrate Substances 0.000 claims description 13
- 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 claims description 13
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 12
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 11
- 239000008103 glucose Substances 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 9
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 8
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 8
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 7
- 229930003268 Vitamin C Natural products 0.000 claims description 7
- 235000019154 vitamin C Nutrition 0.000 claims description 7
- 239000011718 vitamin C Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 5
- 229920001353 Dextrin Polymers 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
- 235000019425 dextrin Nutrition 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 229940090044 injection Drugs 0.000 description 58
- 239000000243 solution Substances 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
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- 230000001105 regulatory effect Effects 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
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- 239000012085 test solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 3
- 206010003658 Atrial Fibrillation Diseases 0.000 description 3
- 206010003662 Atrial flutter Diseases 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 3
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229960005260 amiodarone Drugs 0.000 description 3
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
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- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 3
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 3
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- 230000001954 sterilising effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
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- 229940079593 drug Drugs 0.000 description 2
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- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- DWKVCQXJYURSIQ-UHFFFAOYSA-N n-[2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-yl]methanesulfonamide;hydron;chloride Chemical compound Cl.C1=CC(OCCCN(CCCC)CCCC)=CC=C1C(=O)C1=C(CCCC)OC2=CC=C(NS(C)(=O)=O)C=C12 DWKVCQXJYURSIQ-UHFFFAOYSA-N 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
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- 239000000377 silicon dioxide Substances 0.000 description 2
- 210000001013 sinoatrial node Anatomy 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
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- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940108759 amiodarone injection Drugs 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 238000004090 dissolution Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
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- 238000000338 in vitro Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- -1 iodide ions Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 229940087092 multaq Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
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- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 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
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite 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
- 229940001474 sodium thiosulfate Drugs 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
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- 239000003643 water by type Substances 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a dronedarone hydrochloride injection composition, a preparation method and application thereof. The invention provides a dronedarone hydrochloride injection composition which comprises dronedarone hydrochloride, cyclodextrin, an isotonic regulator, a pH regulator, an antioxidant and water for injection, wherein the cyclodextrin does not comprise beta-cyclodextrin without a substituent. The dronedarone hydrochloride-cyclodextrin inclusion compound disclosed by the invention has the advantages of good stability, greatly improved solubility in water, about 90 times higher solubility than dronedarone hydrochloride, high bioavailability and suitability for industrial production. The preparation method of the dronedarone hydrochloride inclusion compound is simple in operation, and the prepared dronedarone hydrochloride inclusion compound is easy to prepare a preparation. The dronedarone hydrochloride injection prepared by the invention has good stability and can be used for arrhythmia patients who are not suitable for oral administration.
Description
The application claims the priority of the prior application of the injection composition of dronedarone hydrochloride, the preparation method and the application thereof, which is submitted to the China national intellectual property agency by the year 2021, the month 8 and the day 16 and has the patent application number 202110936257.8. The entire contents of said prior application are incorporated by reference into the present application.
Technical Field
The invention belongs to the field of pharmaceutical compositions, and particularly relates to a dronedarone hydrochloride injection composition, a preparation method and application thereof.
Background
Arrhythmia (CARDIAC ARRHYTHMIA) is a common disease, and has extremely high incidence, and the occurrence of arrhythmia seriously jeopardizes the physical health of patients, and also affects the psychological quality of the patients to a certain extent. Arrhythmia is due to abnormal sinus node activation or activation occurs outside the sinus node, and the activation is slow, blocked or conducted through abnormal channels, i.e. the origin of heart activity and/or conduction disorders lead to abnormal frequency and/or rhythm of heart beats. Arrhythmia is an important group of diseases in cardiovascular diseases. It can be used alone or in combination with cardiovascular diseases. Sudden death due to sudden onset may also persist in heart failure. Arrhythmia can be broadly classified into tachyarrhythmia and bradyarrhythmia based on the ventricular rate at which the arrhythmia is initiated. Because of the multiple and uncertainty of arrhythmia, amiodarone injections are often selected for treatment when oral administration is not appropriate. However, adverse reactions caused by iodide ions in amiodarone injection, and the ultra-long half-life of amiodarone, which is simultaneously a liver enzyme inhibitor, limit the clinical application of amiodarone, so that development of an antiarrhythmic injection suitable for patients unsuitable for oral administration is needed.
Dronedarone hydrochloride was developed by the company sonofil, 7.2009, marketed for the first time by the FDA under the trade name MULTAQ (madarone), in the form of tablets, 400mg, for the treatment of cardiac arrhythmias, reducing the risk of developing cardiovascular disease in patients suffering from paroxysmal or sustained Atrial Fibrillation (AF) or Atrial Flutter (AFL), recent episodes of AF/AFL and associated cardiovascular risk factors (e.g. age >70 years), with sinus rhythm or to be cardioverted, hypertension, diabetes, previous cerebrovascular accident, left atrial diameter > 50mm or left ventricular ejection fraction [ LVEF ] < 40%).
Dronedarone hydrochloride (Dronedarone hydrochloride), chemical name N- (2-butyl-3- (4- (3-dibutylaminopropoxy) benzoyl) benzofuran-5-yl) methanesulfonamide hydrochloride, molecular formula C 31H44N2O5 s·hcl, molecular weight 593.2; the chemical structural formula of dronedarone is as follows:
Dronedarone hydrochloride is almost insoluble in water, and is easily soluble in dichloromethane and methanol. The solubility of dronedarone hydrochloride in aqueous solution presents pH dependency, and has the maximum solubility at pH value of 3-5, about 1-2mg/ml; the solubility is obviously reduced at the pH value of 6-7; its solubility was about 10 μg/ml at ph=7. Because of its poor water solubility, no injection has been developed.
Disclosure of Invention
The invention provides a dronedarone hydrochloride clathrate compound which comprises dronedarone hydrochloride and cyclodextrin, wherein the cyclodextrin does not comprise beta-cyclodextrin without substituent groups.
According to an embodiment of the present invention, the cyclodextrin may be selected from one or more of α -cyclodextrin, γ -cyclodextrin, hydroxypropyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin.
According to an embodiment of the invention, the cyclodextrin is preferably hydroxypropyl-beta-cyclodextrin and/or sulfobutyl-beta-cyclodextrin.
According to an embodiment of the present invention, the molar ratio of said cyclodextrin to said dronedarone hydrochloride is preferably between 0.1 and 100, more preferably between 0.2 and 10, still more preferably between 0.3 and 5, for example 1, 1.25, 2, 2.5, 3, 3.8, 4, 5, 10, 20.
According to an embodiment of the present invention, the dronedarone hydrochloride clathrate is preferably composed of dronedarone hydrochloride and cyclodextrin, which does not include unsubstituted β -cyclodextrin. The cyclodextrin is preferably one or more of alpha-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin and sulfobutyl-beta-cyclodextrin.
The invention also provides a dronedarone hydrochloride injection composition which comprises dronedarone hydrochloride, cyclodextrin, an isotonic regulator, water for injection, and optionally a pH regulator and an antioxidant which are contained or not contained, wherein the cyclodextrin does not comprise beta-cyclodextrin without substituent groups.
According to one embodiment of the present invention, the dronedarone hydrochloride injection composition comprises dronedarone hydrochloride, cyclodextrin, an isotonic regulator, a pH regulator, an antioxidant and water for injection, wherein the cyclodextrin does not comprise unsubstituted beta-cyclodextrin.
According to one embodiment of the present invention, the dronedarone hydrochloride injection composition preferably consists of dronedarone hydrochloride, cyclodextrin, an isotonic regulator, a pH regulator, an antioxidant and water for injection, wherein the cyclodextrin does not comprise unsubstituted beta-cyclodextrin.
In the present invention, the cyclodextrin may be selected from one or more of α -cyclodextrin, γ -cyclodextrin, hydroxypropyl- β -cyclodextrin and sulfobutyl- β -cyclodextrin; hydroxypropyl-beta-cyclodextrin and/or sulfobutyl-beta-cyclodextrin are preferred.
According to an embodiment of the invention, the molar ratio of said cyclodextrin to said dronedarone hydrochloride is preferably between 0.1 and 100, more preferably between 0.2 and 10, still more preferably between 0.3 and 5, for example 1, 1.25, 2, 2.5, 3, 3.8, 4, 5, 10, 20.
According to an embodiment of the invention, the isotonic regulator is a substance capable of regulating osmotic pressure, for example sodium chloride and/or glucose.
According to embodiments of the present invention, the concentration of the isotonic regulator may be in the range of 0.1mg/ml to 10mg/ml, for example 1mg/ml to 10mg/ml, such as 0.2mg/ml, 0.95mg/ml, 1mg/ml, 1.0005mg/ml, 1.5mg/ml, 2mg/ml, 4mg/ml or 10mg/ml, the concentration being the ratio of the mass of the isotonic regulator to the volume of the dronedarone hydrochloride injectable composition.
According to an embodiment of the present invention, the pH adjustor is a substance capable of adjusting the pH of the solution, such as one or more of acetic acid, citric acid, sodium citrate, phosphoric acid, sodium hydroxide, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.
According to an embodiment of the present invention, the concentration of the pH adjustor may be 0 to 10.0mg/ml.
In one embodiment, the pH adjustor can be at a concentration of 1.0 to 10.0mg/ml.
For example, the concentration of the pH regulator is 0.005mg/ml, 0.06mg/ml, 0.0075mg/ml, 0.11mg/ml, 3.0mg/ml, 3.2mg/ml, 2.8mg/ml or 2.0mg/ml, and the concentration is the ratio of the mass of the pH regulator to the volume of the dronedarone hydrochloride injection composition.
According to an embodiment of the present invention, the antioxidant may be selected from, for example, one or more of L-cysteine hydrochloride, sodium sulfite, sodium bisulfite, propyl gallate, glutathione, sodium thiosulfate, thiourea, thioglycolic acid, sodium metabisulfite, potassium metabisulfite, vitamin C and vitamin E.
According to embodiments of the present invention, the concentration of the antioxidant may be in the range of 0.001mg/ml to 0.002mg/ml, for example 0.001mg/ml or 0.002mg/ml, the concentration being the ratio of the mass of the antioxidant to the volume of the dronedarone hydrochloride injection composition.
In the present invention, the water is preferably water for injection.
According to an embodiment of the present invention, the dronedarone hydrochloride injection composition may be any one of the following prescriptions:
Prescription 1:12mg/ml dronedarone hydrochloride, 28.8mg/ml hydroxypropyl-beta cyclodextrin, 2mg/ml citric acid, 1mg/ml sodium citrate, 1mg/ml sodium chloride, 0.001mg/ml sodium bisulphite and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is;
prescription 2:12mg/ml dronedarone hydrochloride, 57.6mg/ml hydroxypropyl-beta cyclodextrin, 1.6mg/ml citric acid, 1.6mg/ml sodium citrate, 2mg/ml glucose, 0.002mg/ml sodium bisulphite and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given;
Prescription 3:12mg/ml dronedarone hydrochloride, 43.4mg/ml sulfobutyl-beta cyclodextrin, 1.2mg/ml citric acid, 1.6mg/ml sodium citrate, 4mg/ml sodium chloride, 0.001mg/ml vitamin C and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is;
Prescription 4:12mg/ml dronedarone hydrochloride, 86.8mg/ml sulfobutyl-beta cyclodextrin, 0.6mg/ml citric acid, 1.4mg/ml sodium citrate, 10mg/ml glucose, 0.002mg/ml vitamin C and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is;
Prescription 5:8mg/ml dronedarone hydrochloride, 30mg/ml hydroxypropyl-beta cyclodextrin, 2mg/ml sodium chloride, and 10ml water, wherein the ratio of the weight of each component to the total volume of the dronedarone hydrochloride injection composition is given;
prescription 6:8mg/ml dronedarone hydrochloride, 90mg/ml sulfobutyl-beta cyclodextrin, 1.0mg/ml sodium chloride and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given;
prescription 7:8mg/ml dronedarone hydrochloride, 90mg/ml sulfobutyl-beta cyclodextrin, 0.005mg/ml citric acid, 1.0mg/ml sodium chloride and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is the ratio of the mass to the total volume of the dronedarone hydrochloride injection composition;
Prescription 8:8mg/ml dronedarone hydrochloride, 30mg/ml sulfobutyl-beta cyclodextrin, 0.005mg/ml citric acid, 1.5mg/ml glucose, 0.001mg/ml sodium bisulfite and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is the ratio of the mass to the total volume of the dronedarone hydrochloride injection composition;
Prescription 9:8mg/ml dronedarone hydrochloride, 60mg/ml sulfobutyl-beta cyclodextrin, 0.01mg/ml citric acid, 0.05mg/ml sodium citrate, 1mg/ml sodium chloride, 0.0005mg/ml glucose and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given;
Prescription 10:8mg/ml dronedarone hydrochloride, 120mg/ml sulfobutyl-beta cyclodextrin, 0.01mg/ml citric acid, 0.1mg/ml sodium citrate, 0.2mg/ml glucose, 0.001mg/ml vitamin C and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition.
According to an embodiment of the present invention, the dronedarone hydrochloride injection composition has a pH of 3.0 to 7.0.
In one embodiment, the dronedarone hydrochloride injection composition has a pH of 3.0 to 6.0, for example 3.0, 4.0, 5.0, 6.0, or 7.0.
The invention also provides a preparation method of the dronedarone hydrochloride injection composition, which comprises the following steps:
Step 1: clathrating the cyclodextrin aqueous solution with dronedarone hydrochloride to obtain dronedarone hydrochloride Long Huan dextrin inclusion compound;
Step 2: mixing the dronedarone hydrochloride clathrate compound obtained in the step 1 with an isotonic regulator and water, and optionally adding or not adding a pH regulator and an antioxidant to obtain the dronedarone hydrochloride injection composition;
Or step 2: mixing the dronedarone hydrochloride clathrate compound obtained in the step 1 with an isotonic regulator, and optionally adding or not adding a pH regulator and an antioxidant to obtain the dronedarone hydrochloride injection composition.
In one embodiment, step 2: mixing the dronedarone hydrochloride clathrate compound obtained in the step 1 with an isotonic regulator, an antioxidant and water to obtain the dronedarone hydrochloride injection composition.
In one embodiment, step 2: mixing the dronedarone hydrochloride clathrate compound obtained in the step 1 with an isotonic regulator and an antioxidant to obtain the dronedarone hydrochloride injection composition.
According to an embodiment of the present invention, the dronedarone hydrochloride clathrate of step 1 may be prepared by using conventional inclusion conditions in the art, and the following inclusion conditions are preferably used in the present invention:
in step 1, the mass concentration of the cyclodextrin aqueous solution is preferably 1% to 50%, more preferably 5% to 30%, for example 9%, 15%, 20% or 30%, and the mass concentration is the percentage of the mass of cyclodextrin to the total mass of the cyclodextrin aqueous solution.
According to an embodiment of the invention, in step 1, the temperature of the inclusion is preferably 20 ℃ to 80 ℃, more preferably 40 ℃ to 70 ℃, for example 60 ℃.
According to an embodiment of the present invention, in step 1, the time of the inclusion is preferably 0.5 to 20 hours, more preferably 1 to 10 hours, for example 7 hours.
According to an embodiment of the present invention, in the preparation method of dronedarone hydrochloride clathrate, the mixing is preferably stirring mixing.
According to one embodiment of the invention, step 1 preferably employs the following post-treatment steps: and dissolving dronedarone hydrochloride in cyclodextrin water solution, clathrating, cooling, filtering and drying after clathration is finished to obtain the dronedarone hydrochloride clathrate.
According to an embodiment of the present invention, in the post-treatment step of step 1, the temperature of the cooling is preferably 10 ℃ to 30 ℃, and more preferably 20 ℃ to 25 ℃.
According to an embodiment of the invention, in the post-treatment step of step 1, the filtration is preferably performed using a filter cartridge. The pore diameter of the filter element is preferably 0.22-0.8 microns.
According to an embodiment of the present invention, in the post-treatment step of step1, the drying means is preferably one or more selected from the group consisting of freeze-drying, drying under reduced pressure, drying under normal pressure and spray-drying, and further preferably freeze-drying and/or spray-drying. The freeze-drying may be vacuum freeze-drying.
According to an embodiment of the present invention, the prepared dronedarone hydrochloride injection composition has a pH of 3.0 to 7.0.
In one embodiment, the dronedarone hydrochloride injection composition is prepared having a pH of 3.0 to 6.0, for example 3.0, 4.0, 5.0, 6.0 or 7.0.
The invention also provides application of the dronedarone hydrochloride injection composition in preparation of a preparation.
According to an embodiment of the present invention, the formulation may be an injection.
According to an embodiment of the present invention, the specification of the injection may be 8ml.
According to one embodiment of the invention, the concentration of the injection may be 5 to 12mg/ml, for example 10mg/ml; based on the concentration of dronedarone hydrochloride in the injection; preferably, the dronedarone hydrochloride is present in the injection at least in the form of dronedarone hydrochloride clathrate.
The invention also provides an injection, which contains the dronedarone hydrochloride injection composition.
The invention also provides a preparation method of the dronedarone hydrochloride injection, which comprises the steps of finely filtering the dronedarone hydrochloride injection composition by a microporous filter membrane, filling and sterilizing to obtain the dronedarone hydrochloride injection.
The invention also provides application of the dronedarone hydrochloride injection composition in preparing medicines for treating and/or preventing arrhythmia.
The present invention also provides a method for treating and/or preventing arrhythmia, which is to administer an effective dose of the dronedarone hydrochloride injection composition or formulation to a patient.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
The invention has the beneficial effects that: the invention overcomes the defects of small dronedarone hydrochloride Long Rongjie degree, low in-vitro dissolution speed, low bioavailability, large administration dosage and the like in the prior art, and provides a dronedarone hydrochloride injection composition, a preparation method and application thereof.
The dronedarone hydrochloride-cyclodextrin inclusion compound disclosed by the invention has the advantages of good stability, greatly improved solubility in water, about 90 times higher solubility than dronedarone hydrochloride (the solubility of bulk drugs in water is only 0.69 mg/ml), high bioavailability and suitability for industrial production. The preparation method of the dronedarone hydrochloride inclusion compound is simple in operation, and the prepared dronedarone hydrochloride inclusion compound is easy to prepare a preparation. The dronedarone hydrochloride composition and injection prepared by the invention have good stability and are suitable for arrhythmia patients who are not suitable for oral administration.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Examples 1 to 4
Examples 1-4 dronedarone hydrochloride compositions were formulated as shown in table 1:
TABLE 1
Examples 5 to 10
Examples 5-10 dronedarone hydrochloride compositions were formulated as shown in table 2:
TABLE 2
The preparation process of examples 1-10: preparing cyclodextrin into 30% aqueous solution, adding prescribed amount of dronedarone hydrochloride, stirring at 60 ℃ for 7 hours, cooling to room temperature, filtering, and freeze-drying to obtain dronedarone hydrochloride Long Huan dextrin inclusion compound.
Adding an isotonic regulator, a pH regulator and an antioxidant into a proper amount of water for injection to dissolve, adding dronedarone hydrochloride inclusion compound, dissolving, and regulating the pH to 3-7 by using the pH regulator. Adding water to the preparation amount, finely filtering the obtained solution by using a microporous filter membrane, filling, and sterilizing (121 ℃ for 15 minutes) to obtain the final product of the dronedarone hydrochloride injection.
Samples of examples 5 to 10 above were placed at high temperature (60 ℃) and acceleration (40.+ -. 2 ℃,75% RH.+ -. 5% RH) respectively, and were sampled and tested at the corresponding time points, and the dronedarone hydrochloride content, the pH value of the injection and the related substances were tested. The detection method of dronedarone hydrochloride content and related substances is as follows:
content of dronedarone hydrochloride: measured according to high performance liquid chromatography (general rule 0512);
Solvent: acetonitrile-water (volume ratio, 60:40);
Test solution: the product is diluted with a solvent to prepare a solution containing about 0.08mg of dronedarone per 1 mL.
Control solution: taking a proper amount of dronedarone hydrochloride reference substance, precisely weighing, dissolving with a solvent and quantitatively diluting to prepare a solution containing about 0.08mg of dronedarone in each 1 mL.
Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; 0.2% triethylamine solution (2 mL of triethylamine is precisely measured and placed in 1000mL of water, evenly mixed, and pH value is regulated to 9.0) by phosphoric acid to acetonitrile (10:90) as a mobile phase; the flow rate is 1.0mL per minute; column temperature is 30 ℃; the detection wavelength is 288nm; the sample injection volume is 10 mu L; the run time was 10min.
Related substances: measured according to high performance liquid chromatography (general rule 0512);
Solvent: acetonitrile-water (volume ratio, 60:40);
test solution: the product is diluted with a solvent to prepare a solution containing about 0.8mg of dronedarone per 1 mL.
Control solution: precisely measuring a proper amount of the test solution, and quantitatively diluting the test solution by using a solvent to prepare a solution with about 1.6 mug of dronedarone in each 1 mL.
Chromatographic conditions: octadecylsilane chemically bonded silica is used as filler (Waters XBridge Shield RP, 18,4.6 mm. Times.250 mm,5 μm or equivalent performance column is recommended); taking a 0.2% triethylamine solution (2 mL of triethylamine is precisely measured and placed in 1000mL of water, uniformly mixing, regulating the pH value to 9.0 by phosphoric acid) as a mobile phase A, and acetonitrile as a mobile phase B; the flow rate was 0.8mL per minute; column temperature is 30 ℃; the detection wavelength is 246nm; the sample injection volume is 25 mu L; the run time was 50min.
The stability results are shown in tables 3-5 below:
TABLE 3 results of the high temperature 60℃content [1]
| Examples | Day 0 | For 5 days | For 10 days |
| Example 5 | 101.3 | 101.7 | 101.0 |
| Example 6 | 103.2 | 102.1 | 101.9 |
| Example 7 | 100.9 | 101.0 | 100.4 |
| Example 8 | 100.3 | 99.8 | 100.5 |
| Example 9 | 100.9 | 100.7 | 100.8 |
| Example 10 * | 100.1 | 99.3 | 99.8 |
[1] The content results refer to the percentage of the test content of dronedarone hydrochloride in the clear solution to the theoretical value, which refers to the concentration of the prescribed amount of dronedarone hydrochloride in the prescribed amount of water for injection;
* : example 10 will precipitate during placement and therefore stability will not be examined further.
As is clear from Table 3, the dronedarone hydrochloride content was almost unchanged from the initial value under the conditions of 5 days and 10 days at high temperature. Further testing at high temperature for 30 days and accelerating for 30 days, the content result of dronedarone hydrochloride is not obviously changed compared with the initial value, and the difference value of dronedarone hydrochloride and dronedarone hydrochloride is in the range of 0-5.0%. It is demonstrated that dronedarone hydrochloride injection prepared in examples 5-10 has good stability.
TABLE 4 pH results at high temperature 60℃
| Examples | Day 0 | For 5 days | For 10 days |
| Example 5 | 6.0 | 5.8 | 6.1 |
| Example 6 | 5.7 | 5.3 | 5.1 |
| Example 7 | 4.9 | 4.9 | 4.9 |
| Example 8 | 3.0 | 3.0 | 3.0 |
| Example 9 | 5.5 | 5.5 | 5.5 |
As is clear from Table 4, the pH of dronedarone hydrochloride was almost unchanged from the initial value under the conditions of 5 days and 10 days at high temperature. Further testing at high temperature for 30 days and accelerating for 30 days, the pH result of dronedarone hydrochloride is not obviously changed compared with the initial value, and the difference value of dronedarone hydrochloride and dronedarone hydrochloride is in the range of 0-1.0. It is demonstrated that dronedarone hydrochloride injection prepared in examples 5-9 has good stability.
TABLE 5 results of substances involved at a high temperature of 60 DEG C *
* Less than 0.05% of impurities do not account for total impurities.
As is clear from Table 5, the results of the dronedarone hydrochloride-related substances were almost unchanged from the initial values under the conditions of 5 days and 10 days at high temperature. Further testing at high temperature for 30 days and acceleration for 30 days, the results of the relevant substances of dronedarone hydrochloride are not obviously changed compared with the initial values. It is demonstrated that dronedarone hydrochloride injection prepared in examples 5-9 has good stability.
Amongthem,thestructureoftheknownimpurityIM-Aisasfollows:
The molecular formula is: c 27H36N2O5 S
The molecular weight is as follows: 500.65
The chemical name is: n- [ 2-butyl-3- [4- [3- (butylamino) propoxy ] benzoyl ] -5-benzofuranyl ] methanesulfonamide.
Example 11
The recipe of this example is the same as that of example 7, and the preparation process is as follows: preparing cyclodextrin into water solution with concentration of about 9%, adding prescribed amount of dronedarone hydrochloride, stirring at 60 ℃ for 7 hours, cooling to room temperature, filtering, and freeze-drying to obtain dronedarone hydrochloride Long Huan dextrin inclusion compound.
Adding an isotonic regulator, a pH regulator and an antioxidant into a proper amount of water for injection to dissolve, adding dronedarone hydrochloride inclusion compound, dissolving, and regulating the pH to 3-7 by using the pH regulator. Adding water to the preparation amount, finely filtering the obtained solution by using a microporous filter membrane, filling, and sterilizing (121 ℃ for 15 minutes) to obtain the final product of the dronedarone hydrochloride injection.
The obtained finished product is a clear solution, and the ratio of the test content of dronedarone hydrochloride to the theoretical value is nearly 100% by the content test, which shows that the concentration of dronedarone hydrochloride in the injection is about 8mg/ml. Meanwhile, the stability of the injection of the embodiment can at least reach the stability of the embodiments 5-9.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An injection composition of dronedarone hydrochloride, characterized in that it comprises dronedarone hydrochloride, cyclodextrin, an isotonic regulator and water for injection, optionally with or without a pH regulator and/or an antioxidant, said cyclodextrin being chosen from hydroxypropyl- β -cyclodextrin and/or sulfobutyl- β -cyclodextrin;
the molar ratio of the cyclodextrin to the dronedarone hydrochloride is 1-5;
The isotonic regulator is sodium chloride and/or glucose;
The concentration of the isotonic regulator is 1 mg/ml-10 mg/ml, and the concentration refers to the ratio of the mass of the isotonic regulator to the volume of the dronedarone hydrochloride injection composition;
The pH regulator is citric acid and/or sodium citrate;
the pH of the dronedarone hydrochloride injection composition is 3-6.
2. The dronedarone acid injection composition of claim 1, wherein said composition comprises: dronedarone hydrochloride, cyclodextrin, isotonic regulator, pH regulator, antioxidant and water for injection.
3. The dronedarone hydrochloride injection composition according to claim 1 or 2, characterized in that: the concentration of the pH regulator is 1-10.0 mg/ml, and the concentration refers to the ratio of the mass of the pH regulator to the volume of the dronedarone hydrochloride injection composition.
4. The dronedarone hydrochloride injection composition according to claim 1 or 2, characterized in that: the antioxidant is one or more of sodium bisulphite and vitamin C;
And/or the number of the groups of groups,
The concentration of the antioxidant is 0.001mg/ml-0.002mg/ml, and the concentration refers to the ratio of the mass of the antioxidant to the volume of the dronedarone hydrochloride injection composition.
5. The dronedarone hydrochloride injection composition of claim 1, wherein: the dronedarone hydrochloride injection composition comprises dronedarone hydrochloride, cyclodextrin, an isotonic regulator, a pH regulator and water for injection.
6. The dronedarone hydrochloride injection composition of claim 1,2 or 5, wherein: the dronedarone hydrochloride injection composition is prepared according to any one of the following prescriptions:
Prescription 1:12mg/ml dronedarone hydrochloride, 28.8mg/ml hydroxypropyl-beta cyclodextrin, 2mg/ml citric acid, 1mg/ml sodium citrate, 1mg/ml sodium chloride, 0.001mg/ml sodium bisulphite and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is;
prescription 2:12mg/ml dronedarone hydrochloride, 57.6mg/ml hydroxypropyl-beta cyclodextrin, 1.6mg/ml citric acid, 1.6mg/ml sodium citrate, 2mg/ml glucose, 0.002mg/ml sodium bisulphite and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given;
Prescription 3:12mg/ml dronedarone hydrochloride, 43.4mg/ml sulfobutyl-beta cyclodextrin, 1.2mg/ml citric acid, 1.6mg/ml sodium citrate, 4mg/ml sodium chloride, 0.001mg/ml vitamin C and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is;
Prescription 4:12mg/ml dronedarone hydrochloride, 86.8mg/ml sulfobutyl-beta cyclodextrin, 0.6mg/ml citric acid, 1.4mg/ml sodium citrate, 10mg/ml glucose, 0.002mg/ml vitamin C and 5ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is;
Prescription 5:8mg/ml dronedarone hydrochloride, 30mg/ml hydroxypropyl-beta cyclodextrin, 2mg/ml sodium chloride and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given;
prescription 6:8mg/ml dronedarone hydrochloride, 90mg/ml sulfobutyl-beta cyclodextrin, 1.0mg/ml sodium chloride and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given;
prescription 7:8mg/ml dronedarone hydrochloride, 90mg/ml sulfobutyl-beta cyclodextrin, 0.005mg/ml citric acid, 1.0mg/ml sodium chloride and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is the ratio of the mass to the total volume of the dronedarone hydrochloride injection composition;
Prescription 8:8mg/ml dronedarone hydrochloride, 30mg/ml sulfobutyl-beta cyclodextrin, 0.005mg/ml citric acid, 1.5mg/ml glucose, 0.001mg/ml sodium bisulfite and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is the ratio of the mass to the total volume of the dronedarone hydrochloride injection composition;
Prescription 9:8mg/ml dronedarone hydrochloride, 60mg/ml sulfobutyl-beta cyclodextrin, 0.01mg/ml citric acid, 0.05mg/ml sodium citrate, 1mg/ml sodium chloride, 0.0005mg/ml glucose and 10ml water, wherein the ratio of the mass of each component to the total volume of the dronedarone hydrochloride injection composition is given.
7. Process for the preparation of dronedarone hydrochloride injection composition according to any one of claims 1 to 6, comprising the following steps:
Step 1: clathrating the cyclodextrin aqueous solution with dronedarone hydrochloride to obtain dronedarone hydrochloride Long Huan dextrin inclusion compound;
step 2: mixing the dronedarone hydrochloride clathrate compound obtained in the step 1 with an isotonic regulator, an antioxidant and water to obtain the dronedarone hydrochloride injection composition;
Or step 2: mixing the dronedarone hydrochloride clathrate compound obtained in the step 1 with an isotonic regulator, a pH regulator and an antioxidant to obtain the dronedarone hydrochloride injection composition.
8. Use of the dronedarone hydrochloride injection composition of any one of claims 1-6 in the preparation of a pharmaceutical formulation, said medicament being a medicament for the treatment of cardiac arrhythmias.
9. The use according to claim 8, wherein the pharmaceutical formulation is an injection.
10. An injection comprising the dronedarone hydrochloride injection composition of any one of claims 1 to 6.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110936257 | 2021-08-16 | ||
| CN2021109362578 | 2021-08-16 |
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| CN115702878A CN115702878A (en) | 2023-02-17 |
| CN115702878B true CN115702878B (en) | 2024-05-10 |
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| CN202210438565.2A Active CN115702878B (en) | 2021-08-16 | 2022-04-20 | Dronedarone hydrochloride injection composition, preparation method and application thereof |
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| Country | Link |
|---|---|
| CN (1) | CN115702878B (en) |
| TW (1) | TW202320751A (en) |
| WO (1) | WO2023019993A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102908307A (en) * | 2011-08-03 | 2013-02-06 | 天津市嵩锐医药科技有限公司 | Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof |
| CN103169691A (en) * | 2011-12-22 | 2013-06-26 | 深圳信立泰药业股份有限公司 | Dronedarone or powder of salt thereof and pharmaceutical composition prepared therefrom |
| CN105412027A (en) * | 2015-11-13 | 2016-03-23 | 青岛市海慈医疗集团 | Preparation method of dronedarone hydrochloride tablets |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2817750B1 (en) * | 2000-12-11 | 2003-02-21 | Sanofi Synthelabo | DRONEDARONE PHARMACEUTICAL COMPOSITION FOR PARENTERAL ADMINISTRATION |
| EP2428511A1 (en) * | 2010-09-09 | 2012-03-14 | USV Limited | Synthesis of dronedarone and salts thereof |
-
2022
- 2022-04-20 CN CN202210438565.2A patent/CN115702878B/en active Active
- 2022-04-20 TW TW111115119A patent/TW202320751A/en unknown
- 2022-04-20 WO PCT/CN2022/087977 patent/WO2023019993A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102908307A (en) * | 2011-08-03 | 2013-02-06 | 天津市嵩锐医药科技有限公司 | Dronedarone hydrochloride pharmaceutical composition for injection and preparation method thereof |
| CN103169691A (en) * | 2011-12-22 | 2013-06-26 | 深圳信立泰药业股份有限公司 | Dronedarone or powder of salt thereof and pharmaceutical composition prepared therefrom |
| CN105412027A (en) * | 2015-11-13 | 2016-03-23 | 青岛市海慈医疗集团 | Preparation method of dronedarone hydrochloride tablets |
Non-Patent Citations (1)
| Title |
|---|
| 孟胜男 等.《药剂学》.中国医药科技出版社,2021,280-281. * |
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| Publication number | Publication date |
|---|---|
| WO2023019993A1 (en) | 2023-02-23 |
| TW202320751A (en) | 2023-06-01 |
| CN115702878A (en) | 2023-02-17 |
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