NO812039L - PROCEDURE FOR THE PREPARATION OF PROTRAACTED EFFECTIVE VINCAMIN PREPARATIONS, VINCAMIN PREPARATIONS AND MEDICINES CONTAINING THESE - Google Patents
PROCEDURE FOR THE PREPARATION OF PROTRAACTED EFFECTIVE VINCAMIN PREPARATIONS, VINCAMIN PREPARATIONS AND MEDICINES CONTAINING THESEInfo
- Publication number
- NO812039L NO812039L NO812039A NO812039A NO812039L NO 812039 L NO812039 L NO 812039L NO 812039 A NO812039 A NO 812039A NO 812039 A NO812039 A NO 812039A NO 812039 L NO812039 L NO 812039L
- Authority
- NO
- Norway
- Prior art keywords
- vincamine
- preparations
- acid
- preparation
- salt
- Prior art date
Links
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 title claims description 107
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 title claims description 55
- 238000002360 preparation method Methods 0.000 title claims description 30
- 238000000034 method Methods 0.000 title claims description 10
- 239000003814 drug Substances 0.000 title claims description 7
- WKACQPMBGWZDMR-UHFFFAOYSA-N Vincamin Natural products CC=C1/CN2CCC34CC2C1C(=C3Nc5ccccc45)C=O WKACQPMBGWZDMR-UHFFFAOYSA-N 0.000 title 2
- 229960002726 vincamine Drugs 0.000 claims description 53
- 239000011347 resin Substances 0.000 claims description 24
- 229920005989 resin Polymers 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 19
- 239000003729 cation exchange resin Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 14
- -1 sulfonic acid cation Chemical class 0.000 claims description 13
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 7
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 7
- YGKAKNJJNTVSKB-YAFGAGFVSA-N vincamine hydrochloride Chemical compound Cl.C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 YGKAKNJJNTVSKB-YAFGAGFVSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 3
- 150000003440 styrenes Chemical class 0.000 claims description 3
- 238000006277 sulfonation reaction Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 2
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 239000013543 active substance Substances 0.000 description 17
- 229940023913 cation exchange resins Drugs 0.000 description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
- 238000004132 cross linking Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- 230000003111 delayed effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000007859 condensation product Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229940126601 medicinal product Drugs 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000000979 retarding effect Effects 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000007306 turnover Effects 0.000 description 2
- WHOZNOZYMBRCBL-OUKQBFOZSA-N (2E)-2-Tetradecenal Chemical compound CCCCCCCCCCC\C=C\C=O WHOZNOZYMBRCBL-OUKQBFOZSA-N 0.000 description 1
- OTHYPAMNTUGKDK-UHFFFAOYSA-N (3-acetylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC(C(C)=O)=C1 OTHYPAMNTUGKDK-UHFFFAOYSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- RXPRRQLKFXBCSJ-HLAWJBBLSA-N 16-epivincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-HLAWJBBLSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- OZDNDGXASTWERN-CTNGQTDRSA-N Apovincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-CTNGQTDRSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000002381 Brain Hypoxia Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920000715 Mucilage Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- UFLGIAIHIAPJJC-UHFFFAOYSA-N Tripelennamine Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 UFLGIAIHIAPJJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 229950006936 apovincamine Drugs 0.000 description 1
- OZDNDGXASTWERN-UHFFFAOYSA-N apovincamine Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940096529 carboxypolymethylene Drugs 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960001550 hyoscyamine sulfate Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008385 outer phase Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000008379 phenol ethers Chemical class 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229940044654 phenolsulfonic acid Drugs 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229920000172 poly(styrenesulfonic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229940005642 polystyrene sulfonic acid Drugs 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 150000004961 triphenylmethanes Chemical class 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
Classifications
-
- 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
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/58—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Oppfinnelsen vedrører en fremgangsmåte til fremstilling av protraher.t virkende vincamin-tilberedninger, således dannede vincamin-tilberdninger, og legemidler inneholdende disse. The invention relates to a method for the production of protractor-acting vincamine preparations, thus formed vincamine preparations, and medicinal products containing these.
Vincamin og dens farmasøytiske godtagbaré syre-addigjonssalter har funnet stor interesse som legemidler spesielt i geriatrien, f. eks. til behandling av cerebrale gjennomblødningsforstyrrelser, og cerebral hypoxie og deres følgeforeteelser, og allerede i praksis funnet bred anvendelse. Den foretrukkede daglige dose av vincamin eller dens hydroklorid ved oral administrering.utgjør 60 mg med begynnelsesdoser inntil 80 mg, og vedlikeholdsdoser fra 30 mg tilsvarende dosisenhetsformer inneholder for det meste 10, 15. 20 eller spesielt 30 mg virksomt stoff. Vincamine and its pharmaceutically acceptable bare acid addition salts have found great interest as drugs especially in geriatrics, e.g. for the treatment of cerebral blood flow disorders, and cerebral hypoxia and their sequelae, and has already found wide application in practice. The preferred daily dose of vincamine or its hydrochloride by oral administration is 60 mg with initial doses up to 80 mg, and maintenance doses from 30 mg corresponding dosage unit forms mostly contain 10, 15, 20 or especially 30 mg of active substance.
I den offentliggjorte franske patentsøknadIn the published French patent application
2 253 507, ble det av A. Houdet foreslått å administrere vincamin eller dets derivater i legemiddelform med protrahert virkning. Som slike legemiddelformer nevnes og spesi-fikt omtales spesielt ved hjelp av den virksomme stoffavgivning retarderende bærestoffer som karboksypolymetylen, celluloseacetophthalat eller palmitostearater av glyserol fremstilte tabletter, samt med granulater av det virksomme stoff fylte gelatinkapsier, og for intramuskulær anvendelse av oppløsninger av■vincamin-syreaddisjonsalter i polyvinyl-pyrolidon. Videre nevnes også anvendelsen av syreaddisjonssalter med nedsatt oppløselighet som det allerede i den offentliggjorte franske patentsøknad nr. 2 179 538 omtalte pamoat, og endelig fiksering av vincamin på kationiske ione-utvekslere som mulighet til fremstilling av retardformer av de virksomme stoffer hvis protraherende virkning ikke er avhengig av det anvendte bærestoff, men det gjøres ingen yttreligere angivelser, f. eks. med hensyn til anvendbare typer av kationutveksler og typen av selve omsetningen. 2 253 507, it was proposed by A. Houdet to administer vincamine or its derivatives in pharmaceutical form with prolonged action. As such pharmaceutical forms are mentioned and specifically referred to in particular with the aid of the active substance delivery retarding carriers such as carboxypolymethylene, cellulose acetophthalate or palmitostearates of glycerol tablets, as well as gelatin capsules filled with granules of the active substance, and for intramuscular use of solutions of ■vincamic acid addition alter in polyvinylpyrrolidone. Furthermore, the use of acid addition salts with reduced solubility such as the pamoate already mentioned in the published French patent application no. 2,179,538, and final fixation of vincamine on cationic ion exchangers are also mentioned as possibilities for producing retarded forms of the active substances whose protracting effect is not depending on the carrier material used, but no external indications are made, e.g. with regard to applicable types of cation exchangers and the type of turnover itself.
I DE-0S 27 07 763 foreslås administrering av vincamin eller dets hydroklorid til oral behandling av kretsløpssykdommer i hjernen på slik måte at for oppnåelse av et stoffskifte-effekt, opprettholdes en konsentrasjon av vincamin i blodet på 0,1 til 0,3Mg/ml og for frembringelse av et sentralt karutvidende virkning en konsentrasjon fra 0,2 til 0,5 ug/ml. Dette bevirkes fortrinnsvis ved administrering av vincamin eller dets hydroklorid i form av et legemiddel med forsinket virksomt stoff-frigjøring som strekker seg f. eks. over 2 4. timer. Den forsinkede virksomme stof f-f rig j øring opp-nås ved belegning av det virksomme stoff med et lipid-sjikt eller ved innkapsling i en egnet matrix. En slik matrix kan bestå av polyetylenglykoler eller deres etere, etylcellu-lose eller hydroksypropylcellulose, polymer metakiselsyre, polyvinylklorid, polyvinylacetat, styren-maleinsyre-kopolymere og naturkautsjuk eller deres blandinger, eventuelt sammen med inerte fyllstoffer. De dannede granulater kan anvendes på vanlig måte til fremstilling av tabletter, kapsler, drageer, eller også flytende suspensjoner. DE-0S 27 07 763 proposes the administration of vincamine or its hydrochloride for the oral treatment of circulatory diseases in the brain in such a way that, in order to achieve a metabolic effect, a concentration of vincamine in the blood of 0.1 to 0.3 Mg/ml is maintained and for producing a central vasodilating effect a concentration of from 0.2 to 0.5 ug/ml. This is preferably effected by administering vincamine or its hydrochloride in the form of a drug with delayed active substance release which extends, e.g. over 2 4. hours. The delayed release of the active substance is achieved by coating the active substance with a lipid layer or by encapsulating it in a suitable matrix. Such a matrix can consist of polyethylene glycols or their ethers, ethyl cellulose or hydroxypropyl cellulose, polymer metasilicic acid, polyvinyl chloride, polyvinyl acetate, styrene-maleic acid copolymers and natural rubber or their mixtures, possibly together with inert fillers. The formed granules can be used in the usual way for the production of tablets, capsules, dragees, or also liquid suspensions.
Protrahert virkende preparater med vincamin eller syreaddisjonssalter herav som virksomt stoff anvendes også allerede i betraktelig antall, som handelspreparater i den medisinske praksis sml. f. eks. "Rote Liste" 1 979» Preparat nr. 36O66B, 36078B, 36084B, 36085B, 36092B, 36093B og 36095B, samt som litteratur vedrørende undersøkelse av den forsinkede virksomme stoffavgivning fra slike preparater, Prolonged-acting preparations with vincamine or acid addition salts thereof as active substance are also already used in considerable numbers, as commercial preparations in medical practice etc. e.g. "Rote Liste" 1979» Preparation no. 36O66B, 36078B, 36084B, 36085B, 36092B, 36093B and 36095B, as well as literature regarding the investigation of the delayed active substance release from such preparations,
f. eks.. Pharm. Ztg, 122, 2067-73 (1977), Dtsch, Apoth.-Ztg. 118, 1-4, (1 978), Terapie oche 23, 4709-4714 (1978) og Arzneimittel-Forsch. 28, 2332-6 (1978). Handelspreparater med protrahert virkning til oral administrering er dels kapsler, dels tabletter eller drageer med en matrix, og/eller et overtrekk som sikrer den forsinkede virksomme stoff - avgivning. e.g. Pharm. Ztg, 122, 2067-73 (1977), Dtsch, Apoth.-Ztg. 118, 1-4, (1978), Terapie oche 23, 4709-4714 (1978) and Arzneimittel-Forsch. 28, 2332-6 (1978). Commercial preparations with prolonged effect for oral administration are partly capsules, partly tablets or dragees with a matrix, and/or a coating that ensures the delayed release of the active substance.
Anvendelsen av kationutvekslerharpikser til fremstilling av farmasøytiske tilberedninger med protrahert virkning frå basiske virksomme stoffer, har i og for seg allerede vært kjent lenge. Således omtales i tysk utlegnings-skrift 1 04.5 599 fremstilling av protrahert virkende amin-tilberedninger ved omsetning av terapeutisk virkende amin-forbindelser med sulfonsyre-katoinutvekslerharpikser, Ved sistnevnte dreier det seg spesielt om med 3-12 %, fortrinns vis 5-10 % divinylbenzen fornettede sufonerte polyvinylaryl-forbindelser som som fri syre suspenderes i vann eller vann-metanol, omsettes som baser med amfetamin, pyrilamin eller pyr ibenzamin. Ifølge britisk patent 857 1 94- menes kation- eller anionutvekslerharpikser med hver gang minst to basiske resp. sure terapeutiske virksomme stoffer til tilsvarende kombinasjoner. Eksempelvis omsettes syreformet av en egnet fornettet polystyrensulfonsyreharpiks med den vandige oppløsning av en til metning ikke tilstrekkelig mengde hyoscyamin-sulfat og deretter med vandig oppløsning av hyo - sein -hydrobromid. The use of cation exchange resins for the production of pharmaceutical preparations with prolonged action from basic active substances has in and of itself already been known for a long time. Thus, in German explanatory document 1 04.5 599, the production of prolonged-acting amine preparations by reaction of therapeutically effective amine compounds with sulfonic acid-ketone exchange resins is mentioned. In the latter case, it is particularly about 3-12%, preferably 5-10% divinylbenzene cross-linked sulfonated polyvinylaryl compounds which, as free acid, are suspended in water or water-methanol, are reacted as bases with amphetamine, pyrilamine or pyribenzamine. According to British patent 857 1 94, cation or anion exchange resins are meant with each time at least two basic or acid therapeutic active substances to corresponding combinations. For example, the acid form of a suitable cross-linked polystyrene sulfonic acid resin is reacted with the aqueous solution of an insufficient amount of hyoscyamine sulfate for saturation and then with an aqueous solution of hyoscein hydrobromide.
Fortsett fra omtalen til overnevnte franske patentsøknad nr. 2 179 538 har binding av vincamin til en eller annen kationutvekslerharpiks ikke fått ytterligere iakt-tagelse eller overhodet funnet praktisk anvendelse. Dette kan henge sammen med at de av sulfonsyre-kationutvekslings-harpikser og vincamin direkte dannede vincamin-resinater ikke er stabile. Ifølge søkerens egne undersøkelser inneholder allerede den i tilknytning til omsetningen med kationut-vekslerharpiksen av disse ved finmaling, svelling i vandig natriumacetatoppløsning og kloroform, etterfølgende opp-varming av blandingen til 60°C under tilbakeløp, adskiller og inndamper kloroformfasen igjen frigjorte råbase ifølge bestemmelser ved hjelp av tynnsjiktkromatografi eller liquid-kromatografi minst 10 % apovincamin og ca, 5 % epi-vincamin. Den fastslåtte ustabilitet fører til nedgang av virkningen Continuing from the discussion of the above-mentioned French patent application no. 2 179 538, the binding of vincamine to one or another cation exchange resin has not received further attention or found practical use at all. This may be connected with the fact that the vincamine resinates formed directly from sulphonic acid cation exchange resins and vincamine are not stable. According to the applicant's own investigations, it already contains in connection with the reaction with the cation exchange resin of these by fine grinding, swelling in aqueous sodium acetate solution and chloroform, subsequent heating of the mixture to 60°C under reflux, separates and evaporates the chloroform phase again freed raw base according to provisions of using thin-layer chromatography or liquid chromatography at least 10% apovincamine and approx. 5% epi-vincamine. The established instability leads to a decrease in effectiveness
og endringen av de farmakologiske egenskaper.and the change in the pharmacological properties.
Det er nå overraskende funnet at man får protra-hertvirkende og stabile vincamintilberedninger når man omsetter et syreaddisjonssalt av vincamin med et alkali- It has now surprisingly been found that protra-acting and stable vincamine preparations are obtained when an acid addition salt of vincamine is reacted with an alkali
eller<:>jordalkalimetallsalt av en sulfonsyre- kationutvekslerharpiks i et polart reasjonsmedium. or<:>alkaline earth metal salt of a sulfonic acid cation exchange resin in a polar reaction medium.
Som syreaddisjonssalter,av vincamin egner detAs acid addition salts, of vincamine it is suitable
seg såvel slike med uorganiske som også slike med organiske syrer. Spesielt egnet er addisjonssalter med mineralsyre, spesielt med halogenhydrogensyre, f. eks. klorhydrogensyre, såvel som med svovelsyre, og med organiske sulfonsyrer som both those with inorganic and those with organic acids. Particularly suitable are addition salts with mineral acid, especially with hydrohalic acid, e.g. hydrochloric acid, as well as with sulfuric acid, and with organic sulphonic acids such as
metansulfonsyre, men også med karboksylsyrer, som f. eks. vinsyre, ravsyre eller eddiksyre. methanesulfonic acid, but also with carboxylic acids, such as tartaric acid, succinic acid or acetic acid.
Prinsipielt er alle sulfonsyrer-kationutveksier - harpikser i form av deres jordalkalimetallsalter og spesielt deres •" alkalimetall salter egnet til omsetningen ifølge, oppfinnelsen. Ved sulfonsyrekationutvekslerharpikser forståes ved siden av slike uten andre funksjonelle grupper som en sulfogruppe også fenolsulfonsyre-kationutvekslerharpikser og karboksylsyre-sulfon syre-kationutveksier-harpikser som også slike med ytterligere funksjonelle grupper. Spesielt tilfredsstillende resultater fåes med sulfoneringsprodukter av kopolymere og eventuelt indifferent substituerte styrener og mindre mengder av divinylbenzener som fornetningsmiddel slik de omtales i. US-patent 2 366 007. AV andre egnede kationutvekslerharpikser er f. eks. kondensasjonsprodukter av fenoler eller fenoletere med formaldehyd, eventuelt substituerte benzensulfonsyre eller kondensasjonsprodukter av formaldehyd med ved hjelp av eventuelt foretret hydroksy substituert aromatiske sulfonsyrer, som de i US-patenter 2 729-607 og 2 692 866 som karboksyl syre-sulfonsyre-kationutvekslerharpikser omtalte kondensasjonsprodukter av formaldehyd med naftalinsulfonsyrer og fenoksyeddiksyrer, resp., In principle, all sulfonic acid cation exchange resins in the form of their alkaline earth metal salts and especially their alkali metal salts are suitable for the reaction according to the invention. By sulfonic acid cation exchange resins, besides those without other functional groups such as a sulfo group, also phenol sulfonic acid cation exchange resins and carboxylic acid sulfonic acid are understood -cation exchange resins such as those with additional functional groups. Particularly satisfactory results are obtained with sulfonation products of copolymers and optionally indifferently substituted styrenes and smaller amounts of divinylbenzenes as crosslinking agents as described in US patent 2 366 007. OF other suitable cation exchange resins are f eg condensation products of phenols or phenol ethers with formaldehyde, optionally substituted benzenesulfonic acid or condensation products of formaldehyde with optionally etherified hydroxy substituted aromatic sulfonic acids, such as those in US patents 2 729-607 and 2,692,866 as carboxylic acid-sulfonic acid cation exchange resins mentioned condensation products of formaldehyde with naphthalene sulfonic acids and phenoxyacetic acids, resp.,
av formaldehyd med de ved kondensasjon av benzaldehyddisulfon - syrer med to molekyler fenoksyeddiksyrer dannede trifenyl-metanderivater, samt ytterligere i US-patenter nr. 2.204 of formaldehyde with the triphenyl-methane derivatives formed by condensation of benzaldehyde disulfonic acids with two molecules of phenoxyacetic acids, as well as further in US patents no. 2,204
259 og 2 338 159 omtalte kationutvekslerharpikser.259 and 2,338,159 disclosed cation exchange resins.
De anvendte harpikser kan være ufornettet, fortrinnsvis anvender man imidlertid harpikser med fornetningsgrad mellom ca. 1 og ca. 12 %, spesielt mellom 4 og 8 %. Partikkelstørrelsen av de anvendte harpikser ligger fortrinnsvis mellom ca. 50 og ca, 1000 pm og spesielt f. eks. ved med divihylbenzen fornettet, sulfonert polystyren, mellom ca. The resins used can be non-cross-linked, preferably, however, resins with a degree of cross-linking between approx. 1 and approx. 12%, especially between 4 and 8%. The particle size of the resins used is preferably between approx. 50 and about, 1000 pm and especially e.g. by divihylbenzene cross-linked, sulphonated polystyrene, between approx.
100 og ca. 300 um. Den virksomme stoffavgivningshastighet avtar med økende fornetningsgrad og med økende partikkel-størrelse, derfor kan det overholdes en ønsket avgivnings-hastighet ved harpikser med forskjellig partikkelstørrelse ved endring av fornetningsgraden, f. eks. ved anvendelse av 100 and approx. 300 µm. The effective substance release rate decreases with increasing degree of crosslinking and with increasing particle size, therefore a desired release rate can be observed with resins with different particle sizes by changing the degree of crosslinking, e.g. by application of
en harpiks av overnevnte type med en partikkelstørrelse påa resin of the above type with a particle size of
150 - 300 pm og 4 %- ig f ornetning sgrad for fremstilling av faste orale applikasjonsformer, eller med en partikkel-størrelse fra 50 til'100 um, og 8 %- lg fornetningsgrad 150 - 300 pm and a 4% degree of crosslinking for the production of solid oral application forms, or with a particle size from 50 to 100 µm, and an 8% degree of crosslinking
til fremstilling av oralt administrerbare suspensjonér.for the production of orally administrable suspensions.
Som polar reaksjonsmedia for omsetningen ifølge oppfinnelsen egner det'seg eksempelvis vann og polare organiske oppløsningsmidler som enverdig lavere alkanoler, f. eks. metanol eller etanol eller laverealkanoler, f.eks. aceton eller blandinger av disse oppiøsningsmidler med seg se^v og/eller med vann. Suitable polar reaction media for the reaction according to the invention are, for example, water and polar organic solvents such as monovalent lower alkanols, e.g. methanol or ethanol or lower alkanols, e.g. acetone or mixtures of these solvents with se^v and/or with water.
Ved omsetningen ifølge oppfinnelsen, kan.for å holde oppbud av kationutvekslerharpiks og samlet vekt og- volum av de ferdige tilberedninger lavt, ved tilsvarende valg av mengdeforhold av vincaminsyreaddisjonssalter og alkali- eller jordalkal ime tall salt av kationutvekslere til-strebes sterkest mulig metning av sistnevnte. Avmetnings-graden ligger vanligvis mellom ca. 10 og ca, 40 % bortsett fra mengdeforholdene avhenger den også av anvendt harpiks og omsetningsbetingelser. De resterende sulfonsyreanioner forblir i det vesentlige avmettet med alkali- resp. jordalkalimetall ioner. Omsetningen foregår fortrinnsvis under omrøring ved værelse stemperatur, resp. 20°C til ca, 60°C, spesielt ved ca, 40°C. Den varer eksempelvis ca. 5 til ca. 15 timer. Reaksjonsvarigheten ligger ved anvendelsen av svakt fornettede harpikser eller slike med liten partikkel-størrelse nærmere ved eller også under 5 timer, og i andre tilfellet nærmere ved eller også over 15 timer. Opparbeidel-sen av omsetningsproduktene kan foregå på enkel måte ved frafiltrering og tørkning, fortrinnsvis inntil vektkonstans, In the process according to the invention, in order to keep the supply of cation exchange resin and the total weight and volume of the finished preparations low, by correspondingly choosing the quantity ratio of vincamic acid addition salts and alkali or alkaline earth salts of cation exchangers, the strongest possible saturation of the latter can be strived for . The degree of desaturation is usually between approx. 10 and approx. 40% apart from the quantity ratio, it also depends on the resin used and processing conditions. The remaining sulfonic acid anions remain essentially desaturated with alkali or alkaline earth metal ions. The reaction preferably takes place with stirring at room temperature, resp. 20°C to about 60°C, especially at about 40°C. For example, it lasts approx. 5 to approx. 15 hours. When using weakly cross-linked resins or those with a small particle size, the reaction duration is closer to or less than 5 hours, and in other cases closer to or even more than 15 hours. Processing of the turnover products can take place in a simple way by filtration and drying, preferably until the weight is constant,
f. eks. i vakuum ved temperaturer inntil ca. 80°C, fortrinnsvis ved ca. 50°C. e.g. in vacuum at temperatures up to approx. 80°C, preferably at approx. 50°C.
De ifølge oppfinnelsen fremstilte vincamin-tilberedninger som i det følgende også betegnes som vincamin-resinater er det i motsetning til de ovenfor nevnte ved direkte omsetning av vincamin med sure kationutvekslerharpikser dannede vincamin-resinater meget stabile, etter 6 måneders lagring av let ifølge oppfinnelsen fremstilte rasinat av vincamin med et sulfonert kopolymerisat av styren og divinylbenzen med en fornetningsgrad på 5 % ved 23°C, ved 35°C, The vincamine preparations produced according to the invention, which are also referred to in the following as vincamine resinates, are in contrast to the above-mentioned vincamine resinates formed by direct reaction of vincamine with acidic cation exchange resins very stable, after 6 months of storage of the resinate produced according to the invention of vincamine with a sulfonated copolymer of styrene and divinylbenzene with a degree of crosslinking of 5% at 23°C, at 35°C,
og sogar ved 50°C var de deri inneholdte vincamin ennå praktisk talt uendret. Likeledes omtrent liktblivende var etter disse lagringsforsøk også den virksomme stoffavgivningshastighet. Sistnevnte er også overraskende lite avhengig av omgivende væskes pH-verdi ved et resinat ifølge oppfinnelsen av en kationutvekslerharpiks av overnevnte type, med en: fornetningsgrad på 8 %, og en partikkelstørrelse på 150- and even at 50°C the vincamine contained therein was still practically unchanged. Likewise, after these storage trials, the effective substance release rate was also approximately the same. The latter is also surprisingly little dependent on the surrounding liquid's pH value with a resinate according to the invention of a cation exchange resin of the above-mentioned type, with a: degree of crosslinking of 8%, and a particle size of 150
300 um tilsvarte til den i simulert magevæske av pH 1,2300 µm corresponded to that in simulated gastric fluid of pH 1.2
i løpet av 4- timer avgitte virksomme stoffmengde den i simulert tarmvæske av pH 7,5 i løpet av 6 timer avgitte virksomme stoffmengde.. Derfor ga også avgdvningsforsøk med resinater ifølge oppfinnelsen av harpikser av samme type og fornetningsgrader, og i {5, 6 % og 8 % med 1 times opp-holdstid i den simulerte magevæske, og 7 timer i den simulerte tarmvæske ubrutt forløpende avgivningskurver (abzisseakse tid, ordinatakse frigjort mengde vincamin i % av samlet innhold.). the amount of active substance released over the course of 4 hours was the amount of active substance released over the course of 6 hours in simulated intestinal fluid of pH 7.5. Therefore, release trials with resinates according to the invention also yielded resins of the same type and degrees of crosslinking, and in {5, 6 % and 8% with a residence time of 1 hour in the simulated gastric fluid, and 7 hours in the simulated intestinal fluid with uninterrupted continuous release curves (abscissa axis time, ordinate axis released amount of vincamine in % of total content.).
De ifølge oppfinnelsen fremstilte vincamin-tilberedninger kan administreres som sådanne oralt, fortrinnsvis anvendes de imidlertid analogt krystalliserte, The vincamine preparations produced according to the invention can be administered as such orally, preferably, however, they are used analogously crystallized,
eller på annen måte fremstilte virksomme stoffer til fremstilling av vanlige applikasjonsformer av legemidler til oral administrering. Eksempelvis forarbeides de på vanlig måte og med de vanlige bære- og hjelpestoffer til fast applikasjonsformer, f. eks.- tabletter innbefattende spe sialf or mer som film- eller punkttabletter, til drageer eller kapsler, samt til flytende orale applikasjonsformer spesielt til siruper, d.v.s. aromatiserte siruper, men også til dryppbare suspensjoner. Doseringen kan være den vanlige, eller også or otherwise produced active substances for the production of common application forms of medicinal products for oral administration. For example, they are processed in the usual way and with the usual carriers and excipients into solid application forms, e.g. tablets including special forms such as film or spot tablets, into dragees or capsules, as well as into liquid oral application forms especially into syrups, i.e. flavored syrups, but also for droppable suspensions. The dosage can be the usual one, or also
svakt nedsatt eller forhøyet. Følgelig kan vincamininnholdet av de enkelte do seringsenheter utgjøre en halv, eller ved tilsvarende forsinket virksomt stoffavgivning som kan være ytterligere nedsatt ved vanlig retarderende forholdsregler som anvendelse av tilsvarende matrixmasser, overtrekk eller slightly decreased or increased. Consequently, the vincamine content of the individual dosage units can amount to half, or in the event of a correspondingly delayed release of the active substance which can be further reduced by usual retarding measures such as the use of corresponding matrix masses, coverings or
kapsler, også tilsvare en heldags-dose og derfor for voksne mennesker av normal vekt ligge spesielt mellom 15 til 30 mg, resp. 30 til 60 mg, eller også utgjøre 100 mg. capsules, also correspond to a full day's dose and therefore for adults of normal weight lie especially between 15 to 30 mg, resp. 30 to 60 mg, or also amount to 100 mg.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler for fremstilling av vincaminrasinaterr ifølge oppfinnelsen og bruksferdig applikasjonsformer som inneholder disse. The invention shall be explained in more detail with the help of some examples for the production of vincamine resinate according to the invention and ready-to-use application forms containing these.
Eksempel 1Example 1
a) Forberedning av harpiks:a) Preparation of resin:
1,0 kg "Zerolit" 225-Na (merkebetegning fra dia-prosim Ltd,. England) sulfonert kopolymerisat av styren og divinylbenzen med 4 % fornetting og en partikkelstørrelse på 150 - 300 um, gjennomsnittelig partikkelstørrelse 225 Um, suspenderes i omtrent 5 1 2-n-saltsyre og blandingen om-røres i 2 timer ved 40°C. Den overstående oppløsning dekan-teres og harpiksen vaskes tre ganger med avionisert vann. Derpå tilsettes 5 liter 2-n-natronl.ut og blandingen om-røres i 6 timer ved 40°C. Harpiksen spyles med overskytende varm avionisert vann inntil den bortrennede oppløsnings 1.0 kg "Zerolit" 225-Na (brand name of dia-prosim Ltd,. England) sulfonated copolymer of styrene and divinylbenzene with 4% cross-linking and a particle size of 150 - 300 µm, average particle size 225 µm, suspended for about 5 1 2-n-hydrochloric acid and the mixture is stirred for 2 hours at 40°C. The supernatant solution is decanted and the resin is washed three times with deionized water. 5 liters of 2-n-sodium hydroxide solution are then added and the mixture is stirred for 6 hours at 40°C. The resin is flushed with excess hot deionized water until the run-off dissolves
pH utgjør omtrent 5. De angitte fremgangsmåtetrinn gjentas to ganger for å sikre en god harpikskvalitet. Endelig suspenderes harpiksen i to timer i isopropylalkohol for å fjerne eventuelle organiske forurensninger. Harpiksen filtreres derpå, og vaskes med 2 porsjoner avionisert vann. Det tørkes deretter ved 50°C i vakuum, inntil vektkonstans. The pH is approximately 5. The specified process steps are repeated twice to ensure a good resin quality. Finally, the resin is suspended for two hours in isopropyl alcohol to remove any organic impurities. The resin is then filtered and washed with 2 portions of deionized water. It is then dried at 50°C in a vacuum, until the weight is constant.
b) Oppladning av harpiks med vincamin:b) Charging resin with vincamine:
100 g vincamin-metansulfonat oppløses i 1 liter Dissolve 100 g of vincamine methanesulfonate in 1 litre
avionisert vann. I denne oppløsning dispergeres langsomt 365 g av den i henhold til det overnevnte aktiverte harpiks. Blandingen omrøres deretter ved 40°C inntil hele aktivstof f et. er bundet til harpiksen. Vincamin-saltets restkonsentrasjon i oppløsningen overvåkes ved hjelp av et UV-spektrofoto-meter. Det dannede vincamid-resinat frafilteres og tørkes til vekt-konstans i vakuum ved 50°C. deionized water. 365 g of the activated resin according to the above are slowly dispersed in this solution. The mixture is then stirred at 40°C until all the active substance has dissolved. is bound to the resin. The vincamine salt's residual concentration in the solution is monitored using a UV spectrophotometer. The formed vincamide resinate is filtered off and dried to constant weight in vacuum at 50°C.
c) Fremstilling av en oral applikasjonsform:c) Preparation of an oral application form:
100 g av det dannede tørre vincaminresinat bl.andes med 1 g magnesiumstearat og fylles i kapsler således at hver kapsel har et vincamininnhold som tilsvarer 100 mg vincaminhydroklorid. 100 g of the formed dry vincamine resinate is mixed with 1 g of magnesium stearate and filled into capsules so that each capsule has a vincamine content corresponding to 100 mg of vincamine hydrochloride.
Eksempel 2Example 2
a) Forberedning og oppladning av harpiksen:a) Preparation and charging of the resin:
80 g "Amberlite IRP 69 M", partikkelstørrelse 80 g "Amberlite IRP 69 M", particle size
under 75 um (sulfonert kopolymer av styren med omtrent 8 % divinylbenzen, Rohm & Haas Co, Philadelphia), forberedes som angitt i eksempel 1. below 75 µm (sulfonated copolymer of styrene with about 8% divinylbenzene, Rohm & Haas Co, Philadelphia), is prepared as indicated in Example 1.
Til den våte harpiks settes en 50°C varm opp-løsning som inneholder 20 g vincaminhydroklorid i 1 liter avionisert vann. Den dannede suspensjon omrøres ved 50°C A 50°C warm solution containing 20 g of vincamine hydrochloride in 1 liter of deionized water is added to the wet resin. The resulting suspension is stirred at 50°C
i 24 timer. Det således behandlede harpiks material fra-fil treres, og tørkes ved 50°C i vakuum. Det tørre resinat inneholder vincamin i en mengde som tilsvarer et innhold av 20 vekt$ vincaminhydroklorid. for 24 hours. The resin material treated in this way is spun and dried at 50°C in a vacuum. The dry resinate contains vincamine in an amount corresponding to a content of 20% by weight of vincamine hydrochloride.
b) Fremstilling av en oral applikasjonsform:b) Preparation of an oral application form:
4 g tragant, 1,2 g p-hydroksybenzosyremetylester 4 g tragacanth, 1.2 g p-hydroxybenzoic acid methyl ester
og 0,3 g .p-hydroksybenzosyrepropylester oppløses i en liter vann ved 80 - 90°C. Den dannede gel avkjøles, og 50 g av det ovenfor dannede tørre vincaminresinat tilsettes, og dispergeres grundig under anvendelse av en homogenisator. Deretter tilsettes til disperjonen vann til sluttvolumet and 0.3 g of .p-hydroxybenzoic acid propyl ester are dissolved in one liter of water at 80 - 90°C. The gel formed is cooled, and 50 g of the dry vincamine resinate formed above is added and thoroughly dispersed using a homogenizer. Water is then added to the dispersion to the final volume
på 1 liter, således at den dannede suspensjon inneholder ca. 5 % vincaminresinat. En teskje av denne suspensjon inn-holder omtrent en dose som tilsvarer 50 mg vincaminhydroklorid, nøyaktig er denne dose inneholdt i 2,5.ml suspensjon. of 1 litre, so that the formed suspension contains approx. 5% vincamine resinate. One teaspoon of this suspension contains approximately a dose corresponding to 50 mg of vincamine hydrochloride, exactly this dose is contained in 2.5 ml of suspension.
Eksempel 3Example 3
1,0 kg ifølge eksempel 2 ble f re mstillet, tørt vincaminresinat blandes med 0,5 kg lactose og 0,5 kg mais-stivelse og blandingen knas med 0, 5 1 15 #-ig slim og poly-vinylpyrrolidon i knaer og granuleres deretter. Granulatet tørkes, blandes med 0,02 kg "Aerosil" (høydispers silicagel) og 0,02 kg magnesiumstearat som ytre fase, og presses til tablé.tter av 500 mg vekt (stempeldiameter 11,5 mm). Ta-blettene inneholder vincamin i en dose som omtrent tilsvarer 4.6 mg vincaminhydroklorid. 1.0 kg according to example 2 was produced, dry vincamine resinate is mixed with 0.5 kg of lactose and 0.5 kg of corn starch and the mixture is crushed with 0.5 1 15 # mucilage and polyvinylpyrrolidone in knuckles and granulated thereafter. The granulate is dried, mixed with 0.02 kg "Aerosil" (highly dispersed silica gel) and 0.02 kg magnesium stearate as outer phase, and pressed into tablets of 500 mg weight (piston diameter 11.5 mm). The tablets contain vincamine in a dose roughly equivalent to 4.6 mg of vincamine hydrochloride.
Claims (16)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH480480 | 1980-06-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO812039L true NO812039L (en) | 1981-12-28 |
Family
ID=4282830
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO812039A NO812039L (en) | 1980-06-23 | 1981-06-16 | PROCEDURE FOR THE PREPARATION OF PROTRAACTED EFFECTIVE VINCAMIN PREPARATIONS, VINCAMIN PREPARATIONS AND MEDICINES CONTAINING THESE |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0042818A1 (en) |
JP (1) | JPS5762277A (en) |
KR (1) | KR830005853A (en) |
AU (1) | AU7201781A (en) |
DD (1) | DD159737A5 (en) |
DK (1) | DK274081A (en) |
ES (1) | ES8203891A1 (en) |
FI (1) | FI811934L (en) |
GB (1) | GB2078758A (en) |
GR (1) | GR75708B (en) |
IL (1) | IL63148A0 (en) |
NO (1) | NO812039L (en) |
NZ (1) | NZ197485A (en) |
PT (1) | PT73238B (en) |
ZA (1) | ZA814194B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES8604955A1 (en) * | 1985-11-08 | 1986-03-16 | Covex Sa | Process for the preparation of (-) eburnamenin-14-(15H)-one resinates |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE550150A (en) * | 1955-08-08 | |||
FR2201898A1 (en) * | 1973-05-30 | 1974-05-03 | Sogeras | Vincamine arabogalactan sulphate - with prolonged activity for treating cerebrovascular disorders |
FR2253507A1 (en) * | 1973-12-11 | 1975-07-04 | Houdet Antoine | Vincamine administration using delayed release excipient - allowing prolonged action |
FR2313915A1 (en) * | 1976-01-26 | 1977-01-07 | Corneille Gilbert | Sustained release vincamine microcapsules - with inert core, vincamine (deriv.) intermediate layer and microporous outer coating |
PT66201B (en) * | 1976-02-23 | 1978-11-07 | Corvi Mora E | METHOD AND COMPOSITION FOR THE THERAPEUTICS OF BRAIN CIRCULATORY DISEASES |
-
1981
- 1981-05-30 JP JP56081923A patent/JPS5762277A/en active Pending
- 1981-06-15 GB GB8118289A patent/GB2078758A/en not_active Withdrawn
- 1981-06-16 NO NO812039A patent/NO812039L/en unknown
- 1981-06-17 EP EP81810248A patent/EP0042818A1/en not_active Withdrawn
- 1981-06-18 FI FI811934A patent/FI811934L/en not_active Application Discontinuation
- 1981-06-22 ZA ZA814194A patent/ZA814194B/en unknown
- 1981-06-22 IL IL63148A patent/IL63148A0/en unknown
- 1981-06-22 GR GR65301A patent/GR75708B/el unknown
- 1981-06-22 PT PT73238A patent/PT73238B/en unknown
- 1981-06-22 AU AU72017/81A patent/AU7201781A/en not_active Abandoned
- 1981-06-22 NZ NZ197485A patent/NZ197485A/en unknown
- 1981-06-22 DD DD81231010A patent/DD159737A5/en unknown
- 1981-06-22 DK DK274081A patent/DK274081A/en not_active Application Discontinuation
- 1981-06-22 ES ES503263A patent/ES8203891A1/en not_active Expired
- 1981-06-23 KR KR1019810002271A patent/KR830005853A/en unknown
Also Published As
Publication number | Publication date |
---|---|
PT73238A (en) | 1981-07-01 |
PT73238B (en) | 1983-05-11 |
NZ197485A (en) | 1983-09-30 |
IL63148A0 (en) | 1981-09-13 |
AU7201781A (en) | 1982-01-07 |
FI811934L (en) | 1981-12-24 |
JPS5762277A (en) | 1982-04-15 |
EP0042818A1 (en) | 1981-12-30 |
DD159737A5 (en) | 1983-04-06 |
KR830005853A (en) | 1983-09-14 |
DK274081A (en) | 1981-12-24 |
GB2078758A (en) | 1982-01-13 |
ES503263A0 (en) | 1982-04-01 |
GR75708B (en) | 1984-08-02 |
ES8203891A1 (en) | 1982-04-01 |
ZA814194B (en) | 1982-07-28 |
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