LT3395B - Stable and water-soluble veterinary composition and process for preparing thereof - Google Patents
Stable and water-soluble veterinary composition and process for preparing thereof Download PDFInfo
- Publication number
- LT3395B LT3395B LTIP1448A LTIP1448A LT3395B LT 3395 B LT3395 B LT 3395B LT IP1448 A LTIP1448 A LT IP1448A LT IP1448 A LTIP1448 A LT IP1448A LT 3395 B LT3395 B LT 3395B
- Authority
- LT
- Lithuania
- Prior art keywords
- water
- trimethoprim
- soluble
- weight
- composition
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 64
- 238000004519 manufacturing process Methods 0.000 title description 4
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229960001082 trimethoprim Drugs 0.000 claims abstract description 45
- ODWMXYHUKDMPTR-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(6-chloropyridazin-3-yl)azanide Chemical compound [Na+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=CC=C(Cl)N=N1 ODWMXYHUKDMPTR-UHFFFAOYSA-N 0.000 claims abstract description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 14
- 239000002245 particle Substances 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- XOXHILFPRYWFOD-UHFFFAOYSA-N sulfachloropyridazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=C(Cl)N=N1 XOXHILFPRYWFOD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000654 additive Substances 0.000 claims abstract description 4
- 229950008831 sulfachlorpyridazine Drugs 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 22
- 239000004480 active ingredient Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 239000010453 quartz Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000002016 disaccharides Chemical class 0.000 claims description 5
- 150000002772 monosaccharides Chemical group 0.000 claims description 5
- 150000005846 sugar alcohols Chemical class 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 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 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 13
- -1 poly(vinyl pyrrolidone) Polymers 0.000 abstract description 3
- 159000000000 sodium salts Chemical class 0.000 abstract description 2
- 239000000377 silicon dioxide Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 239000003651 drinking water Substances 0.000 description 9
- 235000020188 drinking water Nutrition 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 229940124530 sulfonamide Drugs 0.000 description 7
- 150000003456 sulfonamides Chemical class 0.000 description 7
- 239000008187 granular material Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 229960004106 citric acid Drugs 0.000 description 5
- 229960001031 glucose Drugs 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 208000035143 Bacterial infection Diseases 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000022362 bacterial infectious disease Diseases 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229960005323 phenoxyethanol Drugs 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229960005404 sulfamethoxazole Drugs 0.000 description 2
- JNMRHUJNCSQMMB-UHFFFAOYSA-N sulfathiazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CS1 JNMRHUJNCSQMMB-UHFFFAOYSA-N 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- ITGGZHSVBBHYHC-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid 2-(1,2-dihydroxypropyl)propanedioic acid Chemical compound OC(C(C(=O)O)C(=O)O)C(C)O.C(C(O)C(O)C(=O)O)(=O)O ITGGZHSVBBHYHC-UHFFFAOYSA-N 0.000 description 1
- IIZVTUWSIKTFKO-UHFFFAOYSA-N 2-hydroxypropanoic acid;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound CC(O)C(O)=O.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IIZVTUWSIKTFKO-UHFFFAOYSA-N 0.000 description 1
- FZIPCQLKPTZZIM-UHFFFAOYSA-N 2-oxidanylpropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FZIPCQLKPTZZIM-UHFFFAOYSA-N 0.000 description 1
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-UHFFFAOYSA-N 0.000 description 1
- DYNLHTRYXKKIDM-UHFFFAOYSA-N 3-[2,4-diamino-5-[(3,4-dimethoxyphenyl)methyl]-1H-pyrimidin-2-yl]-2-hydroxypropanoic acid Chemical compound COC1=C(C=C(C=C1)CC2=CNC(N=C2N)(CC(C(=O)O)O)N)OC DYNLHTRYXKKIDM-UHFFFAOYSA-N 0.000 description 1
- XAGIUDDSDNXTMN-UHFFFAOYSA-N 4-amino-N-(2,3-dimethoxypyridin-4-yl)benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=CC=NC(=C1OC)OC XAGIUDDSDNXTMN-UHFFFAOYSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- YEAICDDXRUOCKJ-UHFFFAOYSA-N 4-amino-n-pyrazin-2-ylbenzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CN=CC=N1 YEAICDDXRUOCKJ-UHFFFAOYSA-N 0.000 description 1
- NWPRCRWQMGIBOT-UHFFFAOYSA-N 7-(2-hydroxyethyl)-1,3-dimethylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CCO)C=N2 NWPRCRWQMGIBOT-UHFFFAOYSA-N 0.000 description 1
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- PJSFRIWCGOHTNF-UHFFFAOYSA-N Sulphormetoxin Chemical compound COC1=NC=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=C1OC PJSFRIWCGOHTNF-UHFFFAOYSA-N 0.000 description 1
- VEXNFKCQMGMBBJ-UHFFFAOYSA-N [1-(dimethylamino)-2-[(dimethylamino)methyl]butan-2-yl] benzoate Chemical compound CN(C)CC(CC)(CN(C)C)OC(=O)C1=CC=CC=C1 VEXNFKCQMGMBBJ-UHFFFAOYSA-N 0.000 description 1
- 150000001243 acetic acids Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229960002303 citric acid monohydrate Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- LDBTVAXGKYIFHO-UHFFFAOYSA-N diaveridine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=CN=C(N)N=C1N LDBTVAXGKYIFHO-UHFFFAOYSA-N 0.000 description 1
- 229950000246 diaveridine Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 229960005387 etofylline Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 150000004682 monohydrates Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000013594 poultry meat Nutrition 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- OMLXVJIPSAWGRY-UHFFFAOYSA-N s-pyrazin-2-ylthiohydroxylamine Chemical compound NSC1=CN=CC=N1 OMLXVJIPSAWGRY-UHFFFAOYSA-N 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- LARLNXOUTTUXPN-UHFFFAOYSA-N sodium;(4-aminophenyl)sulfonyl-(5-methyl-1,2-oxazol-3-yl)azanide Chemical compound [Na+].O1C(C)=CC([N-]S(=O)(=O)C=2C=CC(N)=CC=2)=N1 LARLNXOUTTUXPN-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960004673 sulfadoxine Drugs 0.000 description 1
- ASWVTGNCAZCNNR-UHFFFAOYSA-N sulfamethazine Chemical compound CC1=CC(C)=NC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ASWVTGNCAZCNNR-UHFFFAOYSA-N 0.000 description 1
- 229960001544 sulfathiazole Drugs 0.000 description 1
- 229940072176 sulfonamides and trimethoprim antibacterials for systemic use Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229960001937 trimethoprim lactate Drugs 0.000 description 1
- 229960002712 trimethoprim sulfate Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Išradimas priklauso stabiliai, kietai, tirpiai vandenyje, veterinarijai skirtai kompozicijai, kurios aktyvi medžiaga susideda iš N-(6-chloro-3-piridazinil)sulfanilamido natrio druskos (natrio sulfachlorpiridazinas) ir 2,4-diamino-5-(3’, 4’, 5’-trimetoksibenzil)-pirimidino (trimetoprimas) santykiu 5:1, ir šios kompozicijos paruošimo būdui.The present invention relates to a stable, solid, water-soluble, veterinary composition comprising the active ingredient N- (6-chloro-3-pyridazinyl) sulfanylamide sodium (sodium sulfachloropyridazine) and 2,4-diamino-5- (3 ', 4'). ', 5'-trimethoxybenzyl) -pyrimidine (trimethoprim) in a ratio of 5: 1, and a method for preparing this composition.
Gerai žinoma, kad sulfonamidų veikimą sustiprina trimetoprimas (Didžiosios Britanijos patentas Nr. 1 176 395) . Paprastai, sulfonamidai, įskaitant natrio sulfachlorpiridaziną ir trimetoprimą, yra komponuojami santykiu 5:1. Tokios kombinacijos pasižymi stipriu antimikrobiniu veikimu ir plačiai panaudojamos tiek medicinoje, tiek veterinarijoje.It is well known that the action of sulfonamides is enhanced by trimethoprim (British Patent No. 1,176,395). Typically, sulfonamides, including sodium sulfachloropyridazine and trimethoprim, are formulated in a 5: 1 ratio. Such combinations have strong antimicrobial activity and are widely used in medicine and veterinary medicine.
Panaudojant anksčiau minėtas aktyvių medžiagų kombinacijas veterinarijoje, turi būti vykdomi specialūs reikalavimai. Pavyzdžiui, bakterinės infekcijos, veikiančios didelę gyvulių grupę, atveju yra paprasčiausiai panaudoti aktyvias medžiagas, pridedant jas i maistą. Tačiau sergančių gyvulių gydymas pagal šį būdą nėra efektyvus, nes pablogėja maisto įsisavinimas. Iš principo, yra Įmanoma panaudoti aktyvias medžiagas kietos kompozicijos veterinarijai forma, tokia kaip kapsulės arba tabletės, arba tinkama injekcijai forma, tačiau šis gydymas yra gana varginantis. Faktiškai, smulkesnių gyvulių, tokių kaip naminių paukščių, gydymas, trunkantis nuo 3 iki 5 dienų, praktiškai yra neįmanomas.Specific requirements for the use of the above mentioned active substance combinations in veterinary medicine have to be met. For example, in the case of bacterial infections affecting a large group of animals, it is simply a matter of using the active ingredients by adding them to food. However, treatment of sick animals by this method is ineffective because food intake is impaired. In principle, it is possible to use the active ingredients in the form of a solid veterinary composition, such as capsules or tablets, or in the form of an injection, but this treatment is quite tedious. In fact, treatment of smaller animals, such as poultry, for 3 to 5 days is practically impossible.
Atsižvelgiant i aukščiau išvardintus trūkumus, bakterinės infekcijos, užkrečiančios didelę gyvulių grupę, atveju praktiškiausias ir ekonomiškiausias gydymo būdas, ištirpinus aktyvią medžiagą geriamame vandenyje. Pavyzdžiui, aštrioje ligos stadijoje gyvuliai sunaudoja vandens daugiau, kai tuo tarpu maisto suvartojama mažiau.In view of the above-mentioned disadvantages, for bacterial infections affecting a large group of livestock, the most practical and cost-effective treatment is to dissolve the active substance in drinking water. For example, in the acute phase of the disease, the animals consume more water while the food is consumed less.
Tačiau, pastarasis vaistų vartojimo būdas gali būti naudojamas, jeigu aktyvios medžiagos gerai ir greitai, per kelias minutes, tirpsta geriamame vandenyje. Tuo atveju, kai naudojami sulfonamidai ir trimetoprimas, susidaro problemos, nes šios aktyvios medžiagos, praktiškai, yra netirpios vandenyje. Sulfonamidų tirpumą galima padidinti, panaudojus natrio druskas, ir, bendrai, trimetoprimu yra gydoma, naudojant aktyvią paviršiaus medžiagą tirpumui padidinti. Labiausiai praktikuojama, kai aktyvios medžiagos yra tirpinamos organiniuose tirpikliuose, norint gauti tirpalą, kuris maišytųsi su vandeniu.However, the latter route of administration can be used if the active substances are well and rapidly soluble in drinking water within minutes. Problems arise when sulfonamides and trimethoprim are used, since these active substances are practically insoluble in water. The solubility of sulfonamides can be increased by the use of sodium salts and, in general, trimethoprim is treated using a surfactant to increase solubility. It is most practiced when the active ingredients are dissolved in organic solvents to obtain a solution which is miscible with water.
Literatūroje yra gerai žinomos kompozicijos veterinarijai, kurių sudėtyje yra trimetoprimas ir sulfonamidai.Veterinary formulations containing trimethoprim and sulfonamides are well known in the literature.
Kompozicija miltelių forma, aprašyta Vengrijos patente Nr. 191 890, kur aktyvios medžiagos susideda iš trimetoprimo, natrio sulfachlorpiridazino ir 4-amino-N(5-metil-3-izoksazolil)-benzolsulfonamido (sulfametoksazolas). Gliukozė, natrio chloridas, kalio chloridas, natrio hidrokarbonatas, natrio citratas ir kalcio karbonatas yra skiedikliai. Pagal aprašymą, miltelių mikstūros 25 g peroralinė dozė gali būti panaudojama raguočių, sergančių infekcija, iššaukta Escherichia coli, gydymui. Tačiau žinoma kompozicija negali būti pilnai ištirpinta geriamame vandenyje, nes sulfametoksazolas ir kalcio karbonatas netirpsta vandenyje.The composition in powder form is described in Hungarian patent no. 191,890, wherein the active ingredients consist of trimethoprim, sodium sulfachloropyridazine and 4-amino-N- (5-methyl-3-isoxazolyl) -benzenesulfonamide (sulfamethoxazole). Glucose, sodium chloride, potassium chloride, sodium bicarbonate, sodium citrate and calcium carbonate are diluents. According to the disclosure, an oral dose of 25 grams of powder mixture can be used to treat horns with infection caused by Escherichia coli. However, the known composition cannot be completely dissolved in drinking water because sulfamethoxazole and calcium carbonate are insoluble in water.
Tolimesnė sinergistinė kompozicija yra aprašyta JAV patente Nr. 4 470 978, kur aktyvios medžiagos susideda iš natrio sulfachlorpiridazino, trimetoprimo ir fenoksietanolio. Kaip priedas prie aktyvios medžiagos yra naudojama tiktai sacharozė. Žinoma kompozicija buvo maišoma su geriamu vandeniu, skirtu viščiukams, norint įrodyti šios kompozicijos veiksmingumą. Pagal mūsų testus reikėjo net kelių valandų, kad žinoma kompozicija ištirptų vandenyje.A further synergistic composition is described in U.S. Pat. No. 4,470,978, wherein the active ingredients are sodium sulfachloropyridazine, trimethoprim and phenoxyethanol. Only sucrose is used as an additive to the active substance. The known composition was mixed with drinking water for chickens to demonstrate the efficacy of this composition. According to our tests, it took even several hours for the known composition to dissolve in water.
Vandeninis tirpalas, tinkamas interaveninei injekcijai, yra žinomas iš Vokietijos patento Nr. 30 17 032.An aqueous solution suitable for intravenous injection is known from German patent no. 30 17 032.
Tirpalo sudėtyje, kaip aktyvios medžiagos yra 3-metoksi4-(4'aminobenzolsulfonamido)-1,2,5-tiadiazolas (sulfametrolas) ir trimetoprimas, be to, atitinkamai, cukrus ir cukraus alkoholiai, kaip tirpūs agentai, tačiau trimetoprimo koncentracija vandeninėje kompozicijoje yra 0,6 mg/ml, taigi reikia 10 kartų daugiau skiediklio, norint, kad vanduo būtų tinkamas gerti. Tokiu būdu, reikalingi dideli skiediklio kiekiai, kuriuos reikia transportuoti į fermas.The solution contains as active substances 3-methoxy-4- (4'-aminobenzenesulfonamide) -1,2,5-thiadiazole (sulfamethrol) and trimethoprim, in addition to sugar and sugar alcohols, respectively, as soluble agents, but the concentration of trimethoprim in the aqueous composition is 0.6 mg / ml, so 10 times more diluent is needed to make the water suitable for drinking. This requires large volumes of diluent to be transported to the farms.
Europos Patento paraiškoje Nr. 22 342 nurodyti tirpalai, tinkami parenteraliniam gydymui. Žinomų tirpalų sudėtyje yra trimetoprimas ir sulfametoksazolas arba 4-amino-N(5,6-dimetoksi-4-piridinil)-benzolsulfonamidas (sulfadoksinas) , kaip aktyvios medžiagos, ištirpintos 60-80 % nuo pirolidono svorio, be to 1-5 % nuo benzilo alkoholio ir vandens svorio.In European patent application no. 22,342 indicated solutions suitable for parenteral treatment. Known solutions contain trimethoprim and sulfamethoxazole or 4-amino-N- (5,6-dimethoxy-4-pyridinyl) -benzenesulfonamide (sulfadoxine) as active ingredients, dissolved in 60-80% by weight of pyrrolidone, and 1-5% by weight benzyl alcohol and water by weight.
Kiti žinomi injekcijai tinkami tirpalai, aprašyti Vokietijos Patente Nr. 24 45 400, kur trimetoprimas, 4amino-N-(4,6-dimetil-2-pirimidinil)-benzolsulfonamidas (sulfadiminas) ir 4-amino-N-(2-tiazolil)-benzolsulfonamidas (sulfatiazolis) yra ištirpinti dimetilacetamide, kuriame yra 20 % vandens.Other known injectable solutions described in German patent no. 24 45 400, wherein trimethoprim, 4 amino-N- (4,6-dimethyl-2-pyrimidinyl) -benzenesulfonamide (sulfadimine) and 4-amino-N- (2-thiazolyl) -benzenesulfonamide (sulfathiazole) are dissolved in dimethylacetamide containing 20% water.
Injekcij ai Patento Nr. druskos ir (diaveridino tinkami tirpalai žinomi ir iš Vokietijos 27 04 708, kur sulfonamido dietilaminoInjection Pat. salts and (suitable solutions of diaveridine are also known from Germany 27 04 708, where sulfonamide diethylamine
2,4-diamino-5-veratril-pirimidin-laktatas laktatas) yra ištirpinami mišinyje, susidedančiame iš 10-50 dalių vandens, 15-30 dalių propileno glikolio ir 20-40 dalių N-metil-pirolidono.2,4-Diamino-5-veratryl-pyrimidine-lactate) is dissolved in a mixture of 10-50 parts water, 15-30 parts propylene glycol and 20-40 parts N-methylpyrrolidone.
Pagal Vokietijos Patento Nr. 25 38 678 aprašymą, tirpalai injekcijai paruošiami, trimetoprimo etanolyje tirpalą rūgščiame buferyje liofilinant ir liofilintą produktą prieš pat naudojimą ištirpinant sulfametoksizolio tirpale, paruoštame su propilen glikoliu, etanoliu ir vandeniu.According to German patent no. 25 38 678, the solutions for injection are prepared by lyophilizing a solution of trimethoprim in ethanol in an acidic buffer and dissolving the lyophilized product immediately before use in a solution of sulfamethoxysole in propylene glycol, ethanol and water.
Europos Patento paraiškoje Nr. 7 591 nurodomos skystos kompozicijos, kurios gali būti pridedamos į gyvulių geriamą vandenį. Žinomų kompozicijų aktyvios medžiagos susideda iš trimetoprimo ir sulfachlorpiridazino arba N-pirazinil-sulfanilamido (sulfapirazino) arba sulfonamidų druskų. Aktyvūs komponentai yra ištirpinami Nmetilpirolidone arba N-metil-pirolidono ir glikolio monometilo eterio mišinyje, panaudojant tensidus (tensides) ir tirpumas yra padidinamas, pridedant hidroksietilteofiliną, nikotinamidą arba natrio benzoatą.In European patent application no. No. 7,591 refers to liquid compositions which may be added to animal drinking water. The active ingredients of the known compositions consist of trimethoprim and sulfachloropyridazine or salts of N-pyrazinylsulfanylamide (sulfapyrazine) or sulfonamides. The active components are dissolved in N-methylpyrrolidone or in a mixture of N-methylpyrrolidone and glycol monomethyl ether using tensides and the solubility is increased by the addition of hydroxyethyl theophylline, nicotinamide or sodium benzoate.
Etanolaminas yra tinkamiausias, sudarant sulfonamidų druskas. Nors, kaip aprašyme nurodyta, naudojami nešikliai yra fiziologiškai neutralūs, tačiau ekspertui aišku, kad naudojami tirpikliai, t. y. N-metilpirolidonas ir monometil glikolio eteris yra ne mažiau žalingi negu propileno glikolis, glicerolis, dimetilacetamidas ir kiti, kurie nurodyti aprašyme.Ethanolamine is most suitable for the formation of salts of sulfonamides. Although the carriers used are physiologically neutral, as described in the description, it is clear to the expert that the solvents used, i. y. N-methylpyrrolidone and monomethyl glycol ether are no less harmful than propylene glycol, glycerol, dimethylacetamide and the others described in the description.
Apibendrinant, žinomose veterinarijai kompozicijose, kurios tinkamos įmaišyti gyvuliams į geriamą vandenį, yra arba aktyvios medžiagos žemomis koncentracijomis (Vokietijos Patentas Nr. 30 17 032), arba organiniai tirpikliai (EP Nr. 22 342, ir Nr. 7 591, Vokietijos Patentai Nr. 24 45 400 ir Nr. 27 04 708), arba aktyvios medžiagos yra atskirai ištirpinamos, o tada sumaišomos (Vokietijos Patentas Nr. 25 38 678), arba aktyvios medžiagos gana ilgai tirpinamos vandenyje (JAV Patentas Nr. 4 470 978).In summary, known veterinary compositions suitable for incorporation in drinking water for animals include either low concentrations of the active ingredient (German Patent No. 30,17332) or organic solvents (EP Patent No. 22,342 and No. 7,591, German Patent Nos. 3,281,272 and 7,591). 24,400,400 and 27,04708), either the active substances are dissolved separately and then mixed (German Patent No. 25,387,878), or the active substances are dissolved in water for a relatively long time (U.S. Patent No. 4,470,978).
Išradimo tikslas yra paruošti veterinarijai stabilias ir kietas kompozicijas, kurias būtų galima pridėti gyvuliams į geriamą vandenį, kurios greitai ištirptų vandenyje, aktyvios medžiagos būtų reikiamomis koncentracijomis ir jose nebūtų organinio tirpiklio, kenksmingo gyvuliams.The object of the present invention is to provide veterinary stable and solid compositions which can be added to animals in drinking water that are rapidly soluble in water, contain active ingredients in the required concentrations and do not contain any organic solvent which is harmful to the animals.
Nustatyta, kad aukščiau paminėtas tikslas pasiekiamas išradime pateikta kompozicija, kuri susideda iš mišinio: a) 1,6-3,3 % trimetoprimo citrato, užnešto ant vandenyje tirpaus kieto nešiklio dalelių paviršiaus,It has been found that the above object is achieved by the composition of the present invention, which comprises a mixture of: a) 1.6-3.3% trimethoprim citrate applied to the surface of a water soluble solid carrier;
b) 8,4-16,7 % natrio sulfametoksazolo, ir, pasirinktinai,b) 8.4% to 16.7% sodium sulfamethoxazole, and optionally
c) farmacijai tinkamų priedų, susidedančių iš poli(vinilpirolidono) ir/arba kvarco.(c) pharmaceutically acceptable additives consisting of polyvinylpyrrolidone and / or quartz.
Vandenyje tirpus kietas nešiklis yra monosacharidas, toks kaip D-gliukozė, disacharidas, toks kaip laktozė/4-beta-D-galaktozil-(1,5)-D-gliukozė (1,5)/arba cukraus alkoholis, toks kaip manitas.The water-soluble solid carrier is a monosaccharide such as D-glucose, a disaccharide such as lactose / 4-beta-D-galactosyl- (1,5) -D-glucose (1,5) / or a sugar alcohol such as mannitol.
Išradimas pagrįstas tuo, kad trimetoprimo citratas santykinai gerai tirpsta vandenyje, ir, jeigu trimetoprimo citratas užneštas ant tinkamo vandenyje tirpaus nešiklio, gautas granuliuotas produktas yra suderinamas su natrio sulfachlorpiridazinu, t. y., aktyvios medžiagos mišinyje saugojant nesuskyla. Iš kitos pusės, nešiklio mišinys, apvilktas trimetoprimu ir natrio sulfachlorpiridazinu, paruošimas, ištirpinant vandenyje, ir abi aktyvios medžiagos tiekiamos reikiamomis koncentracijomis.The invention is based on the fact that trimethoprim citrate is relatively water soluble and, when trimethoprim citrate is applied on a suitable water soluble carrier, the resulting granular product is compatible with sodium sulfachloropyridazine, i. i.e., the active substance does not decompose on storage. On the other hand, a carrier mixture coated with trimethoprim and sodium sulfachloropyridazine is prepared by dissolving in water and both active substances are supplied in the required concentrations.
Buvo bandyta pridėti trimetoprimo druskas i, vandenyje tirpų kietą nešikli, norint gauti granuliuotą produktą, kuriame butų reikiamos trimetoprimo koncentracijos, ir kuris greitai tirptų vandenyje. Rūgščių prisijungimo trimetoprimo druskos, susidarančios su tartaro, fumarine, maleino, acto arba vandenilio chlorido rūgštimis, nebetenka tirpumo, reikalingo granuliuoto produkto, turinčio reikiamą trimetoprimo kieki, gavimui. Sprendžiant pagal tirpumą, rūgščių druskos, susidariusios su pieno, sieros ir acto rūgštimis, vienodai tiktų, tačiau kompozicijos, kurių sudėtyje yra trimetoprimo laktatas arba sulfatas, nėra pakankamai stabilios saugojimo metu. Stebėtina, kad karboksilinės rūgštys, turinčios panašią cheminę struktūrą, t.y., tartaro rūgštis (2,3-dihidroksibutandikarboksilinė rūgštis), pieno rūgštis (2-hidroksipropioninė rūgštis) ir citrinos rūgštis (2-hidroksi-l,2,3-propantrikarboksilinė rūgštis) sudaro rūgščių druskas, turinčias gana skirtingas charakteristikas. Tokiu būdu ekspertas negali numatyti, kad veterinarijai tinkamas kompozicijas galima gauti, panaudojant trimetoprimą citrinos rūgšties druskų pavidalu.Attempts have been made to add trimethoprim salts to a water-soluble solid carrier to obtain a granular product having the required concentrations of trimethoprim and rapidly soluble in water. The acid addition salts of trimethoprim formed with tartaric, fumaric, maleic, acetic or hydrochloric acids no longer possess the solubility required to obtain a granular product containing the required amount of trimethoprim. According to solubility, the acid salts formed with lactic, sulfuric and acetic acids are equally suitable, but compositions containing trimethoprim lactate or sulfate are not sufficiently stable during storage. It is surprising that carboxylic acids having a similar chemical structure, namely tartaric acid (2,3-dihydroxybutanedicarboxylic acid), lactic acid (2-hydroxypropionic acid) and citric acid (2-hydroxy-1,2,3-propantricarboxylic acid) acid salts with quite different characteristics. In this way, the expert cannot predict that compositions suitable for veterinary use can be obtained using trimethoprim in the form of citric acid salts.
Pagal išradimą, kompozicijos veterinarijai paruošiamos, reaguojant vandenyje 1,6-3,3 % trimetoprimo su citrinos rūgštimi, gautą trimetoprimo citrato tirpalą, surišant su vandenyje tirpaus nešiklio dalelių paviršiumi, išdžiovinus daleles ir sumaišius jas natrio sulfachlorpiridazinu.According to the invention, compositions for veterinary use are prepared by reacting 1.6-3.3% trimethoprim citrate in water with a solution of trimethoprim citrate obtained by binding to the surface of water soluble carrier particles, drying the particles and mixing them with sodium sulfachloropyridazine.
Jeigu reikia, vandenyje tirpus nešiklis yra veikiamas poli(vinilpirolidonu).If necessary, the water-soluble carrier is treated with poly (vinylpyrrolidone).
Vandenyje tirpaus nešiklio dalelės, apvilktos trimetoprimo citratu gali būti maišomos taip pat su kvarcu, norint išvengti dalelių sulipimo su galutiniu produktu.Water soluble carrier particles coated with trimethoprim citrate may also be mixed with quartz to prevent the particles from sticking to the final product.
Tikslinga naudoti vandenyje tirpų nešiklį, turintį mažą vandens kiekį arba bevandenėje formoje.It is expedient to use a water-soluble carrier having a low water content or anhydrous form.
Pagal pasiūlytą išradime būdą, kompozicija veterinarijai paruošiama taip:According to the method of the invention, the composition is prepared for veterinary use as follows:
Trimetoprimas 40-80°C temperatūroje ištirpinamas santykiu: 1 masės dalis trimetoprimo, 10-50 masės dalių vandens ir 0,5-2,5 masės dalių citrinos rūgšties. Kadangi ruošiamas vandeninis tirpalas, citrinos rūgštis gali būti naudojama tiek bevandenė, tiek monohidrato forma. Gautas tirpalas užnešamas ant nuo 25 iki 100 dalių vandenyje tirpaus kieto nešiklio dalelių paviršiaus, geriausia mono- arba disacharido, arba cukraus alkoholį, arba jų mišinį. Jeigu pageidautina, nešiklis yra prieš tai paveikiamas 0,5-5 dalimis poli(vinil pirolidono) , paskaičiuoto pagal trimetoprimo svorį. Tinkamiausiai, kad kietas nešiklis yra minkomas su trimetoprimo citrato vandeniniu tirpalu, gauta šlapia masė granuliuojama, išspaudžiant ją per sietą. Šlapios dalelės yra džiovinamos, sumažinant vandens kiekį iki mažiau 1 %, tada nusijojama ir/arba sumalama, kad miltelių dalelės būtų mažesnės negu 0,5 mm. Gauti milteliai sumaišomi su natrio sulfachlorpiridazinu, kurio dalelės mažesnės negu 0,5 mm ir, jeigu reikia, su kvarcu. Gautas miltelių mišinys gali būti vėl malamas. Pagal išradimą, gyvulių gydymui kompozicija veterinarijai pridedama į geriamą vandenį, kurio kiekis 100, o dažnai ir 1000 kartų didesnis už kompozicijos kiekį. Kompozicija ištirpinama labai greitai, per 1-2 minutes, ir gaunamas skaidrus arba balkšvos spalvos tirpalas, priklausomai nuo panaudoto kvarco kiekio. Geriamas vanduo, kuriame yra stiprūs anti-bakteriniai agentai, tinkamas gyvulių, užsikrėtusių bakterine infekcija, gydymui; šis gydymo būdas yra labai paprastas, ekonomiškas ir efektyvus.Dissolve trimethoprim at 40-80 ° C in a ratio of 1 part by weight of trimethoprim, 10-50 parts by weight of water and 0.5-2.5 parts by weight of citric acid. As an aqueous solution is prepared, citric acid can be used in both anhydrous and monohydrate forms. The resulting solution is applied to a surface of 25 to 100 parts by weight of a water soluble solid carrier, preferably a mono- or disaccharide, or a sugar alcohol, or a mixture thereof. If desired, the carrier is pretreated with 0.5 to 5 parts by weight of polyvinylpyrrolidone based on trimethoprim. Preferably, the solid carrier is kneaded with an aqueous solution of trimethoprim citrate, and the resulting wet mass is granulated by squeezing it through a sieve. The wet particles are dried by reducing the water content to less than 1%, then sieved and / or ground to give powder particles smaller than 0.5 mm. The resulting powder is mixed with sodium sulfachloropyridazine having a particle size of less than 0.5 mm and quartz if necessary. The resulting powder mixture may be ground again. According to the invention, for the treatment of animals, the veterinary composition is added to drinking water in an amount of 100 and often 1000 times the amount of the composition. The composition dissolves very rapidly within 1-2 minutes to give a clear to off-white solution, depending on the amount of quartz used. Drinking water containing strong anti-bacterial agents suitable for treating animals infected with bacterial infection; this treatment is very simple, cost effective and effective.
Kadangi kompozicija gerai tirpsta vandenyje, tai, palyginus, nedidelis kompozicijos kiekis turi būti transportuojamas į gydymo vietą.Because the composition is highly water soluble, a relatively small amount of the composition should be transported to the treatment site.
Pagal išradimą, kompozicijos stabilumui yra labai svarbus vandens kiekis. Mūsų eksperimentiniais duomenimis nustatyta, kad natrio sulfachlorpiridazino stabilumas yra palaikomas, jeigu vandens kiekis kompozicijoje nedidesnis negu 1 %. Todėl granuliuotos nešiklio dalelės, apvilktos trimetoprimo citratu, prieš tai yra džiovinamos, kol vandens kiekis pasidaro mažesnis negu 1 %. Kadangi granuliuotų nešiklio dalelių, apvilktų trimetoprimo citratu, vandens kiekis būtinai reguliuojamas, todėl nebūtina citrinos rūgštį ir/arba vandenyje tirptų nešėją naudoti bevandenėje formoje.According to the invention, the amount of water is very important for the stability of the composition. Our experimental data have shown that the stability of sodium sulfachloropyridazine is maintained if the water content of the composition is not greater than 1%. Therefore, the granular carrier particles, coated with trimethoprim citrate, are pre-dried until the water content is less than 1%. Because the water content of the granular carrier particles coated with trimethoprim citrate is necessarily controlled, it is not necessary to use citric acid and / or water-soluble carrier in anhydrous form.
Pagal išradimą, kompozicija veterinarijai, kurioje vandens kiekis nedidesnis negu 1 %, yra labai stabili: ji gali būti saugojama 90 dienų 40°C temperatūroje, neskildama ir nekeisdama spalvos.According to the invention, the veterinary composition with a water content of up to 1% is very stable: it can be stored for 90 days at 40 ° C without decomposition and discoloration.
Aprašytos išradime kompozicijos veterinarijai tirpumas buvo lyginamas su žinoma kompozicija pagal JAV Patentą Nr. 4 470 978. Buvo pakartotas JAV Patente Nr. 4 470 978 aprašytas 1 pavyzdys, išskyrus tai, kad nebuvo pridėtas fenoksietanolis. Tokiu būdu, palyginimui, miltelių mišinio sudėtis buvo tokia:The solubility of the veterinary composition of the present invention was compared to a known composition according to U.S. Pat. No. 4,470,978. Repeats U.S. Pat. No. 4,470,978 describes Example 1 except that no phenoxyethanol was added. Thus, for comparison, the composition of the powder mixture was as follows:
natrio sulfachlorpiridazinas trimetoprimas sacharozėsodium sulfachloropyridazine trimethoprim sucrose
39,4 g 7,8 g 13,14 g39.4 g 7.8 g 13.14 g
Gautas miltelių mišinys buvo ištirpintas vandenyje, norint gauti 0,5 g/1 koncentracijos tirpalą, kaip aukščiau pateiktame Patento aprašymo 6 pavyzdyje (žr. 6 pavyzdį, 3 bandymą). Tokiu būdu, į 1 litro talpos stiklinę 20-22°C temperatūroje buvo aukščiau nurodytų miltelių mišinio, maišoma stikline lazdele, ir nustatytas laikas, per kurį milteliai pilnai ištirpo.The resulting powder mixture was dissolved in water to give a solution of 0.5 g / L as in Example 6 of the above patent specification (see Example 6, Test 3). In this way, a 1 liter beaker at 20-22 ° C contained the above powder mixture, stirred with a glass rod and set the time for the powder to completely dissolve.
pridėta 0,5 g kas 5-10 min.0.5 g added every 5-10 min.
Pagal išradimą, kompozicija veterinarijai buvo tikrinama taip pat. Tokiu būdu, į 1 litro talpos stiklinę 20-22°C temperatūroje buvo pridėta 3,0 g kompozicijos, paruoštos pagal išradimo 3 pavyzdį, tada vanduo maišomas stikline lazdele ir nustatytas laikas, per kurį milteliai pilnai ištirpo.According to the invention, the veterinary composition was also tested. In this way, 3.0 g of the composition of Example 3 of the invention was added to a 1 liter beaker at 20-22 ° C, then the water was stirred with a glass rod and the time for the powder to dissolve was determined.
Gautų rezultatų duomenys pateikti 1 lentelėje.The results obtained are shown in Table 1.
LentelėTable
Paruošimas_Tirpumo laikasPreparation_The solubility time
US Patento Nr. 4 470 978 6 Pavyzdys 90 minučiųU.S. Pat. 4,470,978 6 Example 90 minutes
Pateikto išradimo 3 Pavyzdys_1,5 minutėsExample 3 of the present invention_1.5 minutes
Iš 1 lentelės duomenų matoma, kad pateikto išradimo aprašyta kompozicija veterinarijai tirpsta 60 kartų greičiau, negu žinoma kompozicija, su kuria buvo lyginama.From the data in Table 1, it can be seen that the composition described in the present invention is 60 times faster in veterinary dissolution than the known composition with which it was compared.
Toliau išradimas paaiškinamas šiais pavyzdžiais.The invention is further illustrated by the following examples.
PavyzdysAn example
1,5 g citrinos rūgšties, 2,0 g trimetoprimo ir 8,0 ml demineralizuoto vandens supilama į 100 ml talpos stiklinę, ir turinys maišomas, palaikant 75°C, kol io ištirpsta. 81 g bevandenė gliukozė maišoma su trimetoprimo citrato vandeniniu tirpalu, ir šlapia masė praleidžiama per sietelį, kurio akučių dydis - 1,0 mm. Gautos šlapios granulės yra džiovinamos ant padėklo 60°C temperatūroje, kol vandens kiekis masėje sumažėja iki 1 %. Sausos granulės praleidžiamos per sietelį, kurio akučių dydis 0,5 mm, tada sumaišoma su 10 g natrio sulfachlorpiridazino, ir gautas mišinys vėl praleidžiamas per tą patį sietelį.Transfer 1.5 g of citric acid, 2.0 g of trimethoprim and 8.0 ml of demineralized water into a 100 ml beaker and stir the contents at 75 ° C until dissolved. 81 g of anhydrous glucose are mixed with an aqueous solution of trimethoprim citrate and the wet mass is passed through a 1.0 mm mesh sieve. The resulting wet granules are dried on a tray at 60 ° C until the water content decreases to 1% by weight. Pass the dry granules through a 0,5 mm mesh sieve, then mix with 10 g of sodium sulphachloropyridazine and pass through the same sieve again.
Pridėjus 1 g kompozicijos į 1 litrą vandens, ji ištirpsta per 1 minutę, ir gaunamas skaidrus tirpalas.Adding 1 g of composition to 1 liter of water dissolves in 1 minute to give a clear solution.
Produktas buvo saugojamas 90 dienų 40°C temperatūroje: nei išorė, nei tirpumas ir aktyvios medžiagos sudėtis nepasikeitė.The product was stored for 90 days at 40 ° C with no changes in appearance, solubility or composition of the active substance.
PavyzdysAn example
240 g bevandenės gliukozės ir 270 g manito sudedama į mikserį (MS tipo, LČdige gamybos) ir 5 minutes homogenizuojama. į homogeninį miltelių mišinį 70-75°C temperatūroje porcijomis maišant supilamas 12,0 g trimetoprimo ir 9,0 g citrinos rūgšties tirpalas, paruoštas 50 ml distiliuoto vandens. Toliau mišinys 10 min. minkomas, po to, granulės yra džiovinamos skysčio džiovinimo aparatu (Uniglatt gamybos), oro įėjimo temperatūra - 70°C. Džiovinama apie 30 minučių, kol vandens kiekis granulėse sumažėja iki 1,0 %. Sausos granulės yra nusijojamos per vibruojantį granuliavimo aparatą (pagamintą Erweka), panaudojant rūgščiai atsparų tinklelį, kurio akučių dydis 0,5 mm.Add 240 g of anhydrous glucose and 270 g of mannitol to a blender (MS type, Ligige production) and homogenize for 5 minutes. a solution of 12.0 g of trimethoprim and 9.0 g of citric acid in 50 ml of distilled water is added in portions to a homogeneous powder mixture at 70-75 ° C. Continue to mix for 10 min. the granules are then kneaded and then dried in a fluid dryer (Uniglatt production) with an air inlet temperature of 70 ° C. Dry for about 30 minutes until the water content of the granules has dropped to 1.0%. The dry pellets are sieved through a vibrating pelletizer (made by Erweka) using an acid-resistant mesh of 0.5 mm mesh.
57,5 g natrio sulfachlorpiridazino ir 3,0 g koloidinio kvarco sumaišoma su 510 g anksčiau gautų granulių, kuriose yra 11,5 g trimetoprimo. Miltelių mišinys yra sumalamas LU 100 tipo malūne, panaudojant tinklelį, kurio akučių dydis 2 mm.57.5 g of sodium sulfachloropyridazine and 3.0 g of colloidal quartz are mixed with 510 g of previously obtained granules containing 11.5 g of trimethoprim. The powder mixture is ground in a LU 100 type mill using a 2 mm mesh.
Gauto produkto stabilumo ir tirpumo duomenys tokie patys, kaip ir produkto, aprašyto 1 Pavyzdyje.The product obtained has the same stability and solubility data as the product described in Example 1.
PavyzdysAn example
830 g manito ir 30 g poli (vinilpirolidono) (K-30 tipo) įdedama į laboratorinį mikserį (M5 tipo, LČdige gamybos) ir homogenizuojama 3 minutes. Į homogeninį mišinį 65-70°C temperatūroje, pastoviai maišant, pridedamas 20 g trimetoprimo ir 15 g citrinos rūgšties monohidrato tirpalas, paruoštas 150 ml vandens. Maišoma 5 minutes ir masė paduodama į granuliavimo mašiną (pagamintą Erweka) per sietelį, kurio akučių dydis 1,0 mm. Šlapios granulės džiovinamos džiovinimo aparato padėkluose, kaitinant garu. Džiovinama prie 60°C, kol granulėse vandens kiekis tampa mažesnis negu 1 %. Tada sausos granulės praleidžiamos per sietelį, kurio akučių dydis 0,6 mm. Į gautas granules pridedama 100 g sulfachlorpiridazino ir 5 g koloidinio kvarco, mišinys 5 min. homogenizuo j amas mikseryje (L(5dige gamybos), tada sumalama malūne (Alpin gamybos), panaudojant sietelį, kurio akučių dydis 3 mm.830 g of mannitol and 30 g of poly (vinylpyrrolidone) (type K-30) are placed in a laboratory mixer (type M5, Ligige) and homogenized for 3 minutes. A solution of 20 g of trimethoprim and 15 g of citric acid monohydrate in 150 ml of water is added to the homogenous mixture at 65-70 ° C with constant stirring. Stir for 5 minutes and place the mass in a granulating machine (made by Erweka) through a sieve with a mesh size of 1.0 mm. The wet pellets are dried in the dryer trays by steam heating. Dry at 60 ° C until the water content of the granules is less than 1%. The dry pellets are then passed through a sieve with a mesh size of 0.6 mm. To the resulting pellets were added 100 g of sulfachloropyridazine and 5 g of colloidal quartz, a mixture of 5 min. homogenize in a mixer (L (5dig production), then grind in a mill (Alpin)) using a 3 mm mesh sieve.
Produktas buvo saugomas 90 dienų 40°C: nei išorė, nei tirpumas ir aktyvios medžiagos sudėtis nepasikeitė.The product was stored for 90 days at 40 ° C: there was no change in appearance, solubility or composition of the active substance.
Claims (11)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9203477A HU212498B (en) | 1992-11-06 | 1992-11-06 | Process for producing water-soluble pharmaceutical compositions, containing sulfachlorpyridazin-sodium and trimethoprim |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| LTIP1448A LTIP1448A (en) | 1994-11-25 |
| LT3395B true LT3395B (en) | 1995-09-25 |
Family
ID=10982527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LTIP1448A LT3395B (en) | 1992-11-06 | 1993-11-05 | Stable and water-soluble veterinary composition and process for preparing thereof |
Country Status (13)
| Country | Link |
|---|---|
| DE (1) | DE4338047A1 (en) |
| EE (1) | EE9400061A (en) |
| FR (1) | FR2697751A1 (en) |
| GB (1) | GB2272156B (en) |
| HR (1) | HRP931367A2 (en) |
| HU (1) | HU212498B (en) |
| IT (1) | IT1266671B1 (en) |
| LT (1) | LT3395B (en) |
| LV (1) | LV10578B (en) |
| PL (1) | PL300937A1 (en) |
| SI (1) | SI9300580A (en) |
| SK (1) | SK107593A3 (en) |
| YU (1) | YU70493A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106727578A (en) * | 2016-12-22 | 2017-05-31 | 保定冀中药业有限公司 | Compound Sulfachorpyrdazine Sodium Powder and preparation method thereof |
| CN115919863A (en) * | 2023-02-01 | 2023-04-07 | 爱力迈(安徽)动物药业有限公司 | A kind of preparation method of compound sulfachloropyridazine sodium powder |
| CN119970645A (en) * | 2025-01-22 | 2025-05-13 | 中国药科大学 | A soluble compound sulfachloropyridazine sodium powder and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2445400A1 (en) | 1973-09-24 | 1975-04-03 | Wellcome Impfstoff | INJECTABLE THERAPEUTIC PREPARATIONS |
| DE2538678A1 (en) | 1975-08-30 | 1977-03-03 | Boehringer Mannheim Gmbh | Injectable solns. contg. trimethoprim and sulphamethoxazole - of physiologically tolerable pH and contg. only small amts. of organic solvents |
| DE2704708A1 (en) | 1976-02-06 | 1977-08-11 | Rosco As | STABLE INJECTABLE PREPARATIONS AND PROCEDURES FOR THEIR MANUFACTURING |
| EP0007591A1 (en) | 1978-08-01 | 1980-02-06 | Ciba-Geigy Ag | Stable medicinal solution on the basis of 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine(trimethoprim) and a sulphonamide, process for preparing and using it |
| DE3017032A1 (en) | 1979-05-03 | 1980-11-13 | Gea As | A CLEAR INJECTION OR INFUSION SOLUTION CONTAINING A SULPHONAMIDE AND A POTENTIAL |
| EP0022342A2 (en) | 1979-07-05 | 1981-01-14 | Pfizer Inc. | Sulfonamide solutions |
| US4470978A (en) | 1978-07-25 | 1984-09-11 | Abic Ltd. | Synergistic antibacterial composition |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1469521A (en) * | 1973-01-05 | 1977-04-06 | Wellcome Found | Antimicrobial preparations |
| EP0009559B1 (en) * | 1978-08-01 | 1982-08-25 | Ciba-Geigy Ag | Stable, liquid pharmaceutical formulation, its preparation and use |
| HU191890B (en) * | 1983-11-02 | 1987-04-28 | Phylaxia Oltoanyagtermeloe | Process for production of veterinary composition containing sulphamids suitable against illnesses caused by pathogene coli stocks |
| EP0200252B1 (en) * | 1985-05-02 | 1999-03-10 | Yamanouchi Europe B.V. | Tablets comprising trimethoprim and a sulfonamide |
| HU197986B (en) * | 1987-02-25 | 1989-07-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producing veterinary preparation of synergic effect |
-
1992
- 1992-11-06 HU HU9203477A patent/HU212498B/en not_active IP Right Cessation
-
1993
- 1993-10-05 SK SK1075-93A patent/SK107593A3/en unknown
- 1993-10-29 FR FR9312927A patent/FR2697751A1/en not_active Withdrawn
- 1993-11-03 GB GB9322677A patent/GB2272156B/en not_active Expired - Fee Related
- 1993-11-04 PL PL93300937A patent/PL300937A1/en unknown
- 1993-11-04 IT IT93MI002342A patent/IT1266671B1/en active IP Right Grant
- 1993-11-04 HR HR931367A patent/HRP931367A2/en not_active Application Discontinuation
- 1993-11-05 LT LTIP1448A patent/LT3395B/en not_active IP Right Cessation
- 1993-11-05 YU YU70493A patent/YU70493A/en unknown
- 1993-11-05 LV LVP-93-1183A patent/LV10578B/en unknown
- 1993-11-05 SI SI9300580A patent/SI9300580A/en unknown
- 1993-11-08 DE DE4338047A patent/DE4338047A1/en not_active Withdrawn
-
1994
- 1994-06-21 EE EE9400061A patent/EE9400061A/en unknown
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2445400A1 (en) | 1973-09-24 | 1975-04-03 | Wellcome Impfstoff | INJECTABLE THERAPEUTIC PREPARATIONS |
| DE2538678A1 (en) | 1975-08-30 | 1977-03-03 | Boehringer Mannheim Gmbh | Injectable solns. contg. trimethoprim and sulphamethoxazole - of physiologically tolerable pH and contg. only small amts. of organic solvents |
| DE2704708A1 (en) | 1976-02-06 | 1977-08-11 | Rosco As | STABLE INJECTABLE PREPARATIONS AND PROCEDURES FOR THEIR MANUFACTURING |
| US4470978A (en) | 1978-07-25 | 1984-09-11 | Abic Ltd. | Synergistic antibacterial composition |
| EP0007591A1 (en) | 1978-08-01 | 1980-02-06 | Ciba-Geigy Ag | Stable medicinal solution on the basis of 2,6-diamino-5-(3',4',5'-trimethoxybenzyl)-pyrimidine(trimethoprim) and a sulphonamide, process for preparing and using it |
| DE3017032A1 (en) | 1979-05-03 | 1980-11-13 | Gea As | A CLEAR INJECTION OR INFUSION SOLUTION CONTAINING A SULPHONAMIDE AND A POTENTIAL |
| EP0022342A2 (en) | 1979-07-05 | 1981-01-14 | Pfizer Inc. | Sulfonamide solutions |
Also Published As
| Publication number | Publication date |
|---|---|
| LV10578A (en) | 1995-04-20 |
| ITMI932342A0 (en) | 1993-11-04 |
| ITMI932342A1 (en) | 1995-05-04 |
| LV10578B (en) | 1996-06-20 |
| HU212498B (en) | 1996-07-29 |
| GB2272156A (en) | 1994-05-11 |
| YU70493A (en) | 1996-02-19 |
| PL300937A1 (en) | 1994-05-16 |
| FR2697751A1 (en) | 1994-05-13 |
| EE9400061A (en) | 1995-12-15 |
| SI9300580A (en) | 1994-06-30 |
| GB2272156B (en) | 1996-05-08 |
| LTIP1448A (en) | 1994-11-25 |
| SK107593A3 (en) | 1994-05-11 |
| HRP931367A2 (en) | 1995-02-28 |
| DE4338047A1 (en) | 1994-05-11 |
| HU9203477D0 (en) | 1993-01-28 |
| HUT69405A (en) | 1995-09-28 |
| GB9322677D0 (en) | 1993-12-22 |
| IT1266671B1 (en) | 1997-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0427582A2 (en) | Non-aqueous micellar solutions of various drugs | |
| CZ280541B6 (en) | Pharmaceutical mixtures of phlorphenicol | |
| KR100311576B1 (en) | Antimicrobial Compositions for Oral Administration | |
| US7396819B2 (en) | Anthelmintic formulations | |
| BRPI0720118B1 (en) | solid pharmaceutical dosage form for oral administration comprising valganciclovir hydrochloride | |
| EP1634584A1 (en) | Dimeticone-containing sustained formulation | |
| TWI418344B (en) | Stable non-aqueous pour-on compositions | |
| US7582612B2 (en) | Multi-action anthelmintic formulations | |
| BG66212B1 (en) | Formulation | |
| EP1203531B1 (en) | Water soluble compositions containing chlorhexidine and their use | |
| PT712278E (en) | DISPERSIBLE GRANULATES IN WATER FUNGICIDE CONTAINING N-PYRIDYLTOLUIN | |
| JPS6393712A (en) | Manufacture of aqueous drug containing organic acid as effective component | |
| US4950653A (en) | Solid iodophor composition | |
| DE2311214A1 (en) | INGREDIENTS COMBINATION | |
| KR900007310B1 (en) | Process for the preparation of agent for coccidiosis | |
| LT3395B (en) | Stable and water-soluble veterinary composition and process for preparing thereof | |
| SK286194B6 (en) | Aqueous pharmaceutical composition | |
| US5935603A (en) | Water soluble powder form compositions and their applications thereof | |
| JPS6242924A (en) | Vermifuge and fungicide composition | |
| DE69716056T2 (en) | ACYLUREA COMPOUNDS FOR TREATING COCCIDIOIDOMYCOSIS IN WARM-BLOODED ANIMALS | |
| US8715734B2 (en) | Amoxicilline instant granulate | |
| JP2864885B2 (en) | Nicergoline-containing oral dosage form | |
| BE897402A (en) | PREPARATION FOR THE PREPARATION OF AN ORAL ADMINISTRATIVE ANIMAL SOLUTION FOR ANIMALS | |
| JPS63218618A (en) | Non-steroidal anti-inflammatory agent composition for oral administration | |
| JPH041133A (en) | Stable oxophosphoric acid emulsion and production thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM9A | Lapsed patents |
Effective date: 19961105 |