CA2331671C - Effervescent preparations - Google Patents
Effervescent preparations Download PDFInfo
- Publication number
- CA2331671C CA2331671C CA002331671A CA2331671A CA2331671C CA 2331671 C CA2331671 C CA 2331671C CA 002331671 A CA002331671 A CA 002331671A CA 2331671 A CA2331671 A CA 2331671A CA 2331671 C CA2331671 C CA 2331671C
- Authority
- CA
- Canada
- Prior art keywords
- sugar
- effervescent
- effervescent preparation
- sugar alcohol
- substitute
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 25
- 239000003765 sweetening agent Substances 0.000 claims abstract description 25
- 235000021092 sugar substitutes Nutrition 0.000 claims abstract description 24
- 235000000346 sugar Nutrition 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical group [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 20
- 239000013543 active substance Substances 0.000 claims description 16
- 239000000654 additive Substances 0.000 claims description 15
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- 230000002378 acidificating effect Effects 0.000 claims description 13
- 239000000155 melt Substances 0.000 claims description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 10
- 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 7
- 108010011485 Aspartame Proteins 0.000 claims description 6
- -1 antihypotensives Substances 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- 239000000605 aspartame Substances 0.000 claims description 6
- 235000010357 aspartame Nutrition 0.000 claims description 6
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical group OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 6
- 229960003438 aspartame Drugs 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000003172 expectorant agent Substances 0.000 claims description 4
- 239000011159 matrix material Substances 0.000 claims description 4
- 239000001509 sodium citrate Substances 0.000 claims description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 4
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 239000000150 Sympathomimetic Substances 0.000 claims description 2
- 229940035676 analgesics Drugs 0.000 claims description 2
- 230000000954 anitussive effect Effects 0.000 claims description 2
- 229940069428 antacid Drugs 0.000 claims description 2
- 239000003159 antacid agent Substances 0.000 claims description 2
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 230000003266 anti-allergic effect Effects 0.000 claims description 2
- 230000001088 anti-asthma Effects 0.000 claims description 2
- 230000003178 anti-diabetic effect Effects 0.000 claims description 2
- 230000003474 anti-emetic effect Effects 0.000 claims description 2
- 230000002959 anti-hypotensive effect Effects 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims description 2
- 239000000924 antiasthmatic agent Substances 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims description 2
- 229940125683 antiemetic agent Drugs 0.000 claims description 2
- 239000002111 antiemetic agent Substances 0.000 claims description 2
- 229940125715 antihistaminic agent Drugs 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 229940124572 antihypotensive agent Drugs 0.000 claims description 2
- 239000003524 antilipemic agent Substances 0.000 claims description 2
- 239000003434 antitussive agent Substances 0.000 claims description 2
- 229940124584 antitussives Drugs 0.000 claims description 2
- 230000000572 bronchospasmolytic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000003419 expectorant effect Effects 0.000 claims description 2
- 229940066493 expectorants Drugs 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000008141 laxative Substances 0.000 claims description 2
- 229940125722 laxative agent Drugs 0.000 claims description 2
- 229960005015 local anesthetics Drugs 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 230000000510 mucolytic effect Effects 0.000 claims description 2
- 229940066491 mucolytics Drugs 0.000 claims description 2
- 230000001975 sympathomimetic effect Effects 0.000 claims description 2
- 229940064707 sympathomimetics Drugs 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 claims 4
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 claims 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims 2
- 230000000202 analgesic effect Effects 0.000 claims 2
- 239000002552 dosage form Substances 0.000 claims 2
- 238000003860 storage Methods 0.000 abstract description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 14
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 9
- 229910002092 carbon dioxide Inorganic materials 0.000 description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 8
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 7
- 235000015165 citric acid Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000000811 xylitol Substances 0.000 description 7
- 235000010447 xylitol Nutrition 0.000 description 7
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 7
- 229960002675 xylitol Drugs 0.000 description 7
- 239000007938 effervescent tablet Substances 0.000 description 5
- 238000001125 extrusion Methods 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- 229960004889 salicylic acid Drugs 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- 229960004308 acetylcysteine Drugs 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940030600 antihypertensive agent Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 2
- 229960004704 dihydroergotamine Drugs 0.000 description 2
- HESHRHUZIWVEAJ-JGRZULCMSA-N dihydroergotamine Chemical compound C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C3=CC=CC4=NC=C([C]34)C2)C1)C)C1=CC=CC=C1 HESHRHUZIWVEAJ-JGRZULCMSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000905 isomalt Substances 0.000 description 2
- 235000010439 isomalt Nutrition 0.000 description 2
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 2
- 239000000832 lactitol Substances 0.000 description 2
- 229960003451 lactitol Drugs 0.000 description 2
- 235000010448 lactitol Nutrition 0.000 description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000007968 orange flavor Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 229960003908 pseudoephedrine Drugs 0.000 description 2
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 2
- 235000019204 saccharin Nutrition 0.000 description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 2
- 229940081974 saccharin Drugs 0.000 description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
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- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- KVHHQGIIZCJATJ-UHFFFAOYSA-N 1-(4-chlorophenyl)-4-(dimethylamino)-2,3-dimethyl-2-butanol Chemical compound CN(C)CC(C)C(C)(O)CC1=CC=C(Cl)C=C1 KVHHQGIIZCJATJ-UHFFFAOYSA-N 0.000 description 1
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- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- YREYLAVBNPACJM-UHFFFAOYSA-N 2-(tert-butylamino)-1-(2-chlorophenyl)ethanol Chemical compound CC(C)(C)NCC(O)C1=CC=CC=C1Cl YREYLAVBNPACJM-UHFFFAOYSA-N 0.000 description 1
- PTVWPYVOOKLBCG-UHFFFAOYSA-N 3-(4-phenyl-1-piperazinyl)propane-1,2-diol Chemical compound C1CN(CC(O)CO)CCN1C1=CC=CC=C1 PTVWPYVOOKLBCG-UHFFFAOYSA-N 0.000 description 1
- SQVIAVUSQAWMKL-UHFFFAOYSA-N 3-[2-(ethylamino)-1-hydroxyethyl]phenol Chemical compound CCNCC(O)C1=CC=CC(O)=C1 SQVIAVUSQAWMKL-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
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- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 244000248349 Citrus limon Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 241001672694 Citrus reticulata Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- HEBKCHPVOIAQTA-QWWZWVQMSA-N D-arabinitol Chemical compound OC[C@@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-QWWZWVQMSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-threitol Chemical compound OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 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
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- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- FIADGNVRKBPQEU-UHFFFAOYSA-N pizotifen Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2CCC2=C1C=CS2 FIADGNVRKBPQEU-UHFFFAOYSA-N 0.000 description 1
- 229960004572 pizotifen Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003712 propranolol Drugs 0.000 description 1
- 229960002189 propyphenazone Drugs 0.000 description 1
- PXWLVJLKJGVOKE-UHFFFAOYSA-N propyphenazone Chemical compound O=C1C(C(C)C)=C(C)N(C)N1C1=CC=CC=C1 PXWLVJLKJGVOKE-UHFFFAOYSA-N 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- HEBKCHPVOIAQTA-ZXFHETKHSA-N ribitol Chemical compound OC[C@H](O)[C@H](O)[C@H](O)CO HEBKCHPVOIAQTA-ZXFHETKHSA-N 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- 229960001462 sodium cyclamate Drugs 0.000 description 1
- GOZDTZWAMGHLDY-UHFFFAOYSA-L sodium picosulfate Chemical compound [Na+].[Na+].C1=CC(OS(=O)(=O)[O-])=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OS([O-])(=O)=O)C=C1 GOZDTZWAMGHLDY-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229960000859 tulobuterol Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
Classifications
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Abstract
Medicament-containing effervescent preparations are particularly stable on storage when they contain fusible sugar, sugar alcohol and/or sugar substitute.
Description
LeA32842-FC
' -1- Al Effervescent preparations The invention relates to a process for producing medicament-containing effervescent preparations with at least partial melting of a preparation component and to effervescent preparations obtainable by this process.
Effervescent preparations such as, for example, effervescent powders or effervescent tablets are a formulation form, for example for active substances with a long absorption time or with a tendency to irritate the gastric mucosa, which is able to mitigate the disadvantageous properties meritioned for the active substances.
Medicament-containing effervescent preparations therefore enjoy increasing popularity. They are normally produced in 3 to 4 stages, namely by a) granulating the effervescent composition consisting of COZ donor and C02-releasing acidic component, b) mixing the other components (active substances and other ancillary substances), c) combining the components obtained frorn process steps a) and b) and, where appropriate, d) tabletting the mixture obtained in step c).
Since both the CO2 donor and the acidic component are relatively unsuitable for direct tabletting, the components of the effervescent composition have in the past been subjected, where appropriate in combination with the active substance, to a granulation process before the tabletting; compare, for example, German Offenlegungsschrift 22 16 072. The stability of the effervescent tablets produced in this way is, however, still unsatisfactory. The additional use of buffer substances and flavourings (which, after all, usually consist of many individual different compounds) in particular results in a sensitivity to water which leads, on storage, to discoloration, distension and degradation reactions. To avoid these unwanted reactions, effervescent preparations are often sealed in metal foils. Although this measure extends the shelf life, it is not possible reliably to prevent distension of the metal foil sachets on prolonged storage.
It has now been found, surprisingly, that the stability of medicament-containing effervescent preparations can be increased by a process in which a preparation component is melted.
LeA32842
' -1- Al Effervescent preparations The invention relates to a process for producing medicament-containing effervescent preparations with at least partial melting of a preparation component and to effervescent preparations obtainable by this process.
Effervescent preparations such as, for example, effervescent powders or effervescent tablets are a formulation form, for example for active substances with a long absorption time or with a tendency to irritate the gastric mucosa, which is able to mitigate the disadvantageous properties meritioned for the active substances.
Medicament-containing effervescent preparations therefore enjoy increasing popularity. They are normally produced in 3 to 4 stages, namely by a) granulating the effervescent composition consisting of COZ donor and C02-releasing acidic component, b) mixing the other components (active substances and other ancillary substances), c) combining the components obtained frorn process steps a) and b) and, where appropriate, d) tabletting the mixture obtained in step c).
Since both the CO2 donor and the acidic component are relatively unsuitable for direct tabletting, the components of the effervescent composition have in the past been subjected, where appropriate in combination with the active substance, to a granulation process before the tabletting; compare, for example, German Offenlegungsschrift 22 16 072. The stability of the effervescent tablets produced in this way is, however, still unsatisfactory. The additional use of buffer substances and flavourings (which, after all, usually consist of many individual different compounds) in particular results in a sensitivity to water which leads, on storage, to discoloration, distension and degradation reactions. To avoid these unwanted reactions, effervescent preparations are often sealed in metal foils. Although this measure extends the shelf life, it is not possible reliably to prevent distension of the metal foil sachets on prolonged storage.
It has now been found, surprisingly, that the stability of medicament-containing effervescent preparations can be increased by a process in which a preparation component is melted.
LeA32842
-2-The invention thus relates to a process fo:r producing medicament-containing effervescent preparations consisting of A. effervescent composition containing (i) CO2 donor and (ii) acidic component, B. pharmaceutical active substance and C. ancillary substance, characterized in that at least one of the two components A(i), A(ii) and, where appropriate, other effervescent preparation components are dispersed in molten C) sugar and/or sugar alcohol andlor sugar substitute, and the resulting mixture is tabletted where appropriate.
The invention entails dispersing where appropriate one, a plurality or all of the remaining effervescent preparation components in the melt.
A preferred process is characterized in that - a melt of component A(i) and/or A(ii) and C) fusible sugar and/or sugar alcohol and/or sugar substitute is comminuted during or after the cooling, - the comminuted product is mixed with active substance B, with component (i) or (ii), which is still missing where appropriate, of the effervescent composition A
and, where appropriate, with further ancillary substances C and, where appropriate, - the resulting mixture is tabletted.
Preferred CO2 donors A(i) comprise alkali metal and alkaline earth metal carbonates and bicarbonates, especially sodium and potassium carbonates and bicarbonates, and magnesium and calcium carbonates.
Suitable as acidic component A(ii), which liberates carbon dioxide from the COZ
donor A(i), are all physiologically acceptable acids (so-called "acidulants"), which are strong enough to liberate carbon dioxide from component A(i); such acids have a first equilibrium exponent pKa of from 1 to 7, preferably 2 to 6 (at 25 C).
Preferred acidic components A(i) comprise ascorbic acid and polybasic carboxylic acids LeA32842
The invention entails dispersing where appropriate one, a plurality or all of the remaining effervescent preparation components in the melt.
A preferred process is characterized in that - a melt of component A(i) and/or A(ii) and C) fusible sugar and/or sugar alcohol and/or sugar substitute is comminuted during or after the cooling, - the comminuted product is mixed with active substance B, with component (i) or (ii), which is still missing where appropriate, of the effervescent composition A
and, where appropriate, with further ancillary substances C and, where appropriate, - the resulting mixture is tabletted.
Preferred CO2 donors A(i) comprise alkali metal and alkaline earth metal carbonates and bicarbonates, especially sodium and potassium carbonates and bicarbonates, and magnesium and calcium carbonates.
Suitable as acidic component A(ii), which liberates carbon dioxide from the COZ
donor A(i), are all physiologically acceptable acids (so-called "acidulants"), which are strong enough to liberate carbon dioxide from component A(i); such acids have a first equilibrium exponent pKa of from 1 to 7, preferably 2 to 6 (at 25 C).
Preferred acidic components A(i) comprise ascorbic acid and polybasic carboxylic acids LeA32842
-3-having 3 to 8, preferably 4 to 6, C atoms and 2 to 4 carboxyl groups per molecule, such as, for example, vitamin C, malic acid, citric acid, tartaric acid and mixtures thereof.
Suitable pharmaceutical active substances C cornprise analgesics such as ibuprofen, ketoprofen, paracetamol, acetylsalicylic acid, inhibitors such as nimesulide, meloxicam, naproxen, propyphenazone, metamizole, antacids such as hydrotalcite, magaldrate, calciu.m carbonate, antiasthmatics/bronchospasmolytics such as salbutamol, tulobuterol, terbutaline, cromoglicic acid, ketotifen, theophylline, antibiotics such as quinolones, tetracyclines, cephalosporins, penicillins, macrolides, sulphonamides, polypeptides, phychopharmaceuticals such as benzodiazepines, haloperidol, amitryptyline, carbamazepine, antirheumatics such as phenylbutazone, indometacin, diclofenac, piroxicam, antidiabetics such as metformin, glibenclamide, acarbose, glisoxepide, antiallergics/antihistamines such as astemizole, terfenadine, loratadine, clemastine, bamipine, cetirizine, antihypotensives such as etilefrine, norfenefrine, dihydroergotamine mesilate, antitussives such as codeine, dextromethorphan, clobutinol, dropropizine, antihypertensives such as beta blockers such as propranolol, atenolol, metoprolol, prazosin, antihypertensives such as calcium channel blockers such as nifedipine, nitrendipine, diltiazem, verapamil, felodipine, nimodipine, laxatives such as sodium picosulphate, lactulose, lactitol, mucolytics/expectorants such as ambroxol, bromhexine, guaifenesin, acetylcysteine, carbocisteine, H2 blockers such as ranitidine, famotidine, pirenzepine, local anaesthetics such as benzocaine, lidocaine, procaine, antiemetics/prokinetics such as metoclopramide, domperidone, meclozine, dimenhydrinate, lipid lowering agents such as fenofibrate, bezafibrate, pravastatin, fluvastatin, agents effective for migraine, such as caffeine, dihydroergotamine, ergotamine, sumatriptan, pizotifen, sympathomimetics such as pseudoephedrine, pl:ioledrine, vitamins and minerals.
LeA32842
Suitable pharmaceutical active substances C cornprise analgesics such as ibuprofen, ketoprofen, paracetamol, acetylsalicylic acid, inhibitors such as nimesulide, meloxicam, naproxen, propyphenazone, metamizole, antacids such as hydrotalcite, magaldrate, calciu.m carbonate, antiasthmatics/bronchospasmolytics such as salbutamol, tulobuterol, terbutaline, cromoglicic acid, ketotifen, theophylline, antibiotics such as quinolones, tetracyclines, cephalosporins, penicillins, macrolides, sulphonamides, polypeptides, phychopharmaceuticals such as benzodiazepines, haloperidol, amitryptyline, carbamazepine, antirheumatics such as phenylbutazone, indometacin, diclofenac, piroxicam, antidiabetics such as metformin, glibenclamide, acarbose, glisoxepide, antiallergics/antihistamines such as astemizole, terfenadine, loratadine, clemastine, bamipine, cetirizine, antihypotensives such as etilefrine, norfenefrine, dihydroergotamine mesilate, antitussives such as codeine, dextromethorphan, clobutinol, dropropizine, antihypertensives such as beta blockers such as propranolol, atenolol, metoprolol, prazosin, antihypertensives such as calcium channel blockers such as nifedipine, nitrendipine, diltiazem, verapamil, felodipine, nimodipine, laxatives such as sodium picosulphate, lactulose, lactitol, mucolytics/expectorants such as ambroxol, bromhexine, guaifenesin, acetylcysteine, carbocisteine, H2 blockers such as ranitidine, famotidine, pirenzepine, local anaesthetics such as benzocaine, lidocaine, procaine, antiemetics/prokinetics such as metoclopramide, domperidone, meclozine, dimenhydrinate, lipid lowering agents such as fenofibrate, bezafibrate, pravastatin, fluvastatin, agents effective for migraine, such as caffeine, dihydroergotamine, ergotamine, sumatriptan, pizotifen, sympathomimetics such as pseudoephedrine, pl:ioledrine, vitamins and minerals.
LeA32842
-4-The ancillary substances C, which should melt at least partially in the process according to the invention, have, as single substance and/or in mixtures, preferably melting points of from 30 to 200, preferably from 40 to 160 C. Preferred ancillary substances of this type are soluble in water, that is to say they generally have a solubility in water of at least 10, preferably at least 30, and, in particular, at least 40 g/100 ml of water at 20 C.
Fusible sugars C comprise, for example, monosaccharides such as glucose, mannose, galactose, arabinose, xylose, ribose and disaccharides such as sucrose, lactose, maltose. Sugar alcohols C preferred for the iiivention comprise xylitol, mannitol, sorbitol, isomalt, lactitol, erythritol, threitol, ribitol, arabitol and dulcitol. Preferred sugar-alcohols of this type are described, for example, in EP-B 435 450. The term "sugar substitutes" for the purpose of the invention does not include sugar alcohols.
Preferred sugar substitutes C comprise acesulfame, aspartame, saccharin, sodium cyclamate.
Further ancillary substances C comprise flavourings, sweeteners, lubricants, flow regulators, disintegrants and bulking agents such as, for example, starch and starch derivatives, cellulose and cellulose derivatives, polyethylenes.
The effervescent preparations obtainable accorcling to the invention may contain the components in a wide variety of ratios of amounts; preferred effervescent preparations contain (in each case in parts by weight) A: 5 to 95, preferably 10 to 80, B: 5 to 95, preferably 40 to 60, C: 1 to 60, preferably 15 to 30 (sugar, sugar alcohol, or sugar substitute) and, where appropriate, I to 50, preferably 5 to 15 (other ancillaiy substances).
The effervescent composition A preferably contains 30 to 70% by weight of CO2 donor and 70 to 30% by weight of acidic component, in each case based on A.
The melt of effervescent composition A (component) and fusible sugar and/or sugar alcohol and/or sugar substitute C can be prepared, for example, by adding LeA32842
Fusible sugars C comprise, for example, monosaccharides such as glucose, mannose, galactose, arabinose, xylose, ribose and disaccharides such as sucrose, lactose, maltose. Sugar alcohols C preferred for the iiivention comprise xylitol, mannitol, sorbitol, isomalt, lactitol, erythritol, threitol, ribitol, arabitol and dulcitol. Preferred sugar-alcohols of this type are described, for example, in EP-B 435 450. The term "sugar substitutes" for the purpose of the invention does not include sugar alcohols.
Preferred sugar substitutes C comprise acesulfame, aspartame, saccharin, sodium cyclamate.
Further ancillary substances C comprise flavourings, sweeteners, lubricants, flow regulators, disintegrants and bulking agents such as, for example, starch and starch derivatives, cellulose and cellulose derivatives, polyethylenes.
The effervescent preparations obtainable accorcling to the invention may contain the components in a wide variety of ratios of amounts; preferred effervescent preparations contain (in each case in parts by weight) A: 5 to 95, preferably 10 to 80, B: 5 to 95, preferably 40 to 60, C: 1 to 60, preferably 15 to 30 (sugar, sugar alcohol, or sugar substitute) and, where appropriate, I to 50, preferably 5 to 15 (other ancillaiy substances).
The effervescent composition A preferably contains 30 to 70% by weight of CO2 donor and 70 to 30% by weight of acidic component, in each case based on A.
The melt of effervescent composition A (component) and fusible sugar and/or sugar alcohol and/or sugar substitute C can be prepared, for example, by adding LeA32842
-5-effervescent composition A (components) to a melt of sugar and/or sugar alcohol and/or sugar substitute C or by melting a mixture of effervescent composition A
(components) and sugar and/or sugar alcohol and/or sugar substitute C.
However, the process according to the invention can also be carried out by contacting all components of the effervescent preparation with the molten sugar and/or sugar alcohol and/or sugar substitute for the purpose of dispersion, whether by premixing all components and heating together, or whether by melting sugar and/or sugar alcohol and/or sugar substitute and dispersing the remaining components (simultaneously or successively) in the melt. It is, of course, possible to use mixed forms of the process variants described.
The melt can be produced in virtually any suitable manner;
Thus, it is possible straightforwardly to use heatable stirred vessels. It is also possible to use a melt-granulation process as described, for example, in WO 92/6679. A
preferred process is melt extrusion as describeci, for example, in EP-A 686 392. It is possible to employ for the extrusion commerci.ally available single screw and twin-screw extruders. It is moreover possible to feed the starting materials to the extrusion via a weigh feeder. The melt temperature cai7 be 30 to 200 C. The pressure can preferably be 2 to 200 bar, depending on the die orifice (preferably 0.5 to 5 mm) and the speed of rotation (preferably 5 to 400 revolutions/minute). The output can vary within wide limits, but is preferably 1 to 100 kg/hour. The extrudates are cooled where appropriate. After the comminution, they can be mixed with active substance B and, where appropriate, further ancillary substances C, and tabletted where appropriate.
Preferably neither water nor an organic solvent which is volatile under the processing conditions is employed in the process according to the invention, that is to say preferably water and solvent are absent from the process. In other words,: the process is precisely not that described in German Offenlegungsschrift 22 16 072 or in Acta Pharm. Suec., 24, (2), 84, 1987 Drug Dev. Ind. Pharm. 13, (9-11), 1891-1913, 1987 Drug Dev. Ind. Pharm. 14, (13), 1791-98, 1988.
The process according to the invention can be carried out continuously or batchwise.
LeA32842
(components) and sugar and/or sugar alcohol and/or sugar substitute C.
However, the process according to the invention can also be carried out by contacting all components of the effervescent preparation with the molten sugar and/or sugar alcohol and/or sugar substitute for the purpose of dispersion, whether by premixing all components and heating together, or whether by melting sugar and/or sugar alcohol and/or sugar substitute and dispersing the remaining components (simultaneously or successively) in the melt. It is, of course, possible to use mixed forms of the process variants described.
The melt can be produced in virtually any suitable manner;
Thus, it is possible straightforwardly to use heatable stirred vessels. It is also possible to use a melt-granulation process as described, for example, in WO 92/6679. A
preferred process is melt extrusion as describeci, for example, in EP-A 686 392. It is possible to employ for the extrusion commerci.ally available single screw and twin-screw extruders. It is moreover possible to feed the starting materials to the extrusion via a weigh feeder. The melt temperature cai7 be 30 to 200 C. The pressure can preferably be 2 to 200 bar, depending on the die orifice (preferably 0.5 to 5 mm) and the speed of rotation (preferably 5 to 400 revolutions/minute). The output can vary within wide limits, but is preferably 1 to 100 kg/hour. The extrudates are cooled where appropriate. After the comminution, they can be mixed with active substance B and, where appropriate, further ancillary substances C, and tabletted where appropriate.
Preferably neither water nor an organic solvent which is volatile under the processing conditions is employed in the process according to the invention, that is to say preferably water and solvent are absent from the process. In other words,: the process is precisely not that described in German Offenlegungsschrift 22 16 072 or in Acta Pharm. Suec., 24, (2), 84, 1987 Drug Dev. Ind. Pharm. 13, (9-11), 1891-1913, 1987 Drug Dev. Ind. Pharm. 14, (13), 1791-98, 1988.
The process according to the invention can be carried out continuously or batchwise.
LeA32842
-6-In the process according to the invention, component A(i) and/or A(ii) and, where appropriate, further effervescent preparation components are dispersed in the fusible sugar, sugar alcohol or sugar substitute C, that is to say the fusible component C
forms a matrix in which A(i) and/or A(ii) and, where appropriate, further effervescent preparation components are embedded.
Thus the invention also relates to effervescent preparations consisting of A. effervescent composition containing (i) CO2 donor and (ii) acidic component, B. pharmaceutical active substance and C. - ancillary substance, characterized in that ancillary substance C contains fusible sugar and/or sugar alcohol and/or sugar substitute, and component A(i) and/or A(ii) is dispersed in a matrix of fusible sugar and/or sugar alcohol and/or sugar substitute.
The percentage data in the following examples are based on weight in each case.
Examples Example 1 Effervescent preparation consisting of separately extruded components A(i) and A(ii) Extrudate I
Mannitol and sodium bicarbonate are mixed in the ratios indicated in the table. The mixture is processed in a twin-screw extruder (Leistriz Micro 27/40D) at a speed of rotation of 30 rpm and with a die diameter of 1 nim. The dies are arranged around the outer diameter of the screws. Mixing zones and die temperature are at 80 C.
The extrudate is cooled on a cooling belt and then coinminuted with an oscillating sieve.
Extrudate II
Mannitol, citric acid and sodium citrate are mixed and extruded and further processed as above.
LeA32842
forms a matrix in which A(i) and/or A(ii) and, where appropriate, further effervescent preparation components are embedded.
Thus the invention also relates to effervescent preparations consisting of A. effervescent composition containing (i) CO2 donor and (ii) acidic component, B. pharmaceutical active substance and C. - ancillary substance, characterized in that ancillary substance C contains fusible sugar and/or sugar alcohol and/or sugar substitute, and component A(i) and/or A(ii) is dispersed in a matrix of fusible sugar and/or sugar alcohol and/or sugar substitute.
The percentage data in the following examples are based on weight in each case.
Examples Example 1 Effervescent preparation consisting of separately extruded components A(i) and A(ii) Extrudate I
Mannitol and sodium bicarbonate are mixed in the ratios indicated in the table. The mixture is processed in a twin-screw extruder (Leistriz Micro 27/40D) at a speed of rotation of 30 rpm and with a die diameter of 1 nim. The dies are arranged around the outer diameter of the screws. Mixing zones and die temperature are at 80 C.
The extrudate is cooled on a cooling belt and then coinminuted with an oscillating sieve.
Extrudate II
Mannitol, citric acid and sodium citrate are mixed and extruded and further processed as above.
LeA32842
-7-Extrudate I: Extrudate II:
Mannitol 60% 60%
Sodium bicarbonate 40%
Citric acid 6.7%
Sodium citrate 33.3%
Based on a single dose, 125 g of extrudate I and 150 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 5 mg of aspartame and 30 mg of orange flavour and packed in a sachet.
Example 2 In analogy to Example 1, extrudate I and extrudate II are extruded at a temperature of 70 C, with a die diameter of 0.8 mm and a speeci of rotation of 26 rpm.
Extrudate I: Extrudate II:
Xylitol 60% 60%
Sodium bicarbonate 40%
Citric acid 40%
Based on a single dose, 125 mg of extrudate I and 150 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 4 mg of' saccharin and 30 mg of mandarin flavour and packed in a sachet.
Example 3 In analogy to Example 2, extrudate I and Extrudate II are extruded at a temperature of 60 C, with a die diameter of 1 mm and a speed of rotation of 35 rpm.
Extrudate I: Extrudate II:
Xylitol 30% 30%
Sodium bicarbonate 70%
Citric acid 70%
Based on a single dose, 125 mg of each of extn.idate I and II are mixed with 150 mg of ascorbic acid and 2.5 mg of chlorpheniramine maleate and packed in a sachet.
LeA32842
Mannitol 60% 60%
Sodium bicarbonate 40%
Citric acid 6.7%
Sodium citrate 33.3%
Based on a single dose, 125 g of extrudate I and 150 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 5 mg of aspartame and 30 mg of orange flavour and packed in a sachet.
Example 2 In analogy to Example 1, extrudate I and extrudate II are extruded at a temperature of 70 C, with a die diameter of 0.8 mm and a speeci of rotation of 26 rpm.
Extrudate I: Extrudate II:
Xylitol 60% 60%
Sodium bicarbonate 40%
Citric acid 40%
Based on a single dose, 125 mg of extrudate I and 150 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 4 mg of' saccharin and 30 mg of mandarin flavour and packed in a sachet.
Example 3 In analogy to Example 2, extrudate I and Extrudate II are extruded at a temperature of 60 C, with a die diameter of 1 mm and a speed of rotation of 35 rpm.
Extrudate I: Extrudate II:
Xylitol 30% 30%
Sodium bicarbonate 70%
Citric acid 70%
Based on a single dose, 125 mg of each of extn.idate I and II are mixed with 150 mg of ascorbic acid and 2.5 mg of chlorpheniramine maleate and packed in a sachet.
LeA32842
-8-Example 4 In analogy to Example 2, extrudate I and extrudate II are extruded at a temperature of 60 C, with a die diameter of 2 mm and a speed of rotation of 35 rpm Extrudate I: Extrudate II:
Isomalt 60%
Xylitol 60%
Potassium bicarbonate 40%
Ascorbic acid 40%
Based-on a single dose, 125 mg of extrudate I and 250 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 5 mg of saccharin, 2 mg of aspartame and 30 mg of orange flavour and packed in a sachet.
Example 5 In analogy to Example 1, extrudate I and extrudate II are extruded at a temperature of 60 C, with a die diameter of 1 mm and a speed of rotation of 35 rpm.
Extrudate I: Extrudate II:
Mannitol 60% 60%
Sodium bicarbonate 20%
Calcium carbonate 20%
Ascorbic acid 40%
Based on a single dose, in each case 1500 mg of extrudate I and 750 mg of extrudate II are mixed with 5 mg of aspartame and 10 mg of redcunant flavour and packed in a sachet.
Example 6 A formulation with only one extruded componerit, namely A(ii) Extrudate II from Example 2 1200 mg Famotidine 10 mg Sodium bicarbonate 400 mg Sodium carbonate 100 mg Magnesium stearate 20 m LeA32842
Isomalt 60%
Xylitol 60%
Potassium bicarbonate 40%
Ascorbic acid 40%
Based-on a single dose, 125 mg of extrudate I and 250 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 5 mg of saccharin, 2 mg of aspartame and 30 mg of orange flavour and packed in a sachet.
Example 5 In analogy to Example 1, extrudate I and extrudate II are extruded at a temperature of 60 C, with a die diameter of 1 mm and a speed of rotation of 35 rpm.
Extrudate I: Extrudate II:
Mannitol 60% 60%
Sodium bicarbonate 20%
Calcium carbonate 20%
Ascorbic acid 40%
Based on a single dose, in each case 1500 mg of extrudate I and 750 mg of extrudate II are mixed with 5 mg of aspartame and 10 mg of redcunant flavour and packed in a sachet.
Example 6 A formulation with only one extruded componerit, namely A(ii) Extrudate II from Example 2 1200 mg Famotidine 10 mg Sodium bicarbonate 400 mg Sodium carbonate 100 mg Magnesium stearate 20 m LeA32842
-9-In analogy to Example 1, only the acid component is extruded, and the alkaline effervescent component and the active substance are mixed therewith.
Subsequently, magnesium stearate is mixed in. This mixture is compressed to an effervescent tablet.
Example 7 Joint extrusion of A(i) and A(ii) Xylitol 60%
Na citrate 14%
Sodium bicarbonate 23%
Citric acid 3%
Production process: -A) Extrusion in analogy to'Example 1, or B) Melt xylitol at about 120 C and rrteter and stir in the components successively. After cooling, the melt cake is comminuted.
Based on a single dose, in each case 600 mg of the resulting extrudate, 200 mg of acetylcysteine and 10 mg of lemon flavour are inixed. The resulting powder mixture is packed in a sachet.
Example 8 A mixture of 54% xylitol, 6% pseudoephedrine, 14% sodium citrate, 23% sodium bicarbonate and 3% citric acid is extruded in analogy to Example 1. The extrudate is t 25 comminuted and packaged.
Stability comparison of ASA-containing effervescent formulations Determination of the degradation product salicylic acid (SA) after storage in packaging impermeable to water vapour at 25 C for 3 months Initial SA SA content after content 3 months ASA effervescent granules, flavoured* 0.02% 1.61%
ASA effervescent granules (extruded), flavouredXX 0.04% 0.18%
ASA effervescent tablet, flavoured* 0.3% 1.83%
ASA effervescent tablet, unflavoured* 0.17% 0.8%
LeA32842
Subsequently, magnesium stearate is mixed in. This mixture is compressed to an effervescent tablet.
Example 7 Joint extrusion of A(i) and A(ii) Xylitol 60%
Na citrate 14%
Sodium bicarbonate 23%
Citric acid 3%
Production process: -A) Extrusion in analogy to'Example 1, or B) Melt xylitol at about 120 C and rrteter and stir in the components successively. After cooling, the melt cake is comminuted.
Based on a single dose, in each case 600 mg of the resulting extrudate, 200 mg of acetylcysteine and 10 mg of lemon flavour are inixed. The resulting powder mixture is packed in a sachet.
Example 8 A mixture of 54% xylitol, 6% pseudoephedrine, 14% sodium citrate, 23% sodium bicarbonate and 3% citric acid is extruded in analogy to Example 1. The extrudate is t 25 comminuted and packaged.
Stability comparison of ASA-containing effervescent formulations Determination of the degradation product salicylic acid (SA) after storage in packaging impermeable to water vapour at 25 C for 3 months Initial SA SA content after content 3 months ASA effervescent granules, flavoured* 0.02% 1.61%
ASA effervescent granules (extruded), flavouredXX 0.04% 0.18%
ASA effervescent tablet, flavoured* 0.3% 1.83%
ASA effervescent tablet, unflavoured* 0.17% 0.8%
LeA32842
10-* Granules are produced by conventional technology (comparative test) xx According to the invention
Claims (19)
1. Process for producing medicament-containing effervescent preparations consisting of A. effervescent composition containing (i) CO2 donor and (ii) acidic component, B. pharmaceutical active substance and C. ancillary substance, characterized in that at least one of the two components A(i) and A(ii) and, where appropriate, other effervescent preparation components are dispersed in molten C) sugar and/or sugar alcohol and/or sugar substitute, and the resulting mixture is tabletted where appropriate.
2. Process according to Claim 1, wherein - a melt consisting of component A(i) and/or A(ii) and C) fusible sugar, sugar alcohol and/or sugar substitute is comminuted during or after the cooling, - the comminuted product is mixed with active substance B, with component (i) or (ii), which is still missing where appropriate, of the effervescent composition A and, where appropriate, with further ancillary substances C and, where appropriate, - the resulting mixture is tabletted.
3. Process according to Claim 1, wherein an extruder is used for the melting.
4. Process according to Claim 1, wherein the pharmaceutical active substance B
is selected from the group of analgesics, antacids, antiasthmatics/
bronchospasmolytics, antibiotics, psychopharmaceuticals, antidiabetics, antiallergics/antihistamines, antihypotensives, antitussives, laxatives, mucolytics/expectorants, H2 blockers, local anaesthetics, antiemetics/
prokinetics, lipid lowering agents, agents effective for migraine, sympathomimetics, vitamins, minerals.
is selected from the group of analgesics, antacids, antiasthmatics/
bronchospasmolytics, antibiotics, psychopharmaceuticals, antidiabetics, antiallergics/antihistamines, antihypotensives, antitussives, laxatives, mucolytics/expectorants, H2 blockers, local anaesthetics, antiemetics/
prokinetics, lipid lowering agents, agents effective for migraine, sympathomimetics, vitamins, minerals.
5. Process according to Claim 1, wherein the temperature of the melt is 30 to 200°C.
6. Process according to Claim 1, wherein the temperature of the melt is 40 to 160°C.
7. Effervescent preparation comprising A. effervescent preparation composition containing (i) CO2 donor and (ii) acidic component, B. pharmaceutical active substance and C. ancillary substance, wherein the ancillary substance C contains fusible sugar and/or sugar alcohol and/or sugar substitute, and component A(i) and/or A(ii) is dispersed in a matrix of the fusible sugar and/or sugar alcohol and/or sugar substitute.
8. Process according to any one of Claims 1 to 6 wherein the pharmaceutical active substance is acetylsalicylic acid.
9. Effervescent preparation of Claim 7 wherein the pharmaceutical active substance is acetylsalicylic acid.
10. Effervescent preparation of claim 7 or 9, wherein the CO2 donor is sodium hydrogen carbonate.
11. Effervescent preparation of claim 7, 9, or 10, wherein the acidic component is a combination of citric acid and ascorbic acid.
12. Effervescent preparation of claim 7, 9, 10 or 11, wherein the ancillary substance C contains a sugar alcohol and a sugar substitute.
13. Effervescent preparation of claim 12, wherein the sugar alcohol is mannitol.
14. Effervescent preparation of claim 12 or 13, wherein the sugar substitute is aspartame.
15. Effervescent preparation of claim 12, wherein the ancillary substance C further contains sodium citrate and a flavouring.
16. Effervescent preparation of claim 7, 9, 10, 11, 12, 13, 14, or 15, which is in granular form.
17. Effervescent preparation of claim 7, 9, 10, 11, 12, 13, 14, or 15, which is in tablet form.
18. A granular dosage form for use as an analgesic, comprising:
an effervescent preparation composition comprising a CO2 donor and an acidic component;
an analgesic effective amount of acetylsalicylic acid; and a sugar alcohol and/or sugar substitute, wherein the CO2 donor and/or the acidic component are dispensed in a matrix of the sugar alcohol and/or the sugar substitute.
an effervescent preparation composition comprising a CO2 donor and an acidic component;
an analgesic effective amount of acetylsalicylic acid; and a sugar alcohol and/or sugar substitute, wherein the CO2 donor and/or the acidic component are dispensed in a matrix of the sugar alcohol and/or the sugar substitute.
19. The granular dosage form of claim 18, wherein:
the CO2 donor is sodium hydrogen carbonate, the acidic component is a combination of citric acid and ascorbic acid, the amount of acetylsalicylic acid is 500 mg, and which comprises the sugar alcohol and the sugar substitute, and wherein the sugar alcohol is mannitol and the sugar substitute is aspartame.
the CO2 donor is sodium hydrogen carbonate, the acidic component is a combination of citric acid and ascorbic acid, the amount of acetylsalicylic acid is 500 mg, and which comprises the sugar alcohol and the sugar substitute, and wherein the sugar alcohol is mannitol and the sugar substitute is aspartame.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19822036.7 | 1998-05-15 | ||
| DE19822036A DE19822036A1 (en) | 1998-05-15 | 1998-05-15 | Effervescent pharmaceutical composition with improved stability |
| PCT/EP1999/002969 WO1999059553A1 (en) | 1998-05-15 | 1999-05-03 | Effervescent preparations |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2331671A1 CA2331671A1 (en) | 1999-11-25 |
| CA2331671C true CA2331671C (en) | 2008-01-08 |
Family
ID=7868010
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002331671A Expired - Lifetime CA2331671C (en) | 1998-05-15 | 1999-05-03 | Effervescent preparations |
Country Status (30)
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|---|---|
| EP (1) | EP1077684B1 (en) |
| JP (1) | JP4452403B2 (en) |
| KR (1) | KR100629817B1 (en) |
| AR (1) | AR016473A1 (en) |
| AT (1) | ATE246494T1 (en) |
| AU (1) | AU3929799A (en) |
| BR (1) | BR9910454A (en) |
| CA (1) | CA2331671C (en) |
| CO (1) | CO4830457A1 (en) |
| CZ (1) | CZ300778B6 (en) |
| DE (2) | DE19822036A1 (en) |
| DK (1) | DK1077684T3 (en) |
| EE (1) | EE04701B1 (en) |
| ES (1) | ES2203134T3 (en) |
| GT (1) | GT199900062A (en) |
| HN (1) | HN1999000067A (en) |
| HR (1) | HRP20000781B1 (en) |
| HU (1) | HU224034B1 (en) |
| ID (1) | ID27441A (en) |
| IL (1) | IL139240A (en) |
| NO (1) | NO20005722L (en) |
| PA (1) | PA8472001A1 (en) |
| PE (1) | PE20000465A1 (en) |
| PL (1) | PL194347B1 (en) |
| PT (1) | PT1077684E (en) |
| SI (1) | SI1077684T1 (en) |
| SK (1) | SK284621B6 (en) |
| TR (1) | TR200003357T2 (en) |
| UY (1) | UY25510A1 (en) |
| WO (1) | WO1999059553A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11219594B2 (en) * | 2015-12-12 | 2022-01-11 | Steerlife India Private Limited | Effervescent compositions of metformin and processes for preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6649186B1 (en) * | 1996-09-20 | 2003-11-18 | Ethypharm | Effervescent granules and methods for their preparation |
| ES2215025T3 (en) * | 1999-02-11 | 2004-10-01 | Hexal Ag | EFERVESCENT PHARMACEUTICAL FORMULATION, CONTAINING METAMIZOL. |
| FR2823668B1 (en) * | 2001-04-20 | 2004-02-27 | Ethypharm Lab Prod Ethiques | ORODISPERSIBLE EFFERVESCENT TABLETS |
| DE602006001295D1 (en) * | 2005-02-03 | 2008-07-03 | Nycomed Pharma As | Melt granulation of a composition containing a calcium-containing compound |
| GR1007299B (en) * | 2010-03-24 | 2011-06-06 | Uni - Pharma Κλεων Τσετης Φαρμακευτικα Εργαστηρια Αβεε Με Δ.Τ. Uni-Pharma Αβεε, | Original effervescent hydrochloric metformin composition in the form of tablets |
| WO2013022410A2 (en) | 2011-08-08 | 2013-02-14 | Mahmut Bilgic | Production method for effervescent formulations comprising dexketoprofen |
| US20170252295A1 (en) | 2014-09-17 | 2017-09-07 | Steerlife India Private Limited | Effervescent composition and method of making it |
| WO2017011326A1 (en) * | 2015-07-10 | 2017-01-19 | Sanjay Gupta | Nasal foam via cribriform plate for medication delivery to the brain and/or body and for nasal moisturization and hygiene |
| JP2018183067A (en) * | 2017-04-24 | 2018-11-22 | 株式会社松原製餡所 | Expandable additive and bean jam food product |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4004036A (en) * | 1966-05-31 | 1977-01-18 | Alberto Culver Company | Effervescent molded triturate tablets |
| US3653914A (en) * | 1970-03-20 | 1972-04-04 | Alberto Culver Co | Production of tablets |
| ATE108649T1 (en) * | 1990-02-14 | 1994-08-15 | Takeda Chemical Industries Ltd | SHOWER MIX, ITS PRODUCTION AND USE. |
| RU2096955C1 (en) * | 1991-03-01 | 1997-11-27 | Е.И.Дюпон Де Немур Энд Компани | Water-dispersable granulated pesticide composition prepared by extrusion method and a method of its preparing |
| MX9300110A (en) * | 1992-01-13 | 1994-07-29 | Gerhard Gergely | PHARMACEUTICAL PREPARATION IN THE FORM OF AN EFFERVESCENCE OR DISINTEGRATION TABLET OR OF AN INSTANT-TYPE GRANULATE AND PROCEDURE FOR ITS PREPARATION. |
| HU217125B (en) * | 1993-03-10 | 1999-11-29 | Béres Rt. | Sugar- and sodium-free effervescens tablets and granules and process for producing them |
| AU677432B2 (en) * | 1993-09-09 | 1997-04-24 | Gerhard Gergely | Effervescent granulated material and method for its preparation |
| GB2307857B (en) * | 1995-12-04 | 1999-01-27 | Euro Celtique Sa | An effervescent formulation |
-
1998
- 1998-05-15 DE DE19822036A patent/DE19822036A1/en not_active Withdrawn
-
1999
- 1999-04-29 GT GT199900062A patent/GT199900062A/en unknown
- 1999-05-03 DE DE59906519T patent/DE59906519D1/en not_active Expired - Lifetime
- 1999-05-03 ID IDW20002354A patent/ID27441A/en unknown
- 1999-05-03 CZ CZ20004171A patent/CZ300778B6/en not_active IP Right Cessation
- 1999-05-03 CA CA002331671A patent/CA2331671C/en not_active Expired - Lifetime
- 1999-05-03 HU HU0101822A patent/HU224034B1/en active IP Right Grant
- 1999-05-03 IL IL13924099A patent/IL139240A/en not_active IP Right Cessation
- 1999-05-03 PL PL99344140A patent/PL194347B1/en unknown
- 1999-05-03 EP EP99922151A patent/EP1077684B1/en not_active Expired - Lifetime
- 1999-05-03 AU AU39297/99A patent/AU3929799A/en not_active Abandoned
- 1999-05-03 TR TR2000/03357T patent/TR200003357T2/en unknown
- 1999-05-03 PT PT99922151T patent/PT1077684E/en unknown
- 1999-05-03 DK DK99922151T patent/DK1077684T3/en active
- 1999-05-03 WO PCT/EP1999/002969 patent/WO1999059553A1/en active IP Right Grant
- 1999-05-03 SI SI9930356T patent/SI1077684T1/en unknown
- 1999-05-03 AT AT99922151T patent/ATE246494T1/en active
- 1999-05-03 EE EEP200000650A patent/EE04701B1/en not_active IP Right Cessation
- 1999-05-03 ES ES99922151T patent/ES2203134T3/en not_active Expired - Lifetime
- 1999-05-03 SK SK1706-2000A patent/SK284621B6/en not_active IP Right Cessation
- 1999-05-03 JP JP2000549218A patent/JP4452403B2/en not_active Expired - Lifetime
- 1999-05-03 KR KR1020007012745A patent/KR100629817B1/en not_active IP Right Cessation
- 1999-05-03 BR BR9910454-7A patent/BR9910454A/en not_active IP Right Cessation
- 1999-05-06 PA PA19998472001A patent/PA8472001A1/en unknown
- 1999-05-10 AR ARP990102193A patent/AR016473A1/en not_active Application Discontinuation
- 1999-05-10 HN HN1999000067A patent/HN1999000067A/en unknown
- 1999-05-13 CO CO99029806A patent/CO4830457A1/en unknown
- 1999-05-13 PE PE1999000400A patent/PE20000465A1/en not_active Application Discontinuation
- 1999-05-14 UY UY25510A patent/UY25510A1/en not_active IP Right Cessation
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2000
- 2000-11-13 NO NO20005722A patent/NO20005722L/en not_active Application Discontinuation
- 2000-11-15 HR HR20000781A patent/HRP20000781B1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11219594B2 (en) * | 2015-12-12 | 2022-01-11 | Steerlife India Private Limited | Effervescent compositions of metformin and processes for preparation thereof |
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