EP4061370A1 - A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof - Google Patents
A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereofInfo
- Publication number
- EP4061370A1 EP4061370A1 EP20889321.4A EP20889321A EP4061370A1 EP 4061370 A1 EP4061370 A1 EP 4061370A1 EP 20889321 A EP20889321 A EP 20889321A EP 4061370 A1 EP4061370 A1 EP 4061370A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pellet
- composition according
- propiverine
- pellet composition
- acid
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 73
- 239000008188 pellet Substances 0.000 title claims abstract description 71
- QPCVHQBVMYCJOM-UHFFFAOYSA-N Propiverine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCCC)C(=O)OC1CCN(C)CC1 QPCVHQBVMYCJOM-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960003510 propiverine Drugs 0.000 title claims abstract description 30
- 150000003839 salts Chemical class 0.000 title claims abstract description 19
- 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
- 229960001187 propiverine hydrochloride Drugs 0.000 claims description 22
- HWMFFWCDLWDYGX-UHFFFAOYSA-N n-(4-aminophenyl)furan-2-carboxamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC=CO1 HWMFFWCDLWDYGX-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- 239000000945 filler Substances 0.000 claims description 10
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 10
- 230000035699 permeability Effects 0.000 claims description 10
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 230000002708 enhancing effect Effects 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 8
- 229910052623 talc Inorganic materials 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 7
- 239000001069 triethyl citrate Substances 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- 239000000375 suspending agent Substances 0.000 claims description 6
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 5
- 229920002301 cellulose acetate Polymers 0.000 claims description 5
- 125000005397 methacrylic acid ester group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- -1 pH adjusters Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 claims description 2
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims description 2
- 229920001800 Shellac Polymers 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229920002494 Zein Polymers 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229940103272 aluminum potassium sulfate Drugs 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 229940111688 monobasic potassium phosphate Drugs 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000011664 nicotinic acid Substances 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 claims description 2
- 235000001968 nicotinic acid Nutrition 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229940074982 poly(vinylpyrrolidone-co-vinyl-acetate) Drugs 0.000 claims description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 claims description 2
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 2
- 239000004800 polyvinyl chloride Substances 0.000 claims description 2
- GRLPQNLYRHEGIJ-UHFFFAOYSA-J potassium aluminium sulfate Chemical compound [Al+3].[K+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O GRLPQNLYRHEGIJ-UHFFFAOYSA-J 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 229940043266 rosin Drugs 0.000 claims description 2
- 239000004208 shellac Substances 0.000 claims description 2
- 229940113147 shellac Drugs 0.000 claims description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 2
- 235000013874 shellac Nutrition 0.000 claims description 2
- 229920002379 silicone rubber Polymers 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- 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 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims description 2
- 229940001496 tribasic sodium phosphate Drugs 0.000 claims description 2
- 125000005591 trimellitate group Chemical group 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 239000005019 zein Substances 0.000 claims description 2
- 229940093612 zein Drugs 0.000 claims description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 235000002639 sodium chloride Nutrition 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 230000007935 neutral effect Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 229940033134 talc Drugs 0.000 description 7
- 235000012222 talc Nutrition 0.000 description 7
- 206010020853 Hypertonic bladder Diseases 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 6
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 208000020629 overactive bladder Diseases 0.000 description 6
- 235000013769 triethyl citrate Nutrition 0.000 description 6
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 6
- 229920003143 Eudragit® FS 30 D Polymers 0.000 description 5
- 229920003139 Eudragit® L 100 Polymers 0.000 description 5
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 5
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 5
- 229920003141 Eudragit® S 100 Polymers 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 5
- DNKKLDKIFMDAPT-UHFFFAOYSA-N n,n-dimethylmethanamine;2-methylprop-2-enoic acid Chemical compound CN(C)C.CC(=C)C(O)=O.CC(=C)C(O)=O DNKKLDKIFMDAPT-UHFFFAOYSA-N 0.000 description 5
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 4
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- 239000013543 active substance Substances 0.000 description 4
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- 239000008187 granular material Substances 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
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- 229920002472 Starch Polymers 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
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- 235000019698 starch Nutrition 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
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- 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 description 2
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 208000000921 Urge Urinary Incontinence Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
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- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
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- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
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- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003149 muscarinic antagonist Substances 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 235000013856 polydextrose Nutrition 0.000 description 2
- 239000001259 polydextrose Substances 0.000 description 2
- 229940035035 polydextrose Drugs 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Definitions
- the present invention relates to a pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof for oral administration which is formulated as modified release.
- Overactive bladder (OAB) and the related condition of urge urinary incontinence represent the other major disorder of the storage function. They are characterized by a frequent need to void (frequency), with an intense urge to do so (urgency) and a need to void during the night (nocturia). Contrary to stress urinary incontinence, OAB and urge incontinence are not associated with urethral sphincter control but rather involves disturbances in bladder functions and the regulation thereof.
- antimuscarinic agents which exert their effects at muscarinic receptors and suppress or diminish the intensity of involuntary detrusor muscle contractions, are the first-choice pharmacotherapy for OAB, and may be the only therapy available whose efficacy is not in question.
- Propiverine hydrochloride is an extensively studied antimuscarinic and calcium channel blocker agent.
- Propiverine is one of the most frequently prescribed antimuscarinic drugs used for the treatment of overactive bladder and urinary incontinence.
- the chemical name of propiverine is (l-methyl-4-piperidyl diphenylpropoxyacetate) and it is a benzylic acid derivative as shown in Formula I.
- Formula I Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability and high solubility.
- typical anticholinergic side effects like and accommodation disorders have to be accepted with a rapid increase in the blood level. Therefore, these side effects limit the amount of the possible unit dose of non-modified, rapidly releasing dosage forms to 10-20 mg.
- Propiverine in the form of its hydrochloride salt is currently marketed under the trade names Mictonorm® / Detrunorm®/ Proprinorm® by Apogepha Arzneistoff GmbH in two different dosage forms as immediate -release (IR) and modified-release (MR).
- IR immediate -release
- MR modified-release
- TR 2012/11270 patent application discloses an oral pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof as an anticholinergic active agent.
- composition comprising propiverine or a pharmaceutically acceptable salt thereof which overcomes the above described problems in the prior art and has additive advantages over them.
- the main object of the present invention is to provide a composition comprising propiverine or a pharmaceutically acceptable salt thereof having high stability by the help of using a pellet composition.
- modified release refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
- propiverine or a pharmaceutically acceptable salt thereof are thus not suitable for the realization of a modified release formulation.
- propiverine or a pharmaceutically acceptable salt thereof especially propiverine hydrochloride, is sensitive to environmental conditions and excipients used. Therefore, the steps and polymers employed to make modified-release are important in the present invention.
- Pellets can be blended to deliver incompatible active agents.
- the reproducibility of the pellet formulations is also much better than the reproducibility of the single-unit dosage forms. They are suitable systems for film coating with respect to the low surface area-volume ratios.
- one of the advantageous properties of the pellet formulations is being good resistance to external factors such as moisture, air and light.
- pellets have excellent flow properties. Considering all these advantages, the pellet form is best for use in propiverine-containing formulation.
- a pellet composition comprises propiverine or a pharmaceutically acceptable salt thereof, wherein the pellet composition is formulated as modified release.
- propiverine or a pharmaceutically acceptable salt thereof is propiverine hydrochloride.
- the amount of propiverine hydrochloride is present between 5.0% and 40.0%, 7.0% and 35.0%, 10.0% and 30.0%, 11.0% and 25.0%, 12.0% and 20.0%, 12.0% and 18.0% by weight of the pellet.
- propiverine hydrochloride is also present outside the pellet.
- the amount of propiverine hydrochloride is present between 1.0% and 30.0%, 1.0% and 25.0%, 1.0% and 20.0%, 1.0% and 15.0%, 1 .0% and 10.0%, 1.0% and 6.0% by weight of the total composition.
- the pellets further comprises at least one release modifying agent.
- Suitable release modifying agent is selected from the group comprising poly(methacrylic acid-co-methylmethacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co- ethylacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co- vinylacetate), silicone elastomers, shellac, zein, rosin esters or mixtures thereof.
- the amount of the release modifying agent is between 1.0% and 25.0%, 2.0% and 20.0%, 3.0% and 15.0%, 5.0% and 10.0% by weight of the pellet.
- the amount of the release modifying agent is between 0.5% and 10.0%, 1.0% and 8.0%, 1.0% and 6.0%, 1.0% and 4.0% by weight of the total composition.
- the release modifying agent is poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100) or poly(methacrylic acid-co- methylmethacrylate) 1 :1 (Eudragit L 100) or poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid) 7:3:1 (Eudragit FS 30 D) , they can be used together or separately.
- the optimum amounts of the excipients for example the composition of the corresponding mixtures depend on several factors, like for example the desired retarding effect, the kind of the release modifying agent having their specific solubility and permeability, and the ratio of acidic substance to active agent propiverine. These parameters vary completely independently from each other and are of essential importance for the controlled and long- lasting, modified release of the propiverine.
- the preferred dosage forms are tablets or capsules filled with pellets as these are more convenient and easier to administer.
- the form of the composition is a tablet.
- Pellet is located within a tablet.
- the tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, pH adjusters, binders, disintegrants, plasticizers, lubricants, glidants, suspending agents, permeability enhancing agents or mixtures thereof.
- Suitable fillers are selected from the group comprising neutral microcrystalline cellulose pellets, lactose, microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, isomalt, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof.
- the amount of the fillers is between 5.0% and 35.0%, 7.0% and 30.0%, 9.0% and 25.0%, 10.0% and 20.0% by weight of the pellet.
- the amount of the fillers is between 50.0% and 87.0%, 55.0% and 84.0%, 60.0% and 80.0%, 65.0% and 75.0% by weight of the total composition.
- the filler is neutral microcrystalline cellulose pellets or lactose or microcrystalline cellulose or mixtures thereof.
- fillers should be as inert as possible to prevent them from interacting with propiverine hydrochloride, they should serve only as a carrier to enable propiverine hydrochloride.
- neutral microcrystalline cellulose pellets support the formulation, such as by improving propiverine hydrochloride solubility, improving dissolution and enhancing stability. So, neutral microcrystalline cellulose pellets are used in pellets as fillers.
- compositions comprise at least one pharmaceutically acceptable organic or inorganic acid having a pKa value of less than 6.65.
- Acidic compound is used to provide pH-independent solubility of propiverine and the salts thereof by forming aquasiionpair of propiverine and acid, leading to a sufficient release in the whole intestinal tract, independent from the kind of the propiverine salt present.
- Suitable pH adjusters are selected from the group comprising citric acid, aluminum potassium sulfate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.
- the weight ratio of acidic substance (pH adjusters) to propiverine or a pharmaceutically acceptable salt thereof is between 0.1 and 6.0, 0.5 and 5.0, 1.0 and 4.0 or preferably between 1.5 and 3.5.
- the amount of the pH adjusters is between 30.0% and 60.0%, 32.0% and 50.0%, 35.0% and 45.0% by weight of the pellet.
- the amount of the pH adjusters is between 1 .0% and 30.0%, 3.0% and 25.0%, 5.0% and 20.0%, 7.0% and 15.0% by weight of the total composition.
- the pH adjuster is citric acid.
- Suitable binders are selected from the group comprising polyvinylpyrrolidone, sugars, glycose syrup, natural gums, gelatin, agar, alginates, co-povidone, sodium alginate, guar gum, starch mucilage, acacia mucilage, bentonite, laponit, cetostearyl alcohol, polydextrose, polyethylene oxide, pectin, aluminum hydroxide, hyaluronic acid or mixtures thereof.
- the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the pellet.
- the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the total composition.
- the binder is polyvinylpyrrolidone.
- Suitable plasticizers are selected from the group comprising triethyl citrate, polyethylene glycols, triacetin, tributyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols or mixtures thereof.
- the amount of the plasticizers is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the pellet.
- the amount of the plasticizers is between 0.01% and 5.0%, 0.05% and 3.0% by weight of the total composition.
- the plasticizer is triethyl citrate.
- Suitable disintegrants are selected from the group comprising croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch or mixtures thereof.
- the amount of the disintegrants is between 1.0% and 15.0% by weight of the total composition.
- Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or mixtures thereof.
- the lubricant is magnesium stearate.
- the amount of the lubricants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
- the lubricant is magnesium stearate.
- Suitable glidants are selected from the group comprising colloidal silicon dioxide, water soluble excipient, hydrophilic polymers, silicon dioxide or mixtures thereof.
- the amount of the glidants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
- the glidant is colloidal silicon dioxide.
- Suitable suspending agents are selected from the group comprising talc, xanthan gum, guar gum, glycerol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose or mixtures thereof.
- the suspending agent is talc.
- the amount of the suspending agents is between 5.0% and 25.0%, 8.0% and 20.0%, 9.0% and 17.0% by weight of the pellet.
- the amount of the suspending agents is between 0.5% and 10.0%, 1 .0% and 8.0% by weight of the total composition.
- Suitable permeability enhancing agents are selected from the group comprising ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester, ethanol, isopropyl alcohol, propylene glycol or mixtures thereof.
- Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability. So, it is important to permeability enhancing agents used.
- BCS Biopharmaceutical Classification System
- the amount of the permeability enhancing agents is between 0.5% and 6.0%, 1 .0% and 4.0% by weight of the pellet.
- the amount of the permeability enhancing agents is between 0.05% and 4.0%, 0.1% and 2.0% by weight of the total composition.
- the permeability enhancing agent is ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL) or mixtures thereof.
- Said pharmaceutical composition is compressed into tablets after direct compression or dry granulation or wet granulation.
- the tablets may be film-coated in a conventional manner.
- the pellets comprises;
- the tablet comprises;
- Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL)
- EXAMPLE 1 A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE
- EXAMPLE 2 A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE Process for example for 1 or 2;
- pellet For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
- Steps after obtained pellet c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 , d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.
- EXAMPLE 3 A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE Process for example for 3;
- pellet For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
- Steps after obtained pellet c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 and croscarmellose sodium and propiverine hydrochloride, d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.
Abstract
The present invention relates to a pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof for oral administration which is formulated as modified release.
Description
A PELLET COMPOSITION COMPRISING PROPIVERINE OR A PHARMACEUTICALLY
ACCEPTABLE SALT THEREOF
Field of the Invention
The present invention relates to a pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof for oral administration which is formulated as modified release.
Background of the Invention
Overactive bladder (OAB) and the related condition of urge urinary incontinence represent the other major disorder of the storage function. They are characterized by a frequent need to void (frequency), with an intense urge to do so (urgency) and a need to void during the night (nocturia). Contrary to stress urinary incontinence, OAB and urge incontinence are not associated with urethral sphincter control but rather involves disturbances in bladder functions and the regulation thereof.
Several classes of medications have been used to treat and manage overactive bladder, including antimuscarinic agents. Antimuscarinic agents, which exert their effects at muscarinic receptors and suppress or diminish the intensity of involuntary detrusor muscle contractions, are the first-choice pharmacotherapy for OAB, and may be the only therapy available whose efficacy is not in question. Propiverine hydrochloride is an extensively studied antimuscarinic and calcium channel blocker agent.
Propiverine is one of the most frequently prescribed antimuscarinic drugs used for the treatment of overactive bladder and urinary incontinence. The chemical name of propiverine is (l-methyl-4-piperidyl diphenylpropoxyacetate) and it is a benzylic acid derivative as shown in Formula I.
Formula I
Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability and high solubility.
Propiverine in the form of its hydrochloride salt in rapidly releasing oral dosage forms in several preparations, e.g. Mictonorm, has been on the market for years. The dosage used so far of e.g. three times a day of one pill of Mictonorm at 15 mg propiverine-hydrochloride each results in relatively heavily fluctuating blood levels with repeated daily peaks. Because of the anticholinergic effect of propiverine typical anticholinergic side effects like and accommodation disorders have to be accepted with a rapid increase in the blood level. Therefore, these side effects limit the amount of the possible unit dose of non-modified, rapidly releasing dosage forms to 10-20 mg.
Propiverine in the form of its hydrochloride salt is currently marketed under the trade names Mictonorm® / Detrunorm®/ Proprinorm® by Apogepha Arzneimittel GmbH in two different dosage forms as immediate -release (IR) and modified-release (MR).
TR 2012/11270 patent application discloses an oral pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof as an anticholinergic active agent.
In the prior art, there are also several patents which disclose propiverine or a pharmaceutically acceptable salt thereof in oral pharmaceutical dosage forms. However, many of the formulations in the art rely on a complex formulation which can add to the cost of the manufacture of the drug and it was formed without considering the physicochemical properties of the active substance.
Therefore, there is still need for a composition comprising propiverine or a pharmaceutically acceptable salt thereof which overcomes the above described problems in the prior art and has additive advantages over them.
Detailed Description of the Invention
The main object of the present invention is to provide a composition comprising propiverine or a pharmaceutically acceptable salt thereof having high stability by the help of using a pellet composition.
It is an additional object of the present invention to obtain a modified release dosage formulation for propiverine or a pharmaceutically acceptable salt thereof that can provide continuous and therapeutic levels to the patient in need of such treatment for twenty-four (24h) hour period. More specifically, the present invention relates to an oral dosage form in the form of pellets comprising propiverine or a pharmaceutically acceptable salt thereof
wherein the release of the active ingredient is controlled with release modifying agent in the presence of pH adjusters.
The term “modified release” refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
These physicochemical properties of propiverine or a pharmaceutically acceptable salt thereof are thus not suitable for the realization of a modified release formulation. Because propiverine or a pharmaceutically acceptable salt thereof, especially propiverine hydrochloride, is sensitive to environmental conditions and excipients used. Therefore, the steps and polymers employed to make modified-release are important in the present invention.
Pellets can be blended to deliver incompatible active agents. The reproducibility of the pellet formulations is also much better than the reproducibility of the single-unit dosage forms. They are suitable systems for film coating with respect to the low surface area-volume ratios. Also, one of the advantageous properties of the pellet formulations is being good resistance to external factors such as moisture, air and light. Also, pellets have excellent flow properties. Considering all these advantages, the pellet form is best for use in propiverine-containing formulation.
According to one embodiment of the present invention, a pellet composition comprises propiverine or a pharmaceutically acceptable salt thereof, wherein the pellet composition is formulated as modified release.
According to one embodiment of the present invention, propiverine or a pharmaceutically acceptable salt thereof is propiverine hydrochloride.
According to one embodiment of the present invention, the amount of propiverine hydrochloride is present between 5.0% and 40.0%, 7.0% and 35.0%, 10.0% and 30.0%, 11.0% and 25.0%, 12.0% and 20.0%, 12.0% and 18.0% by weight of the pellet.
According to one embodiment of the present invention, propiverine hydrochloride is also present outside the pellet.
According to one embodiment of the present invention, the amount of propiverine hydrochloride is present between 1.0% and 30.0%, 1.0% and 25.0%, 1.0% and 20.0%, 1.0% and 15.0%, 1 .0% and 10.0%, 1.0% and 6.0% by weight of the total composition.
According to one embodiment of the present invention, the pellets further comprises at least one release modifying agent.
Suitable release modifying agent is selected from the group comprising poly(methacrylic acid-co-methylmethacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co- ethylacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co- vinylacetate), silicone elastomers, shellac, zein, rosin esters or mixtures thereof.
According to one embodiment of the present invention, the amount of the release modifying agent is between 1.0% and 25.0%, 2.0% and 20.0%, 3.0% and 15.0%, 5.0% and 10.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the release modifying agent is between 0.5% and 10.0%, 1.0% and 8.0%, 1.0% and 6.0%, 1.0% and 4.0% by weight of the total composition.
An embodiment of this present invention, the release modifying agent is poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100) or poly(methacrylic acid-co- methylmethacrylate) 1 :1 (Eudragit L 100) or poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid) 7:3:1 (Eudragit FS 30 D) , they can be used together or separately.
The optimum amounts of the excipients, for example the composition of the corresponding mixtures depend on several factors, like for example the desired retarding effect, the kind of the release modifying agent having their specific solubility and permeability, and the ratio of acidic substance to active agent propiverine. These parameters vary completely independently from each other and are of essential importance for the controlled and long- lasting, modified release of the propiverine.
According to one embodiment of the present invention, the preferred dosage forms are tablets or capsules filled with pellets as these are more convenient and easier to administer.
An embodiment of this present invention, the form of the composition is a tablet. Pellet is located within a tablet.
According to one embodiment of the present invention, the tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising
fillers, pH adjusters, binders, disintegrants, plasticizers, lubricants, glidants, suspending agents, permeability enhancing agents or mixtures thereof.
Suitable fillers are selected from the group comprising neutral microcrystalline cellulose pellets, lactose, microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, isomalt, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof.
According to one embodiment of the present invention, the amount of the fillers is between 5.0% and 35.0%, 7.0% and 30.0%, 9.0% and 25.0%, 10.0% and 20.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the fillers is between 50.0% and 87.0%, 55.0% and 84.0%, 60.0% and 80.0%, 65.0% and 75.0% by weight of the total composition.
According to one embodiment of the present invention, the filler is neutral microcrystalline cellulose pellets or lactose or microcrystalline cellulose or mixtures thereof.
According to one embodiment of the present invention, fillers should be as inert as possible to prevent them from interacting with propiverine hydrochloride, they should serve only as a carrier to enable propiverine hydrochloride. Thus, neutral microcrystalline cellulose pellets, support the formulation, such as by improving propiverine hydrochloride solubility, improving dissolution and enhancing stability. So, neutral microcrystalline cellulose pellets are used in pellets as fillers.
The preferred inventive compositions comprise at least one pharmaceutically acceptable organic or inorganic acid having a pKa value of less than 6.65. Acidic compound is used to provide pH-independent solubility of propiverine and the salts thereof by forming aquasiionpair of propiverine and acid, leading to a sufficient release in the whole intestinal tract, independent from the kind of the propiverine salt present.
Suitable pH adjusters are selected from the group comprising citric acid, aluminum potassium sulfate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic
acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.
According to one embodiment of the present invention, the weight ratio of acidic substance (pH adjusters) to propiverine or a pharmaceutically acceptable salt thereof is between 0.1 and 6.0, 0.5 and 5.0, 1.0 and 4.0 or preferably between 1.5 and 3.5.
According to one embodiment of the present invention, the amount of the pH adjusters is between 30.0% and 60.0%, 32.0% and 50.0%, 35.0% and 45.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the pH adjusters is between 1 .0% and 30.0%, 3.0% and 25.0%, 5.0% and 20.0%, 7.0% and 15.0% by weight of the total composition.
According to one embodiment of the present invention, the pH adjuster is citric acid.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, sugars, glycose syrup, natural gums, gelatin, agar, alginates, co-povidone, sodium alginate, guar gum, starch mucilage, acacia mucilage, bentonite, laponit, cetostearyl alcohol, polydextrose, polyethylene oxide, pectin, aluminum hydroxide, hyaluronic acid or mixtures thereof.
According to one embodiment of the present invention, the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the total composition.
According to one embodiment of the present invention, the binder is polyvinylpyrrolidone.
Suitable plasticizers are selected from the group comprising triethyl citrate, polyethylene glycols, triacetin, tributyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols or mixtures thereof.
According to one embodiment of the present invention, the amount of the plasticizers is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the plasticizers is between 0.01% and 5.0%, 0.05% and 3.0% by weight of the total composition.
According to one embodiment of the present invention, the plasticizer is triethyl citrate.
Suitable disintegrants are selected from the group comprising croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch or mixtures thereof.
According to one embodiment of the present invention, the amount of the disintegrants is between 1.0% and 15.0% by weight of the total composition.
Suitable lubricants are selected from the group comprising magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or mixtures thereof. Preferably, the lubricant is magnesium stearate.
According to one embodiment of the present invention, the amount of the lubricants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
According to one embodiment of the present invention, the lubricant is magnesium stearate.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, water soluble excipient, hydrophilic polymers, silicon dioxide or mixtures thereof.
According to one embodiment of the present invention, the amount of the glidants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.
Suitable suspending agents are selected from the group comprising talc, xanthan gum, guar gum, glycerol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose or mixtures thereof.
According to one embodiment of the present invention, the suspending agent is talc.
According to one embodiment of the present invention, the amount of the suspending agents is between 5.0% and 25.0%, 8.0% and 20.0%, 9.0% and 17.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the suspending agents is between 0.5% and 10.0%, 1 .0% and 8.0% by weight of the total composition.
Suitable permeability enhancing agents are selected from the group comprising ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester, ethanol, isopropyl alcohol, propylene glycol or mixtures thereof.
Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability. So, it is important to permeability enhancing agents used.
According to one embodiment of the present invention, the amount of the permeability enhancing agents is between 0.5% and 6.0%, 1 .0% and 4.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the permeability enhancing agents is between 0.05% and 4.0%, 0.1% and 2.0% by weight of the total composition.
According to one embodiment of the present invention, the permeability enhancing agent is ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL) or mixtures thereof.
Said pharmaceutical composition is compressed into tablets after direct compression or dry granulation or wet granulation. The tablets may be film-coated in a conventional manner.
According to one embodiment of the present invention, the pellets comprises;
• Propiverine hydrochloride
• Neutral microcrystalline cellulose pellet
• Citric acid
• Polyvinylpyrrolidone
• Lactose
• Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL)
• Poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100)
• Poly(methacrylic acid-co-methylmethacrylate) 1 :1 (Eudragit L 100)
• Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit FS30D)
• Triethylcitrate
• Talc
• Magnesium stearate
According to one embodiment of the present invention, the tablet comprises;
Propiverine hydrochloride
Neutral microcrystalline cellulose pellet
Citric acid
Polyvinylpyrrolidone
Lactose
Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL)
Poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100)
Poly(methacrylic acid-co-methylmethacrylate) 1 :1 (Eudragit L 100)
Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit FS30D)
Triethylcitrate
Talc
Magnesium stearate Microcrystalline cellulose Ph 101 Colloidal silicone dioxide
EXAMPLE 1 : A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE
EXAMPLE 2: A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE
Process for example for 1 or 2;
For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
Steps after obtained pellet: c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 , d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.
EXAMPLE 3: A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE
Process for example for 3;
For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
Steps after obtained pellet: c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 and croscarmellose sodium and propiverine hydrochloride, d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.
Claims
1. A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof, wherein the pellet composition is formulated as modified release.
2. The pellet composition according to claim 1 , wherein propiverine or a pharmaceutically acceptable salt thereof is propiverine hydrochloride.
3. The pellet composition according to claim 2, wherein the amount of propiverine hydrochloride is present between 5.0% and 40.0% by weight of the pellet.
4. The pellet composition according to claim 2, wherein the amount of propiverine hydrochloride is present between 1 .0% and 30.0% by weight of the total composition.
5. The pellet composition according to any preceding claims, wherein the pellets further comprising at least one release modifying agent.
6. The pellet composition according to claim 5, wherein the release modifying agent is selected from the group comprising poly(methacrylic acid-co-methylmethacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co- ethylacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co- vinylacetate), silicone elastomers, shellac, zein, rosin esters or mixtures thereof.
7. The pellet composition according to claim 5 or 6, wherein the amount of the release modifying agent is between 1.0% and 25.0% by weight of the pellet.
8. The pellet composition according to claim 5 or 6, wherein the amount of the release modifying agent is between 0.5% and 10.0% by weight of the total composition.
9. The pellet composition according to any preceding claims, wherein the form of the composition is tablet or capsule.
10. The pellet composition according to claim 9, wherein the form of the composition is a tablet.
11. The pellet composition according to claim 10, wherein the tablet further comprising at least one pharmaceutically acceptable excipient which is selected from the group
comprising fillers, pH adjusters, binders, disintegrants, plasticizers, lubricants, glidants, suspending agents, permeability enhancing agents or mixtures thereof.
12. The pellet composition according to claim 11 , wherein the amount of the fillers is between 5.0% and 35.0% by weight of the pellet.
13. The pellet composition according to claim 11 , wherein the amount of the fillers is between 50.0% and 87.0% by weight of the total composition.
14. The pellet composition according to claim 11 , wherein pH adjusters are selected from the group comprising citric acid, aluminum potassium sulfate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.
15. The pellet composition according to claim 14, wherein the weight ratio of acidic substance (pH adjusters) to propiverine or a pharmaceutically acceptable salt thereof is between 0.1 and 6.0, 0.5 and 5.0, 1 .0 and 4.0 or preferably between 1 .5 and 3.5.
16. The pellet composition according to claim 14, wherein the amount of the pH adjusters is between 30.0% and 60.0% by weight of the pellet.
17. The pellet composition according to claim 14, wherein the amount of the pH adjusters is between 1 .0% and 30.0% by weight of the total composition.
18. The pellet composition according to claim 10, wherein the pellets comprising; -Propiverine hydrochloride
-Neutral microcrystalline cellulose pellet -Citric acid - Polyvinylpyrrolidone -Lactose
-Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester
-Poly(methacrylic acid-co-methylmethacrylate) 1 :2
-Poly(methacrylic acid-co-methylmethacrylate) 1 :1
-Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1
-Triethylcitrate
-Talc
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2019/18013A TR201918013A2 (en) | 2019-11-19 | 2019-11-19 | A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof |
| PCT/TR2020/050998 WO2021101481A1 (en) | 2019-11-19 | 2020-10-27 | A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP4061370A1 true EP4061370A1 (en) | 2022-09-28 |
| EP4061370A4 EP4061370A4 (en) | 2023-08-02 |
Family
ID=75980701
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP20889321.4A Pending EP4061370A4 (en) | 2019-11-19 | 2020-10-27 | A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP4061370A4 (en) |
| CA (1) | CA3162408A1 (en) |
| TR (2) | TR201918013A2 (en) |
| WO (1) | WO2021101481A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023080856A1 (en) * | 2021-11-03 | 2023-05-11 | Santa Farma Ilac Sanayii A.S. | Enteric coated pharmaceutical composition of propiverine hydrochloride |
| WO2023128906A1 (en) * | 2021-12-30 | 2023-07-06 | Santa Farma Ilac Sanayii A.S. | Release of propiverine compositions in gastric conditions |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10149674A1 (en) * | 2001-10-09 | 2003-04-24 | Apogepha Arzneimittel Gmbh | Orally administered composition for sustained release of propiverine, useful for treatment of hypertonic bladder disorders, especially by once-daily administration |
| ITMI20061024A1 (en) * | 2006-05-25 | 2007-11-26 | Eurand Pharmaceuticals Ltd | PELLETS BASED ON LIPOIC ACID |
| TWI519322B (en) * | 2008-04-15 | 2016-02-01 | 愛戴爾製藥股份有限公司 | Compositions comprising weakly basic drugs and controlled-release dosage forms |
| CN102579404A (en) | 2012-01-17 | 2012-07-18 | 广州科的信医药技术有限公司 | Sustained-release capsule containing propiverine hydrochloride and preparation method of sustained-release capsule |
-
2019
- 2019-11-19 TR TR2019/18013A patent/TR201918013A2/en unknown
-
2020
- 2020-10-12 TR TR2020/16210A patent/TR202016210A2/en unknown
- 2020-10-27 CA CA3162408A patent/CA3162408A1/en active Pending
- 2020-10-27 WO PCT/TR2020/050998 patent/WO2021101481A1/en unknown
- 2020-10-27 EP EP20889321.4A patent/EP4061370A4/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| TR202016210A2 (en) | 2021-06-21 |
| EP4061370A4 (en) | 2023-08-02 |
| WO2021101481A1 (en) | 2021-05-27 |
| TR201918013A2 (en) | 2021-06-21 |
| CA3162408A1 (en) | 2021-05-27 |
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