OA16606A - Pharmaceutical composition. - Google Patents
Pharmaceutical composition. Download PDFInfo
- Publication number
- OA16606A OA16606A OA1201300415 OA16606A OA 16606 A OA16606 A OA 16606A OA 1201300415 OA1201300415 OA 1201300415 OA 16606 A OA16606 A OA 16606A
- Authority
- OA
- OAPI
- Prior art keywords
- acid
- active agent
- composition according
- complex
- cellulose
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 108
- 239000002245 particle Substances 0.000 claims abstract description 94
- 239000000463 material Substances 0.000 claims abstract description 77
- 239000000227 bioadhesive Substances 0.000 claims abstract description 51
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 42
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 42
- 239000011247 coating layer Substances 0.000 claims abstract description 34
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 112
- 239000011347 resin Substances 0.000 claims description 84
- 229920005989 resin Polymers 0.000 claims description 84
- WTDRDQBEARUVNC-LURJTMIESA-N 3-hydroxy-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 82
- 229960004502 levodopa Drugs 0.000 claims description 82
- -1 choiestyramine Chemical compound 0.000 claims description 55
- 239000011248 coating agent Substances 0.000 claims description 49
- 238000000576 coating method Methods 0.000 claims description 49
- 239000010410 layer Substances 0.000 claims description 47
- 229960004205 CARBIDOPA Drugs 0.000 claims description 45
- TZFNLOMSOLWIDK-JTQLQIEISA-N Carbidopa Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 claims description 45
- 239000002702 enteric coating Substances 0.000 claims description 41
- 238000009505 enteric coating Methods 0.000 claims description 41
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 26
- 229920002678 cellulose Polymers 0.000 claims description 22
- 229920001577 copolymer Polymers 0.000 claims description 22
- 229920000642 polymer Polymers 0.000 claims description 21
- 235000010980 cellulose Nutrition 0.000 claims description 18
- 239000001913 cellulose Substances 0.000 claims description 17
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 15
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 claims description 14
- JRURYQJSLYLRLN-BJMVGYQFSA-N Entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 claims description 14
- 229960003337 entacapone Drugs 0.000 claims description 14
- 229960000911 Benserazide Drugs 0.000 claims description 12
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 12
- 125000003010 ionic group Chemical class 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 11
- 239000001856 Ethyl cellulose Substances 0.000 claims description 10
- 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 10
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical class C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 10
- 125000000129 anionic group Chemical group 0.000 claims description 10
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 10
- 229920001249 ethyl cellulose Polymers 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 10
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 9
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 8
- KWGRBVOPPLSCSI-WPRPVWTQSA-N Ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 8
- UHSKFQJFRQCDBE-UHFFFAOYSA-N Ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 8
- 229960001879 ropinirole Drugs 0.000 claims description 8
- KVWDHTXUZHCGIO-UHFFFAOYSA-N Olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 7
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 7
- 229960005017 olanzapine Drugs 0.000 claims description 7
- 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 claims description 6
- 229940100467 POLYVINYL ACETATE PHTHALATE Drugs 0.000 claims description 6
- LOUPRKONTZGTKE-LHHVKLHASA-N Quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 229920001800 Shellac Polymers 0.000 claims description 6
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims description 6
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 6
- 230000003111 delayed Effects 0.000 claims description 6
- 230000005484 gravity Effects 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920000609 methyl cellulose Polymers 0.000 claims description 6
- 239000001923 methylcellulose Substances 0.000 claims description 6
- 235000010981 methylcellulose Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000004208 shellac Substances 0.000 claims description 6
- 229940113147 shellac Drugs 0.000 claims description 6
- 235000013874 shellac Nutrition 0.000 claims description 6
- 229960004343 Alendronic acid Drugs 0.000 claims description 5
- 229920002301 Cellulose acetate Polymers 0.000 claims description 5
- SGTNSNPWRIOYBX-UHFFFAOYSA-N Verapamil 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 claims description 5
- 125000005250 alkyl acrylate group Chemical group 0.000 claims description 5
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 5
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 5
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 5
- 229960001722 verapamil Drugs 0.000 claims description 5
- 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 4
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 4
- 229940062527 Alendronate Drugs 0.000 claims description 4
- 229960001985 Dextromethorphan Drugs 0.000 claims description 4
- MKXZASYAUGDDCJ-SZMVWBNQSA-N Dextromethorphan Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 claims description 4
- ODQWQRRAPPTVAG-GZTJUZNOSA-N Doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 claims description 4
- 229960005426 Doxepin Drugs 0.000 claims description 4
- 229960001031 Glucose Drugs 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims description 4
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims description 4
- 229960002179 ephedrine Drugs 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 4
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 claims description 4
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- GSDSWSVVBLHKDQ-JTQLQIEISA-N (2S)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.0^{5,13}]trideca-5(13),6,8,11-tetraene-11-carboxylic acid Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 3
- 229930006677 A03BA01 - Atropine Natural products 0.000 claims description 3
- MCGSCOLBFJQGHM-SCZZXKLOSA-N Abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 3
- KRMDCWKBEZIMAB-UHFFFAOYSA-N Amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 claims description 3
- 229960000836 Amitriptyline Drugs 0.000 claims description 3
- RKUNBYITZUJHSG-SPUOUPEWSA-N Atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 claims description 3
- 229960000396 Atropine Drugs 0.000 claims description 3
- JPYQFYIEOUVJDU-UHFFFAOYSA-N Beclamide Chemical compound ClCCC(=O)NCC1=CC=CC=C1 JPYQFYIEOUVJDU-UHFFFAOYSA-N 0.000 claims description 3
- QWCRAEMEVRGPNT-UHFFFAOYSA-N Buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 claims description 3
- FAKRSMQSSFJEIM-RQJHMYQMSA-N Captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 3
- 229960003677 Chloroquine Drugs 0.000 claims description 3
- WHTVZRBIWZFKQO-UHFFFAOYSA-N Chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims description 3
- SOYKEARSMXGVTM-UHFFFAOYSA-N Chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 claims description 3
- 229920002307 Dextran Chemical class 0.000 claims description 3
- AAOVKJBEBIDNHE-UHFFFAOYSA-N Diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 3
- HSUGRBWQSSZJOP-RTWAWAEBSA-N Diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N Diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 3
- UVTNFZQICZKOEM-UHFFFAOYSA-N Disopyramide Chemical compound C=1C=CC=NC=1C(C(N)=O)(CCN(C(C)C)C(C)C)C1=CC=CC=C1 UVTNFZQICZKOEM-UHFFFAOYSA-N 0.000 claims description 3
- 229960003722 Doxycycline Drugs 0.000 claims description 3
- 229960000873 Enalapril Drugs 0.000 claims description 3
- 108010061435 Enalapril Proteins 0.000 claims description 3
- GBXSMTUPTTWBMN-XIRDDKMYSA-N Enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 3
- WVVSZNPYNCNODU-CJBNDPTMSA-N Ergometrine Natural products C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-CJBNDPTMSA-N 0.000 claims description 3
- 229940011336 Ergonovine Drugs 0.000 claims description 3
- AEUTYOVWOVBAKS-UWVGGRQHSA-N Ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 3
- 229960000285 Ethambutol Drugs 0.000 claims description 3
- 229960002464 Fluoxetine Drugs 0.000 claims description 3
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 claims description 3
- 229960002474 Hydralazine Drugs 0.000 claims description 3
- LLPOLZWFYMWNKH-CMKMFDCUSA-N Hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 claims description 3
- BCGWQEUPMDMJNV-UHFFFAOYSA-N Imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 claims description 3
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 3
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 3
- DLNKOYKMWOXYQA-APPZFPTMSA-N L-Norpseudoephedrine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
- SGUAFYQXFOLMHL-UHFFFAOYSA-N Labetalol Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 claims description 3
- WVVSZNPYNCNODU-XTQGRXLLSA-N Lysergic acid propanolamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-XTQGRXLLSA-N 0.000 claims description 3
- 229960002237 Metoprolol Drugs 0.000 claims description 3
- IUBSYMUCCVWXPE-UHFFFAOYSA-N Metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 3
- 229960000282 Metronidazole Drugs 0.000 claims description 3
- 229960003793 Midazolam Drugs 0.000 claims description 3
- DDLIGBOFAVUZHB-UHFFFAOYSA-N Midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 3
- DYKFCLLONBREIL-KVUCHLLUSA-N Minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 claims description 3
- 229960004023 Minocycline Drugs 0.000 claims description 3
- BQJCRHHNABKAKU-KBQPJGBKSA-N Morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 3
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 claims description 3
- UZHSEJADLWPNLE-GRGSLBFTSA-N Naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 claims description 3
- 229960004127 Naloxone Drugs 0.000 claims description 3
- LMOINURANNBYCM-UHFFFAOYSA-N Orciprenaline Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 claims description 3
- XADCESSVHJOZHK-UHFFFAOYSA-N Petidina Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 3
- VEQOALNAAJBPNY-UHFFFAOYSA-N Phenazone Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 claims description 3
- 229960005190 Phenylalanine Drugs 0.000 claims description 3
- 229960000395 Phenylpropanolamine Drugs 0.000 claims description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
- INDBQLZJXZLFIT-UHFFFAOYSA-N Primaquine Chemical compound N1=CC=CC2=CC(OC)=CC(NC(C)CCCN)=C21 INDBQLZJXZLFIT-UHFFFAOYSA-N 0.000 claims description 3
- ZGUGWUXLJSTTMA-UHFFFAOYSA-N Promazinum Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZGUGWUXLJSTTMA-UHFFFAOYSA-N 0.000 claims description 3
- AQHHHDLHHXJYJD-UHFFFAOYSA-N Proprasylyt Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims description 3
- KWGRBVOPPLSCSI-WCBMZHEXSA-N Pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 claims description 3
- 229960003908 Pseudoephedrine Drugs 0.000 claims description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
The invention relates to an oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion-exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material. The invention also relates to a process for preparing the oral pharmaceutical composition.
Description
O.A.P.I. - B.P. 887, YAOUNDE (Cameroun) - Tel. (237) 22 20 57 00- Fax: (237) 22 20 57 27- Site web: http:/www.oapi.int - Email: oapi@oapi.int
Pharmaceutical composition
The présent invention relates to oral pharmaceutical compositions providing controlled and site spécifie drug release.
Background of the invention
The controlled release of active agents is an important aspect in the oral administration of any drug. It is particularly 10 important for the oral administration of active agents having narrow therapeutic Windows. One example of such active agents is levodopa, the drug of choice in the treatment of Parkinson's disease.
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which typically affect the elderly. Several classes of drugs hâve been utilized in the treatment of Parkinson's disease with varying degrees of success.
The prevalence of diagnosed PD in the population above the âge of 55 is about 1.4 % and it increases with âge. Moreover, Parkinsonian sîgns in the elderly are estimated to occur in 30% of the population over the âge of 65. Although PD is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta. PD becomes symptomatic only after degeneration of about 60-80 % of these dopaminergic neurons, or after the loss of about 90% of the striatal dopamine. Dopamine, which is produced within the substantia nigra, normally reaches the striatum via the nigro-striatal tract and is released at the striatal synapses. Dopamine deficiency in the striatum, due to the degeneration of the dopaminergic neurons in the substantia nigra, is considered to 35 be the cause of PD. However, dopamine itself is neither
- 2 absorbed from the gastrointestinal tract nor able to pass across the brain-blood barrier.
Drugs comprising the natural metabolic dopamine precursor levodopa presently provide the most effective treatment of PD. Levodopa is capable of crossing the blood-brain barrier into the basal ganglia, where it is decarboxylated by the enzyme aromatic L-amino acid decarboxylase (AADC) to form dopamine, thereby replacing the missing neurotransmitter. However, AADC is also présent in the gut wall, liver, kidney and cérébral capillaries, and the resulting peripheral décarboxylation of levodopa and formation of levodopa métabolites gives rise to a number of side-effects such as nausea, vomiting, cardiac dysrhythmias and postural hypotension. Peripheral levodopa décarboxylation can be largely prevented by additional administration of a sélective extracerebral decarboxylase inhibitor, such as carbidopa or benserazide, which cannot itself pass the blood-brain-barrier. Levodopa combined with carbidopa or benserazide is now the treatment of choice when levodopa is indicated. Solid dosage forms containing a combination of levodopa and carbidopa are known and used to treat PD and other movement disorders. For instance, a rapid release oral tablet containing levodopa and carbidopa together with cellulose, magnésium stéarate and starch is marketed under the name SINEMET*. However, even the levodopa/carbidopa combination therapy is often associated with severe side effects such as dyskinesias and psychiatrie disturbances.
Moreover, the currently available préparations are effective only for a relatively short period and can be even deleterious under certain conditions. Using immédiate release préparations of levodopa results in blood levels spikes with blood levels of levodopa that are initially too high and then soon afterwards too low to be effective. Moreover, only about 5 % of the levodopa dose thus administered reaches the brain.
Involuntary movements (dyskinesias) in the form of orofacial or limb chorea or dystonia are common side effects of levodopa which often limit the possible dosage. Other side effects of 5 levodopa include orthostatic hypotension, nightmares, hallucinations and, occasionally, toxic delirium. Hallucinations and delirium are most common in elderly, demented patients. In some patients, the drug cannot reduce Parkinsonism without producing some degree of dyskinesia or other side effects.
These side effects tend to occur at lower doses as treatment continues, and the so-called wearing-off and on-off phenomena hâve emerged as major problems in the levodopa longterm treatment of Parkinson's disease. After 2 to 5 years of 15 treatment, >50 % of patients begin to expérience fluctuations in their response to levodopa. In most of these patients the benefit from each dose becomes shorter (the wearing-of f11 effect) and some patients alternate unpredictably between mobility and immobility (the on-off effect). On periods 20 are usually associated with high or rising plasma levodopa concentrations and often include abnormal involuntary movements, i.e. dyskinesias, and uncontrollable hyperactivity.
Off periods hâve been correlated with low or falling plasma levodopa levels and bradykinetic épisodes. Swings from on to 25 off periods can occur many times a day. Traditionally, such swings hâve been managed by keeping individual doses of levodopa as low as possible and using dosing intervals as short as every 1 to 2 hours.
A number of techniques are generally known for formulating oral pharmaceutical compositions to control the release behavior of the pharmaceutically active agent.
US 4,221,778 describes prolonged continuous release 35 pharmaceutical préparations containing an ion exchange resin
P
- 4 having a pharmaceutically active drug adsorbed thereon to provide a drug/resin complex wherein at least a portion of the complex is treated with a solvating agent and provided with a diffusion barrier coating. US 4,847,077, US 4,859,461, US 4,859,462 and US 4,959,219 describe similar préparations using different solvating agents and plasticizers.
US 6,001,392 describes a controlled-release antitussive syrup suspension for oral administration comprising a mixture of coated and non-coated cation exchange resins onto which dextromethorphan has been loaded, wherein about 30% of the drug/resin complexes are coated with a mixture of ethyl cellulose or ethyl cellulose latexes with plasticizers and water dispersible polymers.
US 4,361,545 describes solid, orally administrable pharmaceutical compositions for the slow, zéro order release of drugs having a water solubility of about 1/5-1/500 (w/w) which comprises a combination of a surface controlling compound having a water solubility of about 1/1-1/40 (w/w), an érosion controlling compound having a water solubility of about 1/1-1/10 (w/w), a surface activator and a surfactant.
WO 94/06416 Al describes a pharmaceutical tablet consisting of a first layer containing one or more drugs with immédiate or controlled release formulation, a second layer containing one or more drugs, either equal to or different from those of the first layer, with slow release formulation, and a lowpermeability barrier-type layer coating said second layer or, alternatively, placed between the first and second layer.
Efforts hâve also been made to provide controlled release oral dosage combinations of levodopa and carbidopa.
US 4,832,957, US 4,900,755 and US 4,983,400 describe a matrix or monolithic drug delivery System containing carbidopa and
* f
- 5 levodopa as active agents wherein the drugs are uniformly dispersed in a polymer vehicle at a concentration that is greater than either drug solubility in the polymer vehicle. The preferred vehicle is a combination of the water soluble polymer hydroxypropylcellulose and the less water soluble copolymer of polyvinyl acetate crotonic acid. Another preferred vehicle is polymethyl méthacrylate.
US 2003/0224045 Al describes a pharmaceutical dosage form comprising both immédiate release and controlled release components comprising a combination of carbidopa and levodopa for the treatment of ailments associated with depleted amounts of dopamine in a patient's brain tissue.
WO 01/019Θ4 Al describes pharmaceutical compositions comprising levodopa, carbidopa and entacapone, and in particular an oral solid composition comprising pharmacologically effective amounts of levodopa, carbidopa and entacapone wherein a substantial amount of carbidopa is separated from entacapone and/or levodopa.
WO 99/17745 Al describes a controlled-release monolithic System for oral administration comprising a disintegrating layer, an erodible layer and a swelling layer, of which two are external and one is intermediate, each layer containing one or more drugs such as levodopa and/or carbidopa.
A controlled release solid oral dosage formulation comprising levodopa and carbidopa in a polymer vehicle of hydroxypropylcellulose and polyvinylacetate-crotonic acid copolymer is marketed under the name SINEMET* CR.
The existing controlled release formulations comprising levodopa/carbidopa suffer from a number of disadvantages. In particular, these préparations typically exhibit a delayed
B onset. For example, the peak effect of the commercially available SINEMET* CR tablets was shown to occur one hour later than that of conventional SINEMET* tablets. Moreover, the bioavailability of existing controlled release formulations is 5 low. At the same time, the clinical response to controlled release tablets was found to be less reliable and less predictable as compared to conventional formulations. Existing controlled release formulations of levodopa suffer from inadéquate inter and intra patient reproducibility of blood 10 levels. This is particularly problematic in the case of levodopa, where dosage often has to be increased over time to maintain efficacy, which further contributes to the development of long-term side effects.
In particular, it has been found that existing controlled release formulations of levodopa fail to provide a favorable effect comparable with continuous administration of levodopa such as via intravenous infusion. One the other hand, intravenous infusion of levodopa, in addition to being much 20 less convenient for the patient, was found to frequently cause sclerosis of the peripheral veins.
US 2008/0051459 Al describes a duodenal pump with intestinal administration of a composition comprising levodopa and 25 optionally carbidopa continuously over a period greater than hours. The clear disadvantage of this method of levodopa/carbidopa drug delivery is a need for a patient to hâve permanent duodenal or jejunal intubation, which is cumbersome, painful and prone to infections.
It is therefore an object of the présent invention to overcome the disadvantages of the prior art and to provide an oral delivery System allowing for controlled and site spécifie release of drugs, and in particular drugs with narrow 35 therapeutic Windows such as levodopa and other drugs used in * >
the treatment of Parkinson's disease and other movement disorders, to achieve maximal absorption, bioavailability, and optimal blood levels.
Description of the invention
In one aspect the invention relates to an oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion-exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material.
The composition according to the invention comprises at least one active agent. It will be understood that any such active agent is generally présent in the composition in a therapeutically effective amount. The terni therapeutically effective amount refers to an amount or quantity of active agent that is sufficient to elicit an appréciable biological response when administered to a patient.
Ail pharmacologically active agents are generally suitable for use in the composition of the invention. Preferred classes of active agents include antiparkinsonics, antiepileptics, antipsychotics, antidepressants, narcotics, antihypertensives, antioxidants, antineoplastics, cytostatics, gastrointestinal drugs and musculoskeletal drugs.
Examples of suitable active agents include ondansetron, setron, sulfasalazine, doxazosin, thiazide, verapamil, quinapril, valsartan, rosuvastatin, gemfibrozil, fenofibrate, tropisetron, dolasetron, atenolol, amlodipine, enalapril, fosinopril, lovastatin, carvedilol, diltiazem, cilazapril, simvastatin, graniaprepitant, hydrochloronifedipine, ramipril, losartan, palonosetron, bisoprolol, felodipine, lisinopril, trandolapril, fluvastatin, atorvastatin, cholestyramine, oxy« J butynin, propiverine, solifenacin, sildenafil, phentolamine, tamsulosin, phamide, chlorambucil, melphalan, trospium, darifenacin, finasteride, cyclophosbusulfan, lomustin, temozolomide, methotrexate, mercaptopurine, thioguanine, cladribine, capecitabine paclitaxel rubicin, mitomycin, rituximab, sorafenib, amsacrine, irinotecan, megestrol, anastrazole, fludarabine, cytarabine, 5-fluorouracil, gemcitabine, Vinblastine, vincristine, vindesine, etoposide, actinomycin D, doxorubicin, daunoidarubicin, mitoxantrone, bleomycin, carboplatin, oxaliplatin, procarbazine, cetuximab, bevacizumab, sunitinib, lapatinib, nilotinib, temsirolimus, hydroxyurea, estramustine, topotecan, bortezomib, erlotinib, anagrelide, flutamide, nilutamide, bicalutamide, exemestane, mycophenolate mofetil, t
, docetaxel, epirubicin, cisplatin, trastuzumab, dasatinib, asparaginase, imatinib, tamoxifen, letrozole, sirolimus, everolimus, cyclosporine, tacrolimus, azathioprine, etidronic acid (e.g. étidronate sodium), clodronic acid (e.g. clodronate sodium), pamidronic acid (e.g. pamidronate sodium), alendronic acid (e.g. alendronate sodium), tiludronic acid (e.g. tiludronate sodium), ibandronic acid (e.g. ibandronate sodium), risedronic acid (e.g. risedronate sodium), zoledronic acid (e.g. zolédronate sodium), morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprénorphine, tramadol, acetylsalicylic acid, metamizole, paracétamol, sumatriptan, methylphenobarbital, phénobarbital, primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabide, tiagabine, suitiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, trihexyphenidyl, biperiden, amantadine, levodopa, carbidopa, benserazide, entacapone, bromocriptine, pergolide, dihydroergocryptine, ropinirole, rotigotine, pramipexole, selegiline, cabergoline, rasagiline, apomorphine, tolcapone, piribedil, entacapone, budipine, levomepromazine, chlorpromazine, promazine, fluphen-
I
- 9 azine, perazine, haloperidol, sertindole, ziprazidone, zuclopenthixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium (e.g. lithium carbonate), prothipendyl, rispéridone, clotiapine, mosapramine, zotepine, aripiprazole, paliperidone, diazepam, alprazolam, meprobamate, flurazepam, nitrazepam, midazolam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidon, escitalopram, mirtazapine, venlafaxine, methylphenidate, modafinil, neostigmine, pyridostigmine, disulfiram, naloxone, methadone, riluzole, abacavir, aciclovir, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonovine, ethambutol, glucose, imipramine, ketorolac, ketoprofen, labetalol, levofloxacin, metoprolol, metronidazole, minocycline, misoprostol, phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorphan, hydrocodone, hydralazine, metaproterenol, phenylpropanolamine and pseudoephedrine.
The composition of the invention is particularly suitable for active agents belonging to Class I of the Biopharmaceutics Classification System (BCS). BCS Class I active agents are characterized in exhibiting both high permeability and high solubility. Examples of BCS Class I active agents include abacavir, aciclovir, amitriptyline, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, cyclophosphamide, desipramine, diazepam, diltiazem, diphenhydramine, disopyramide, doxepin, ergonovine, ethambutol, ketorolac, ketoprofen, doxycycline, enalapril, ephedrine, fluoxetine, glucose, imipramine, labetalol, levodopa, levofloxacin, metoprolol, metronidazole, midazolam, minocycline, misoprostol, nifedipine, paracétamol, pethidine, phenazone, phénobarbital, phenylalanine, prednisolone, primaquine,
- 10 promazine, propranolol, quinidine, rispéridone, rosiglitazone, salicylic acid, theophylline, verapamil and zidovudine.
Active agents having short biological half-lives in the order of up to about 8 hours are also preferred. Examples include codeine, dextromethorphan, doxepin, ephedrine, hydrocodone, hydralazine, metaproterenol, morphine, levodopa, carbidopa, benserazide, entacapone, phenylpropanolamine, pseudoephedrine and verapamil.
Levodopa, carbidopa, benserazide, entacapone and mixtures thereof are particularly preferred.
The composition of the invention can comprise a combination of two or more active agents. Preferred combinations of active agents include bisoprolol/hydrochlorothiazide, verapamil/trandolapril, amlodipine/atorvastatin, tramadol/paracetamol, beclamide/trihexyphenidyl, buprénorphine/naloxone, levodopa/carbidopa, levodopa/ benserazide and levodopa/carbidopa/entacapone.
Unless indicated otherwise, ail references to active agents herein are meant to include pharmaceutically acceptable salts and solvatés thereof. Such references are further meant to include both crystalline and amorphous forms. As used herein, the term pharmaceutically acceptable refers to materials that are suitable for use in humans and animais without excessive toxicity, commensurate with a reasonable benefit/risk ratio.
The composition of the invention comprises coated particles of a complex of at least one active agent with an ion exchange resin.
Suitable ion exchange resins are typically water-insoluble and comprise a pharmacologically inert organic or inorganic matrix containing covalently bound functional groupa that are ionic t
- 11 or capable of being ionized under appropriate pH conditions. Examples of organic matrices include synthetic matrices (e.g. polymers or copolymers of acrylic acid, methacrylic acid, styrene sulfonate or divinylbenzene sulfonate) and partially synthetic matrices (e.g. modified cellulose or dextran). Examples of inorganic matrices include silica gel modified by the addition of ionic groups. The covalently bound ionic groups can be strongly acidic (e.g. sulfonic acid groups), weakly acidic (e.g. carboxylic acid groups), strongly basic (e.g. quaternary ammonium groups), weakly basic (e.g. primary amine groups) or a combination of acidic and basic groups. Ion exchange resins suitable for ion exchange chromatography or deionization of water are normally also suitable for use in the présent invention. Such ion exchange resins are for instance described by H. F, Walton, Principles of Ion Exchange11 in E. Heftmann (Ed.), Chromatography: A laboratory handbook of chromatographie and electrophoretic methods, 3rd ed. , Van Nostrand, New York, 1975, pp. 312-343. Suitable ion exchange resins typically hâve exchange capacities below about 6 meq./g (milliequivalents per gram) and particularly below about 5.5 meq./g of dry resin (free acid or base form).
The ion exchange resin is preferably selected from the group consisting of polymers and copolymers of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups and silica gel modified with ionic groups. Suitable ionic groups include sulfonate groups, tertiary amine groups and quaternary ammonium groups. Polymers and copolymers of styrenesulfonate, styrylmethyltrimethylammonium salts and dimethylaminomethylstyrene are particularly preferred.
It is further preferred that the ion exchange resin is crosslinked with a crosslinking agent. Suitable crosslinking agents are generally known in the art. Preferred crosslinking
agents are divinyl and polyvinyl compounds, most preferably divinylbenzene. The ion exchange resin is preferably crosslinked to an extent of about 3 to about 20 wt.%, particularly about 4 to about 16 wt.%, more preferably about 6 to about 5 10 wt.%, and most preferably about 8 wt.% based on the total weight of dry resin (free acid or base form).
It is particularly preferred that the ion exchange resin is a crosslinked sulfonated copolymer of styrene and divinyl10 benzene, which is preferably crosslinked to an extent of about wt.% based on the total weight of dry resin (H+-form) . This ion exchange resin typically has an ion exchange capacity of about 4.5 to 5.5 meq./g of dry resin (H+-form) . Another preferred ion exchange resin is a crosslinked copolymer of 15 styrene functionalized with quaternary ammonium groups and divinylbenzene, which is preferably crosslinked to an extent of about 8 wt.% based on the total weight of dry resin (H+form). This ion exchange resin typically has an ion exchange capacity of about 3 to 4 meq./g of dry resin (H+-form).
The ion exchange resin preferably has an average particle size in the range of from about 10 to about 1000 pm, particularly in the range of from about 20 to about 250 μτη, most preferably in the range of from 25 to about 200 pm. The ion exchange 25 resin can be in the form of irregularly shaped particles having an average particle size in the range of from about 4 0 to about 250 pm, or spherical particles having an average particle size in the range of from about 45 to about 150 pm.
It is further preferred that the complex of the at least one active agent with the ion-exchange resin comprises the active agent(s) in an amount of about 5 to 80 wt.%, particularly 10 to 70 wt.%, more preferably 20 to 60 wt.%, and most preferably 30 to 50 wt.%, based on the total weight of the complex.
- 13 The average particle size of the complex of the at least one active agent with the ion exchange resin is preferably about 10 to 3000 μτη, particularly about 30 to 2000 μτπ, and most preferably about 50 to 1000 μτη. It is further preferred that at least about 85 %, particularly at least about 95 %, and most preferably at least about 98 % by volume of the particles hâve an average particle size within these preferred ranges. As used herein, the term average particle size refers to the volume average. Particle size can be determined by sieve analysis or laser diffraction analysis as generally known in the art. Sieve analysis is typically performed on a dry powder sample. Laser diffraction analysis can be performed using a sample as dry powder or suspended in an inert liquid vehicle such as purified water for instance using a Malvern Mastersizer Apparatus MS 2000.
The coated particles further comprise a bioadhesive coating layer comprising at least one bioadhesive material. The term bioadhesive generally refers to a material which is capable of imparting adhesion of particles to a biological surface (e.g. tissue and/or cells) and in particular to a mucous membrane.
Suitable bioadhesive materials generally include modified and unmodified natural or synthetic hydrophilic homopolymers, copolymers and hydrogels. Examples include polycarboxylates, hyaluronan, chitosan, alginates such as sodium alginate, pectin, xanthan gum, poloxamers, cellulose dérivatives, polyvinyl acetate and polyvinylpyrrolidone. Preferred are modified and unmodified synthetic polycarboxylate polymers, which typically hâve a weight average molecular weight of at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about 100,000 Daltons, still more preferably at least about 1,000,000 Daltons, and most preferably from about 1,000,000 to about 10,000,000 Daltons.
k.
Modifications can include crosslinking, neutralization, hydrolysis and full or partial estérification.
Preferred bioadhesive materials include optionally crosslinked polymers and copolymers of acrylic acid or alkylacrylic acids, particularly optionally crosslinked copolymers of acrylic acid or methacrylic acid with (Cio-C3o) alkyl acrylate. Suitable crosslinkers include vinyl and allyl ethers of polyalcohols, particularly allyl sucrose, allyl pentaerythritol and divinyl glycol. Homopolymers of acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol and copolymers of acrylic acid and (Ci0-C3o) alkyl acrylate crosslinked with allyl pentaerythritol are particularly preferred.
It is further preferred that the bioadhesive coating layer is présent in an amount of 1 to 30 wt.%, particularly 2 to 10 wt.% and more preferably 3 to 7 wt. % based on the combined weight of the complex, an optionally présent release modifying coating layer and the bioadhesive coating layer.
The coated particles optionally comprise a release modifying coating layer which is placed between the complex and the bioadhesive layer and comprises at least one release modifying material. In certain embodiments, particularly if the active agent(s) belong to Class II or IV of the Biopharmaceutics Classification System (BCS), which active agents are characterized in exhibiting low solubility, the composition can consist exclusively of particles that do not comprise a release modifying coating layer. Preferably at least a portion of the coated particles comprise the release modifying coating layer. The release modifying material is preferably selected from delayed release materials and/or controlled release materials.
ι
- 15 Suitable delayed release materials typically possess no or limited solubility or erodibility in a first environment, while being soluble and/or erodible in a second environment. Examples of suitable delayed release materials include anionic cellulose dérivatives, anionic vinyl resins, anionic acrylic resins and combinations thereof. Preferred anionic cellulose dérivatives include cellulose ethers, cellulose esters and cellulose ester-ethers, particularly alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses and acylcelluloses, which are esterified with di- or tricarboxylic acids. Cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate are particularly preferred. Preferred anionic vinyl resins include polyvinylesters which are esterified with di- or tricarboxylic acids. Polyvinyl acetate phthalate is particularly preferred. Preferred anionic acrylic resins include polymers and copolymers of acrylic acid or alkylacrylic acid, particularly copolymers of acrylic or methacrylic acid with alkylacrylates or alkylmethacrylates. Poly(methacrylic acid-co-ethylacrylate) and poly(methacrylic acid-co-methylmethacrylate) are particularly preferred. Most preferred as delayed release materials are cellulose acetate phthalate, polyvinyl acetate phthalate, poly(methacrylic acid-co-ethylacrylate) 1:1, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-comethylmethacrylate) 1:1, poly(methacrylic acid-co-methylmethacrylate) 1:2 and combinations thereof, and most preferably cellulose acetate phthalate, polyvinyl acetate phthalate, poly(methacrylic acid-co-ethylacrylate) 1:1, hydroxypropyl methylcellulose acetate succinate and combinations thereof.
Suitable controlled release materials generally include natural and synthetic film-forming materials having diffusion barrier properties. Such materials generally should be insoluble in water and permeable to water and active agent.
However, it can be désirable to incorporate a water-soluble substance, such as methyl cellulose, to alter the permeability of the coating, or to incorporate an acid-insoluble, basesoluble substance to act as an enteric coating. Examples of 5 suitable controlled release materials are also described by R.
C. Rowe in Materials used in Pharmaceutical Formulation, A.
T. Florence (Ed.), Blackwell Scientific Publications, Oxford, 1984, pp. 1-36. Examples of suitable controlled release materials include cellulose dérivatives such as cellulose 10 ethers and cellulose esters, (meth)acrylic resins such as acrylate and méthacrylate polymers and copolymers, vinyl resins such as polymers and copolymers of vinylpyrrolidone, vinylacetate and vinylchloride, shellac, zein, rosin esters, silicone elastomers and mixtures thereof. Preferred cellulose 15 dérivatives include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses and acylcelluloses, particularly ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose and cellulose acetate. Preferred (meth)acrylic resins include acrylate and méthacrylate copolymers optionally 20 comprising quaternary amine functional groups, particularly poly(ethyl acrylate-co-methyl méthacrylate) and poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl méthacrylate chloride), more particularly poly(ethyl acrylate-comethyl méthacrylate) 2:1, poly(ethyl acrylate-co-methyl 25 methacrylate-co-trimethylammonioethyl méthacrylate chloride)
1:2:0.1 and poly(ethyl acrylate-co-methyl methacrylate-cotrimethylammonioethyl méthacrylate chloride) 1:2:0.2. Preferred vinyl resins include polyvinylpyrrolidone, poly(vinylpyrrolidoneco-vinylacetate) and mixtures thereof. Ethyl cellulose, methyl 30 cellulose and mixtures thereof are particularly preferred.
Most preferably the controlled release coating comprises a water-based ethyl cellulose latex or pseudolatex plasticized with dibutyl sebacate or vegetable oils.
- 17 The release modifying coating layer is preferably présent in an amount of from about 5 to about 70 wt.%, particularly about 10 to about 60 wt.%, and more preferably about 20 to about 50 wt.%, based on the combined weight of the complex and the release modifying coating layer. Variations in the amount of release modifying material and/or the use of mixtures of coated and uncoated particles can be employed to selectively modify the dissolution profile as desired. It is preferred that about 20 to about 80 %, more preferably about 30 to about 70 % and most preferably about 40 to about 60 % of the particles comprise a release modifying coating layer.
According to a preferred embodiment, the composition comprises at least two groups of coated particles differing in the amount and/or the composition of release modifying material and/or comprising different active agents.
In one embodiment, the composition comprises a first group of coated particles comprising a release modifying layer and a second group of coated particles having no release modifying layer or having a release modifying layer with a lower amount of release modifying material.
In another embodiment, the composition comprises two groups of coated particles comprising release composition of the modifying layers release modifying differing material.
in the
In these embodiments, those particles having no release modifying layer or having a release modifying layer with a lower amount of release modifying material will exhibit a faster release of active agent. Likewise, groups of particles differing in the composition of the release modifying material will exhibit different release behaviors.
When the composition comprises at least two different groups of coated particles, the active agent(s) of these groups of particles can be the same or different. When the active
- 18 agent (s) are the sanie, the combination of different groups of coated particles exhibiting different release behavior can be used to adapt the overall release profile of the active agent. When the active agent(s) are different, the different active agents can be provided according to different release profiles, e.g. one active agent can be released faster and/or earlier than another active agent.
It will be appreciated that these and other embodiments can also be combined to provide compositions comprising any number of different groups of coated particles. For example, a composition in accordance with the invention can comprise a first group of coated particles comprising a first active agent or combination of active agents and a release modifying layer, a second group of coated particles comprising the same active agent or combination of active agents without a release modifying layer and a third group of coated particles comprising a different active agent or combination of active agents.
The coated particles optionally comprise an enteric coating layer which is placed over the bioadhesive layer and comprises at least one enteric coating material. The enteric coating layer is preferably placed directly over the bioadhesive layer, i.e. without another layer between the bioadhesive layer and the enteric coating layer. Suitable enteric coating materials are generally known in the art. They are typically substantially résistant to gastric juices so as to largely prevent release of active agent in the stomach and thus promote enteric release. Examples of suitable enteric coating materials include anionic cellulose dérivatives, anionic vinyl resins, anionic acrylic resins.
Preferred anionic cellulose dérivatives include cellulose ethers, cellulose esters and cellulose ester-ethers such as alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkyl16606 celluloses or acylcelluloses, which are esterified with di- or tricarboxylic acids such as phthalic acid, hexahydrophthalic acid, trimellitic acid or succinic acid and pharmaceutically acceptable saits thereof. Cellulose ether phthalates, 5 cellulose ester phthalates, cellulose ester-ether phthalates and pharmaceutically acceptable saits thereof are preferred. Particularly preferred are cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, methylcellulose phthalate, hydroxypropyl cellulose phthalate, 10 hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate and pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts include alkaline, alkaline earth and ammonium salts, particularly sodium cellulose acetate phthalate, calcium cellulose acetate phthalate and ammonium hydroxypropyl methylcellulose phthalate.
Preferred anionic vinyl resins include polyvinylesters which are esterified with di- or tricarboxylic acids such as 20 phthalic acid, hexahydrophthalic acid, trimellitic acid or succinic acid and pharmaceutically acceptable salts thereof. Polyvinyl acetate phthalate is particularly preferred. Even more preferred are mixtures of anionic vinyl resins with phthalate plasticizers such as dialkyl phthalates, e.g. 25 diethyl phthalate or dibutyl phthalate, alkylaryl phthalates or diarylphthalates.
Preferred anionic acrylic resins include polymers and copolymers of acrylic acid or alkylacrylic acid, and in particular 30 copolymers of acrylic or methacrylic acid with alkylacrylates or alkylmethacrylates. Examples include poly(methacrylic acidco-ethylacrylate), poly(methacrylic acid-co-methylmethacrylate) and combinations thereof, preferably poly(methacrylic acid-comethylmethacrylate) 50:50, poly(methacrylic acid-co-methylmeth35 acrylate) 30:70, poly(methacrylic acid-co-dimethylaminoethyl16606 methacrylate-co-ethylacrylate), poly(methacrylic acid-co-methylmethacrylate-co-ethylacrylate), and combinations thereof, more preferably poly(methacrylic acid-co-methylmethacrylate) 50:50 having an average molecular weight of about 135,000 g/mol, 5 poly(methacrylic acid-co-methylmethacrylate) 30:70 having an average molecular weight of about 135,000 g/mol, poly(methacrylic acid-co-dimethylaminoethylmethacrylate-co-ethylacrylate) having an average molecular weight of about 750,000 g/mol, poly(methacrylic acid-co-methylmethacrylate-co-ethylacrylate) having an average 10 molecular weight of about 1,000,000 g/mol and combinations thereof.
Other suitable enteric coating materials include: (a) keratin, keratin sandarac-tolu, salol (phenyl salicylate), salol beta15 naphthylbenzoate and acetotannin, salol with balsam of Peru, salol with tolu, salol with gum mastic, salol and stearic acid, and salol and shellac; (b) formalized protein, formalized gelatin, and formalized crosslinked gelatin and ion exchange resins; (c) myristic acid-hydrogenated castor oil20 cholestérol, stearic acid-mutton tallow, stearic acid-balsam of tolu, and stearic acid-castor oil; (d) shellac, ammoniated shellac, ammoniated shellac-salol, shellac-wool fat, shellaccetyl alcohol, shellac-stearic acid-balsam of tolu, and shellac n-butyl stéarate; (e) abietic acid, methyl abictate, 25 benzoin, balsam of tolu, sandarac, mastic with tolu, and mastic with cetyl alcohol.
The presence and nature of an enteric coating can be chosen according to the desired site of release of the active agent.
If the active agent is to be released in the stomach, the particles will usually not comprise an enteric coating layer.
If the active agent is to be released in the duodénum, the enteric coating material is preferably chosen to dissolve at a pH in the range of about 5.0-6.0 and in particular about 5.516606
6.0. Particles comprising such an enteric coating are particularly preferred when the active agent is levodopa. Suitable enteric coating matériels include poly(methacrylic acid-co-ethyl acrylate) and particularly poly(methacrylic 5 acid-co-ethyl acrylate) 1:1.
If the active agent is to be released in the ileum, the enteric coating material is preferably chosen to dissolve at a pH in the range of about 6.0 to 7.0 and in particular about 10 6.0 to 6.5. Suitable enteric coating materials include poly(methacrylic acid-co-methyl méthacrylate) and particularly poly(methacrylic acid-co-methyl méthacrylate) 1:1.
If the active agent is to be released in the colon, the 15 enteric coating material is preferably chosen to dissolve at a pH in the range of about 6.5 to 7.5 and in particular above 7.0. Suitable enteric coating materials include poly(methacrylic acid-co-methyl méthacrylate) and poly(methyl acrylateco-methyl methacrylate-co-methacrylic acid) and particularly 20 poly(methacrylic acid-co-methyl méthacrylate) 1:2 and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.
It is further preferred that the enteric coating layer is présent in an amount of 1 to 90 wt.%, particularly 10 to 25 60 wt.%, and more preferably 30 to 50 wt.%, based on the total weight of the coated particles.
It has surprisingly been found that the oral pharmaceutical composition according to the invention provides a reproducible, 30 site spécifie and controlled release of active agents whereby the active agents are released initially fast, to hâve a fast onset of action, and then slowly and substantially continuously over an extended period of time, e.g. over a 1 to 10-hour period, to provide blood levels that are within the therapeutic 35 window. These superior properties reduce the required total daily dose as well as the number of daily doses, thereby reducing both short and long-term side effects.
Without wishing to be bound by any particular theory, it is believed that the bioadhesive material provides for the rétention of the multitude of coated particles via adhérence to a biological surface at the desired site of absorption of the active agent, such as a desired site within a patient's gastrointestinal tract. The rate of release of the active 10 agent from its complex with the ion exchange resin dépends in particular on the ionic strength of the surrounding fluid at the particular site of absorption, which is relatively constant intra and inter patient. An uncontrolled and irregular release of active agent, for instance throughout the 15 patient's gastrointestinal tract, is thus prevented.
The composition preferably exhibits a release of active agent characterized in that the total amount of active agent released is not more than 60 wt.% after 2 h, not more than 70 wt.% after 20 4 h and not more than 90 wt.% after Θ h (USP method #2, paddle rotation speed 50 rpm, 37 °C, dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-12 h: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 6.25, ionic strength 0.075).
It is particularly preferred that the composition exhibits a zéro order, pseudo-zero order, first order or pseudo-first order release profile. A zéro order release profile characterizes the release profile of a dosage form that releases a constant amount of drug per unit time. A pseudo zéro order release 30 profile is one that approximates a zero-order release profile.
A first order release profile characterizes the release profile of a dosage form that releases a constant percentage of an initial drug charge per unit time. A pseudo-first order release profile is one that approximates a first order 35 release profile.
- 23 The average particle size of the coated particles is preferably about 20 to about 5000 pm, particularly about 50 to about 4000 pm, and most preferably about 70 to about 3000 pm.
It is further preferred that at least about 85 %, particularly at least about 95 %, and most preferably at least about 98 % by volume of the particles hâve an average particle size within these preferred ranges.
The coated particles typically hâve a spécifie gravity (SG) that is higher than the spécifie gravity of duodenal fluids (SG = 1.008-1.03) or intestinal fluids (SG = 1.007-1.009). As used herein, the term spécifie gravity means the ratio of the density of the particles to the density of water at 4 °C.
Preferably the coated particles hâve a spécifie gravity in the range from 1.1 to 2.0, more preferably from 1.2 to 1.8. Spécifie gravity of the coated particles can be calculated from the volume of water displacement (AV) resulting from addition of a sample into water at 4 °C, the mass of the
20 | sample (m) and the density of water accordance with the following formula: | at 4 ’C | (pH2O) | in |
SG = (m/AV)/pH2O. | ||||
25 | The coated particles in accordance | with the | invention | |
typically exhibit a large spécifie surface area. | As | used | ||
herein, the term spécifie surface area | typically | means | BET |
surface area. BET-surface areas can be determined by calculation from desorption data of nitrogen obtained on a BET 30 FlowSorb II 2300 (Micromeritics Instrument Corp., USA) using a mixture of 30 vol. % nitrogen and 70 vol. % hélium at 77 K.
Preferably, the coated particles exhibit a spécifie surface area in the range of from about 3,000 to 20,000 m2/m3. In another embodiment, the coated particles exhibit a spécifie 35 surface area in the range of from about 1 to 200 m2/g.
t
- 24 In one embodiment, the oral pharmaceutical composition according to the invention comprises coated particles of a complex of at least one active agent with an ion-exchange resin, wherein (i) said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material and (ii) the coated particles further comprise an enteric coating layer which is placed, preferably directly, over the bioadhesive layer and comprises at least one enteric coating material.
In another embodiment, the oral pharmaceutical composition according to the invention comprises coated particles of a complex of at least one active agent with an ion-exchange resin, wherein (i) said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material and (ii) at least a portion of the coated particles further comprises a release modifying coating layer which is placed between the complex and the bioadhesive layer and comprises at least one release modifying material.
According to a preferred embodiment, the oral pharmaceutical composition according to the invention comprises coated particles of a complex of at least one active agent with an ion-exchange resin, wherein (i) said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material and (ii) the coated particles further comprise an enteric coating layer which is placed over the bioadhesive layer and comprises at least one enteric coating material and (iii) at least a portion of the coated particles further comprises a release modifying coating layer which is placed between the complex and the bioadhesive layer and comprises at least one release modifying material.
- 25 According to a particularly preferred embodiment, the coated particles comprise:
(a) 1 to 50 wt.%, particularly 5 to 40 wt.% and preferably 10 to 20 wt.% of the at least one active agent;
(b) 1 to 50 wt.%, particularly 10 to 35 wt.% and preferably 15 to 25 wt.% of the ion-exchange resin;
(c) 0 to 50 wt.%, particularly 1 to 50 wt.%, preferably 10 to 40 wt.% and more preferably 15 to 30 wt.% of the release modifying material;
(d) 0.5 to 30 wt.%, particularly 1 to 10 wt.% and preferably 2 to 8 wt.% of the bioadhesive material; and (e) 0 to 80 wt.%, particularly 1 to 80 wt.%, preferably 10 to 60 wt.% and more preferably 30 to 50 wt.% of the enteric coating material;
based on the total weight of the coated particles.
The composition can further comprise at least one active agent, or a pharmaceutically acceptable sait or solvaté thereof, outside the coated particles to provide an immédiate boost of active agent. The active agent(s) can be identical with or different from the active agent(s) contained in the coated particles. The active agent(s) can optionally be combined or coated with an enteric material.
The composition according to the invention is particularly suitable for active agents having narrow therapeutic Windows such as levodopa, carbidopa, benserazide and/or entacapone.
In a particularly preferred embodiment, the composition comprises levodopa and carbidopa or benserazide in a ratio of 20:1 to 1:1, preferably 15:1 to 2:1, and most preferably 10:1 to 4:1.
»
- 26 In the final formulation, besides the coated particles in the various forms defined above, other suitable substances can be admixed. These other substances can be bound to the ion exchange resin, and coated with some or ail of the coating layers defined above as necessary to provide désirable dissolution profile, or they can be in their free native solid or liquid form.
The composition of the invention can further comprise excipients. Suitable types of excipients include adsorbents, antioxidants, acidifying agent, alkalizing agent, buffering agents, colorants, flavorants, sweetening agents, antiadhèrents, binders, diluents, direct compression excipients, disintegrants, glidants, lubricants, opacifiera and/or polishing agents.
The term antioxidant generally refers to an excipient used to inhibit oxidation and thus prevent détérioration of active agents by oxidative processes. Suitable antioxidants include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldéhyde sulfoxylate and sodium metabisulfite.
The term sweetening agent generally refers to an excipient used to impart sweetness to a pharmaceutical composition. Suitable sweetening agents include aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol and sucrose.
The term colorant generally refers to an excipient used to impart color to a pharmaceutical composition. Suitable colorants include FD&C Red No. 3, FD&C Red No. 20, FD&.C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. Θ, other F.D. & C. dyes, caramel, red ferrie oxide, and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annatto, carminé, turmeric paprika. The amount of colorant used will vary as desired.
or to a
generally
The term flavorant generally refers to an excipient used impart a pleasant flavor and often also odor to pharmaceutical composition, Suitable flavorants include synthetic flavoring oils, flavoring aromatics, natural oils, extracts from whole plants or parts thereof such as leaves, flowers, fruits or combinations thereof. Examples include cinnamon oil, wintergreen oil, peppermint oils, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, nutmeg oil, sage oil, bitter almond oil Other useful flavorants include as lemon, orange, grape, lime such as apple, pear, plum, found to essences cherry, hâve been available mixtures number of can be adapted as art. Particularly flavors and citrus orange, thereof.
factors, and cassia oil. fruit oils such oil, and fruit raspberry, that commercially flavors and dépend on a vanilla, citrus or grapefruit peach, strawberry, pineapple or apricot essence. Flavorants be particularly useful include grape, cherry The amount of including needed by preferred fruit flavors such as orange flavor.
and bubble gum flavoring can organoleptic effect desired, the those of ordinary skill in the flavors are grape and cherry also
Plasticizers can composition to modify the polymers used in composition. The term be included in the pharmaceutical the properties and characteristics of the coating layers or core of the plasticizer generally refers to a compound used to plasticize or soften a component, such as a polymer or binder, of the pharmaceutical composition. Suitable plasticizers generally include low molecular weight polymers, oligomers, copolymers, oils, small organic molécules, low molecular weight polyols having aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, polypropyleneglycols, multi-block polymers, single-block polymers, low molecular
weight polyethyleneglycol, citrate ester-type plasticizers, triacetin, propylene glycol and glycerin. Such plasticizers can also preferably include ethylene glycol, 1,2-butylene glycol, 2,3-butylène glycol, styrene glycol, diethylene glycol, 5 triethylene glycol, tetraethylene glycol and other polyethyleneglycol compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, acetyltributylcitrate, 10 most preferably triethyl citrate, dibutylsebacate, acetyl triethyl citrate, tributyl citrate and allyl glycolate. Ail such plasticizers are generally commercially available. It is also contemplated that a combination of plasticizers can be used in the présent formulation. The PEG based plasticizers 15 are available commercially or can be made by a variety of methods, such as disclosed in Poly(ethylene glycol) Chemistry: Biotechnical and Biomédical Applications (J. M. Harris, Ed. ; Plénum Press, NY).
The compositions of the invention can also include oils, for example fixed oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and most preferably olive oil, fatty acids such as oleic acid, stearic acid and isostearic acid, fatty acid esters such as ethyl oleate, isopropyl myristate, fatty acid 25 glycerides and acetylated fatty acid glycerides. Optional further ingrédients include alcohols such as éthanol, isopropanol, hexadecanol, glycerol and propylene glycol, glycerol ketals such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers such as poly(ethyleneglycol) 450, petroleum hydrocarbons such as minerai 30 oil and petrolatum, water or mixtures thereof with or without the addition of a pharmaceutically suitable surfactant, suspending agent or emulsifying agent.
Soaps and synthetîc détergents can be employed as surfactants 35 and as vehicles for detergent compositions. Suitable soaps
- 29 include alkaline, ammonium and triethanolamine salts of fatty acids. Suitable détergents include cationic détergents, such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides and alkylamine acétates, anionic détergents, such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates. Preferred détergents include amphoteric détergents, such as alkyl-beta-aminopropionates and 2-alkylimidazoline quaternary ammonium salts and mixtures thereof, most preferably nonionic détergents, such as fatty amine oxides, fatty acid alkanolamides and poly(oxyethylene)-block-poly(oxypropylene) copolymers.
Various other components can be added to the compoistion for optimization of a desired active agent release profile including glycerylmonostearate, nylon, cellulose acetate butyrate, d,1-poly(lactic acid), 1,6-hexanediamine, diethylenetrïamine, starches, dérivâtized starches, acetylated monoglycerides, gelatin coacervates, poly(styrene-co-maleic acid), glycowax, castor wax, stearyl alcohol, glycerol palmitostearate, polyethylene, polyvinylacetate, polyvinylchloride, 1,3-butylene-glycoldimethacrylate, ethyleneglycoldimethacrylate and méthacrylate hydrogels.
It should be understood that compounds used in the art of pharmaceutical formulation may serve a variety of functions or purposes. Thus, if a compound named herein is mentioned only once or is used to define more than one term herein, its purpose or function should not be construed as being limited solely to that named purpose(s) or function(s).
The pharmaceutical composition of the invention can assume any shape or form known in the art of pharmaceutical sciences. In particular, it can be a bar, plate, paraboloid of révolution, ellipsoid of révolution or the like. Preferably the composition is in the form of a capsule, such as a hard or soft gélatine or vegetable capsule, a tablet, an oblong tablet, a caplet, a pill, a sphere, a powder or a liquid suspension such as an unhydrous suspension with olive oil, glycérine, polyethylene glycol or other suitable non-ionic 5 vehicle. Most preferably the composition is in the form of a capsule. The final form of the composition can also include surface markings, cuttings, grooves, letters and/or numerals for the purposes of décoration, identification and/or other purposes. The dosage form can include a finish coat to provide 10 the desired shine, color, taste or other aesthetic characteristics. Materials suitable for preparing the finish coat are generally known in the art.
Further preferred embodiments of the composition according to 15 the invention are represented by oral formulations, particularly hard vegetable capsules, comprising:
1) Levodopa/carbidopa in a weight ratio of 4:1, particularly levodopa 50 mg/carbidopa 12,5 mg, wherein carbidopa is in native powder immédiate release form, and levodopa is in the form of ion exchange resin/drug particles coated with bioadhesive and enteric coating layers.
2) Levodopa/carbidopa in a weight ratio of 4:1, particularly 25 levodopa 100 mg/carbidopa 25 mg, wherein carbidopa is in native powder immédiate release form, and levodopa is in the form of a mixture of ion exchange resin/drug particles coated with bioadhesive and enteric coating layers and ion exchange resin/drug particles coated with release control, bioadhesive 30 and enteric coating layers.
3) Levodopa/carbidopa in a weight ratio of 4:1, particularly levodopa 200 mg/carbidopa 50 mg, wherein carbidopa is in native powder immédiate release form, and levodopa is in the form of a mixture of ion exchange resin/drug particles coated with bioadhesive and enteric coating layers and ion exchange resin/drug particles coated with release control, bioadhesive and enteric coating layers.
4) Levodopa/entacapone/carbidopa in a weight ratio of 525:20:1-5, particularly levodopa 50-250 mg, entacapone 200 mg, carbidopa 10-50 mg, wherein levodopa is in the form of a mixture of ion exchange resin/drug particles coated with bioadhesive and enteric coating layers and ion exchange 10 resin/drug particles coated with release control, bioadhesive and enteric coating layers, and entacapone and carbidopa are in form of ion exchange resin/drug particles coated with bioadhesive and enteric coating layers or in native powder forms.
Alternatively, in the above embodiments, carbidopa can be replaced by benserazide.
The oral pharmaceutical composition of the présent invention can be prepared by methods generally known in the art. A 20 typical process for preparing the composition comprises the steps of:
(i) contacting an active agent with an ion-exchange resin to obtain an active agent/ion exchange resin complex;
(ii) optionally coating the complex of step (i) with a coating layer comprising a release modifying material;
(iii) coating the complex of step (i) or the coated complex of step (ii) with a coating layer comprising a bioadhesive material; and (iv) optionally coating the coated complex of step (iii) with a coating layer comprising an enteric coating material.
In step (i) , the active agent is preferably mixed with an aqueous suspension of the resin, and the resulting complex is 35 washed and dried. Adsorption of active agent onto the resin can be detected by measuring a change in the pH of the reaction medium, or by measuring a change in concentration of counterions and/or active agent. The complex is typically washed with an alcohol such as éthanol and/or water to insure 5 removal of any unbound active agent. The complexes are usually air-dried in trays at room température or elevated température. The binding can be performed, for example, as a batch or column process, as is known in the art.
Binding of active agent to resin can generally follow one of four general reaction types. In the case of binding a basic active agent to a cation exchange resin these are: (a) resin (sait form, e.g. Na+-form) plus active agent (sait form), (b) resin (sait form, e.g. Na+-form) plus active agent (free base), (c) resin (H+-form) plus active agent (sait form), and (d) resin (H+-form) plus active agent (free base) . In the case of binding an acidic active agent to an anion exchange resin these are: (a) resin (sait form, e.g. Cl'-form) plus active agent (sait form), (b) resin (sait form, e.g. Cl'-form) plus active agent (free acid), (c) resin (OH'-form) plus active agent (sait form) ; and (d) resin (OH'-form) plus active agent (free acid) . Ail of these reactions except (d) involve byproducts formed by a compétition of counterions with the active agent for binding sites on the resin, thereby reducing the amount of active agent bound at equilibrium. Thus, both for acidic and basic active agent truly stoichiometric binding of active agent to resin is accomplished only through reaction (d).
In steps (ii) to (iv), conventional coating solvents and 30 coating procedures, such as fluid bed coating or spray coating, can be employed to coat the particles. Techniques of fluid bed coating are taught, for example, in US 3,089,824, US 3,117,027 and US 3,253,944. The coating is normally applied to the complex of active agent and ion exchange resin, but 35 alternatively can be applied to the resin before complexing
- 33 with the active agent. The coating mixture is typically applied as a solution, dispersion or émulsion in a coating solvent. Examples of suitable coating solvents include methanol, éthanol, isopropanol, isobutanol, n-butyl acetate, ethyl acetate, acetone, methyl ethyl ketone, hexane, methyl isobutyl ketone, carbon tetrachloride, methylene chloride, ethylene chloride, trichloroethylene, tetrahydrofuran, 2nitropropane, toluene, xylene, mixtures thereof such as a mixture of methylene chloride and acetone. Methanol, éthanol, 10 isopropanol, isobutanol, n-butyl acetate and ethyl acetate are preferred.
The invention will be further illustrated by way of the following examples.
Brlef description of the drawings
Fig. 1 shows the release of levodopa from 500 mg of the levodopa drug resin complex obtained in Example IA dispersed 20 in deionized water at room température under stirring with a magnetic stirrer. NaCl was added as follows: 9 min: 200 mg; 36 min: 700 mg; 52 min: 1200 mg; 61 min: 3300 mg.
Fig. 2 shows the dissolution profile of coated LDRC obtained 25 in Example 1B-1 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, pH 5.5, ionic strength 0.075).
Fig. 3 shows the dissolution profile of coated LDRC obtained in Example 1B-3 in phosphate buffer (USP method #2, paddle 30 rotation speed 50 rpm, 37 °C, pH 5.5, ionic strength 0.075)
Fig. 4 shows the dissolution profiles of coated LDRC obtained in Examples 1B-2 to 1B-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 qC, pH 6.0, ionic strength 35 0.075).
Fig. 5 shows the dissolution profile of coated LDRC obtained in Example 1C-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, pH 6.0, ionic strength 0.075).
Fig. 6 shows the dissolution profile of coated LDRC obtained in Example 1C-5 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, pH 6.0, ionic strength 0.075).
Fig. 7 shows the dissolution profiles of coated LDRC obtained in Examples 1D-2 to 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075).
Fig. 8 shows the dissolution profiles of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075).
Fig. 9 shows the dissolution profiles of uncoated ropinirole drug resin complex (RoDRC) obtained in Example 2A and coated RoDRC obtained in Example 2D before and after sieving (USP method #2, paddle rotation speed 75 rpm, 37 °C, dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-10 h: buffer mixture [500 ml
0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength
0.075).
Fig. 10 shows the dissolution profile of coated alendronate drug resin complex (A1DRC) obtained in Example 3D (USP method #2,
0 paddle rotation speed 75 rpm, 37 °C, dissolution medium 1000 ml 0.1 M NaCl).
Fig. 11 shows the dissolution profile of coated rispéridone drug resin complex (RiDRC) obtained in Example 4D (USP method #2, paddle rotation speed 75 rpm, 37 °C, dissolution medium 0-1 h:
- 35 500 ml 0.1 N HCl, 1-12 h: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075).
Fig. 12 shows the dissolution profile of coated olanzapine drug resin complex (OzDRC) obtained in Example 5D (USP method #2, paddle rotation speed 75 rpm, 37 °C, dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-12 h: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075; 10 g of NaCl was added after 10.5 h).
Examples
Release of levodopa was measured spectrophotometrically at 280 nm.
Exemple 1
Ά) Préparation of levodopa drug resin complex (LDRC)
400 g of a sodium polystyrène sulfonate cation exchange resin crosslinked with divinylbenzene (125-400 mesh) were mixed with 1200 ml of deionized water under slow stirring for 1 h. The resin was allowed to settle and the water was decanted. Diluted HCl was prepared by adding 300 ml of conc. HCl to 1200 ml of deionized water and mixing. The resin was mixed with 250 ml of the diluted HCl for 30 min and then allowed to settle, the supernatant was decanted and this step was repeated until ail of the diluted HCl had been used up. The resin was washed by mixing with 500 ml of deionized water for 10 min, allowing the resin to settle, decanting the supernatant and repeating this step 8 times or until the supernatant was neutral to litmus paper.
A mixture of 300 ml of éthanol and 300 ml of deionized water was added to the resin and 250 g of levodopa were added and treated with the resin for 4 h while mixing for 1 min every 30 min. The resin was allowed to settle overnight and then the
- 36 supernatant was decanted. The resin was washed by mixing with 300 ml of a water/éthanol (3:2) mixture, allowing the resin to settle, decanting the supernatant and repeating this step until no levodopa crystals were visible under a microscope after evaporating the supernatant. The obtained levodopa drug resin complex was dried in a furnace at 60 °C. Moisture content (LOD [loss on drying] ) : 5 ± 0.5 wt.%, levodopa content (HPLC):
± 1 wt.%. The obtained complex was found to be stable against exposure to air at room température for at least 6 months.
Ionie binding of levodopa in the complex was tested by adding increasing amounts of electrolyte (NaCl) to a slurry of LDRC in deionized water. Release of levodopa is shown in Fig. 1.
B) Coating with a release modifying coating layer
Example | 1B-1 | 1B-2 | 1B-3 | 1B-4 |
Release modifying material | 20% | 30% | 40% | 50% |
Drug resin complex (Example) | IA | IA | IA | IA |
Drug resin complex (g) | 74 | 5Θ | 58 | 58 |
Coating dispersion | ||||
Ethylcellulose (g) | 20 | |||
Ethylcellulose (g) | 124 | 212 | 2 90 | |
(pre-plasticized, 20 wt% solids) | ||||
Dibutyl sebacate (g) | 4 | |||
Olive oil (g) | 2 | |||
Ethanol 96 vol.% (g) | 374 | |||
Deionized water (g) | 83 | 141 | 193 | |
Coating conditions | ||||
Nozzle diameter (mm) | 0.5 | 0.5 | 0.5 | 0.5 |
Fluidizing air pressure (bar) | 0.2 | 0.2 | 0.2 | 0.2 |
Fluidizing air température (°C) | 50 | 75 | 75 | 75 |
Nozzle air pressure (bar) | 2 | 1.5 | 1.5 | 1.5 |
Product température (°C) | 30 | 37 | 37 | 37 |
Pump speed (g/min) | 2 | 2.5 | 2.5 | 2.5 |
Yield (g) | 95 | 80 | 98 | 110 |
Moisture content (wt.%,LOD) | 5 | 5 | 5 | 5 |
Levodopa content (wt.%,HPLC) | 29 | 27 | 23 | 20 |
Levodopa drug resin complex (LDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus and dried in situ to 45-50 ’C. The product was sifted through
- 37 a 40 mesh stainless steel screen. Microscopie examination revealed uniformly coated particles with moderate agglomération. The coated products obtained in Examples 1B-2 to 1B4 were further cured for 2 h at 60 °C,
Dissolution profiles of coated LDRC obtained in Examples 1B-1 and 1B-3 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, pH 5.5, ionic strength 0.075) are shown in Figs. 2 and 3. Dissolution profiles of coated LDRC obtained in Examples 1B-2 to 1B-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, pH 6.0, ionic strength 0.075) are shown in Fig. 4.
C) Coating with a bioadheaive coating layer
Example | 1C-1 | 1C-2 | 1C-3 | 1C-4 | 1C-5 |
Release modifying material | - | 30% | 40% | 50% | 40% |
Bioadhesive material | 5% | 5% | 5% | 5% | 10% |
Drug resin complex (Example) | IA | 1B-2 | 1B-3 | 1B-4 | 1B-3 |
Drug resin complex (g) | 57 | 57 | 57 | 57 | 54 |
Coating dispersion Carboxypolymethylene* (g) | 3 | 3 | 3 | 3 | 6 |
Ethanol 96 vol.% (g) | 197 | 197 | 197 | 197 | 194 |
Coating conditions Nozzle diameter (mm) | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 |
Fluidizing air pressure (bar) | 0.15 | 0.15 | 0.15 | 0.15 | 0.15 |
-0.7 | -0.7 | -0.7 | -0.7 | -0.7 | |
Fluidizing air température (°C) | 50 | 50 | 50 | 50 | 65 |
Nozzle air pressure (bar) | 1.5 | 1.5 | 1.5 | 1.5 | 1.5 |
Product température (°C) | 37 | 37 | 37 | 37 | 35 |
Pump speed (g/min) | 3 | 3 | 3 | 3 | 2.5 |
Yield (g) | 59 | 59 | 59 | 59 | 59 |
Moisture content (wt.%,L0D) | 5.5 | 5.5 | 5.5 | 5.5 | 4.5 |
Levodopa content (wt.%,HPLC) | 38 | 26 | 21 | 19 | 20 |
*High molecular weight polymer of acrylic acid crosslinked with allyl ethers and pentaerythritol
Levodopa drug resin complex (LDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus and dried in situ to 5 0 °C. The product was sifted through a
- 38 40 mesh stainless steel screen. Microscopie examination revealed uniformly coated particles with moderate agglomération.
Dissolution profiles of coated LDRC obtained in Examples 1C-3 5 and 1C-5 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, pH 6.0, ionic strength 0.075) are shown in Figs. 5 and 6.
D) Coating with an enteric coating layer
Example | 1D-1 | 1D-2 | 1D-3 | 1D-4 |
Release modifying material | - | 30% | 40% | 50% |
Bioadhesive material | 5% | 5% | 5% | 5% |
Amount of enteric coating mat. | 40% | 40% | 40% | 40% |
Drug reain complex (Example) | 1C-1 | 1C-2 | 1C-3 | 1C-4 |
Drug resin complex (g) | 58 | 58 | 58 | 58 |
Coating dispersion Methacrylic acid copolymer* (g) | 35 | 35 | 35 | 35 |
Triethyl citrate (g) | 3.5 | 3.5 | 3.5 | 3.5 |
Ethanol 96 vol.% (g) | 300 | 300 | 300 | 300 |
Coating conditions Nozzle diameter (mm) | 0.5 | 0.5 | 0.5 | 0.5 |
Fluidizing air pressure (bar) | 0.4- | 0.4- | 0.4- | 0.4- |
0.6 | 0.6 | 0.6 | 0.6 | |
Fluidizing air température (°C) | 60 | 60 | 60 | 60 |
Nozzle air pressure (bar) | 1.5 | 1.5 | 1.5 | 1.5 |
Product température (°C) | 45 | 45 | 45 | 45 |
Pump speed (g/min) | 3 | 3 | 3 | 3 |
Yield (g) | 95 | 94 | 96 | 95 |
Moisture content (wt.%,LOD) | 5.1 | 5.3 | 5.0 | 4.9 |
Levodopa content (wt.%,HPLC) | 23 | 16 | 12 | 11 |
*Commercially available methacrylic acid copolymer with dispersing agents formulated for easy dispersion in water
- 39 Levodopa drug resin complex (LDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus and dried in situ to 55 °C. The product was sifted through a 40 mesh stainless steel screen. Microscopie examination revealed uniformly coated particles with moderate agglomération.
Dissolution profiles of coated LDRC obtained in Examples 1D-2 to 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, dissolution medium 0-1 h: 0.1 N HCl, 112 h: phosphate buffer pH 6.25, ionic strength 0.075) are shown in Fig. 7. Dissolution profiles of coated LDRC obtained in Examples 1D-1 and 1D-4 in phosphate buffer (USP method #2, paddle rotation speed 50 rpm, 37 °C, dissolution medium 0-1 h: 0.1 N HCl, 1-12 h: phosphate buffer pH 6.25, ionic strength 0.075) are shown in Fig. 8.
E) Hard gelatin capsules comprising levodopa and carbidopa
Example | 1E-1 | 1E-2 |
LDRC from Example 1D-1 (mg) | 218.0 | 130.0 |
LDRC from Example 1D-4 (mg) | - | 635.0 |
Carbidopa (mg) | 12.5 | 25.0 |
Magnésium stéarate or talcum (mg) | 10.5 | 20.0 |
Total (mg) | 241.0 | 810.0 |
Levodopa content (mg) | 50.0 | 100.0 |
Carbidopa content (mg) | 12.5 | 25.0 |
One or more levodopa drug resin complexes were dry mixed with carbidopa and magnésium stéarate or talcum as indicated. The obtained mixture was filled into hard gelatin capsules.
- 40 F) Tablet comprising levodopa and carbidopa
Exemple1F
LDRC from Example 1D-4 (mg)909
Carbidopa (mg)25
Sodium carboxymethylcellulose (mg)50
Maize starch (mg)25
Talc (mg)25
Magnésium stéarate (mg)41
Total (mg)1075
Levodopa content (mg)100
Carbidopa content (mg)25
Tablet diameter (mm)10
Hardness (kg/cm2)5
Levodopa drug resin complex was dry mixed with carbidopa and 5 excipients as indicated. The obtained mixture was compressed into tablets.
Examples 2-5
A) Préparation of drug resin complexes (DRCs)
2A) Préparation of ropinirole drug resin complex (RoDRC)
100 g of sodium polystyrène sulfonate cation exchange resin 15 crosslinked with divinylbenzene (125-400 mesh) was added to
500 ml of deionized deaerated water and mixed occasionally under argon for 1 h. The resulting slurry was transferred to a 250 ml glass column and washed with 200 ml of deionized deaerated water. 40 g of ropinirole hydrochloride was dissolved in 20 300 ml deionized deaerated water and passed through the column at a rate of 10 ml per min. The column was washed with 1000 ml of deionized deaerated water. The obtained drug resin complex was taken out of the column and dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt.%.
- 41 The dissolution profile of the obtained uncoated ropinirole drug resin complex (RoDRC; USP method #2, paddle rotation speed 75 rpm, 37 °C, dissolution medium 0-1 h: 0.1 N HCl, 1-10 h: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer] , pH 5.6, ionic strength 0.075) is shown in Fig. 9.
3A) Préparation of alendronate drug resin complex (A1DRC) g of cholestyramine anion exchange resin (Cl_-form, 99% < 100 μ, 56% < 50 μ) was washed with 5 x 200 ml of deaerated water. The final portion of water was decanted after 5 h.
300 ml of deaerated water and 16.25 g of alendronate sodium were added to the resin. The resulting slurry was mixed at room température for 60 min, centrifuged and the solvent decanted. This was repeated three more times until a total of 65 g of alendronate sodium had been used. The obtained drug resin complex was washed with 3 1 of water and dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt.%.
4A) Préparation of rispéridone drug resin complex (RiDRC)
100 g of polystyrène sulfonate cation exchange resin crosslinked with divinylbenzene (H+-form) was washed with 500 ml of deionized deaerated water for 30 min. The water was decanted and the resin was washed with 300 ml 96% éthanol.
100 g of rispéridone was added to 300 ml of 96% éthanol. The slurry was heated to 60°C, added to the resin and mixed for 12 h under argon. The solvent was decanted and the resin was washed with 5 x 250 ml of 96% éthanol. The last portion of éthanol was left overnight under argon. The éthanol was decanted and the obtained drug resin complex was dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt.%.
- 42 5A) Préparation of olanzapine drug resin complex (OzDRC)
100 g of polystyrène sulfonate cation exchange resin crosslinked with divinylbenzene (H+-form) was washed with 500 ml of deaerated 96% éthanol. The éthanol was decanted.
g of olanzapine was dispersed in 500 ml of deaerated 96% éthanol at 4 0 °C and added to the resin. The resulting slurry was mixed for 5 h at 40 °C under argon and then left overnight at room température. The solvent was decanted and the obtained olanzapine drug resin complex was washed with 10 x 500 ml of deaerated 96% éthanol. The obtained drug resin complex was dried first on filter paper and then in vacuum over silica to a moisture content of 5 wt.%.
B) Coating with a release modifying coating layer
2B) Coating RoDRC with a release modifying coating layer
Release modifying material | 43% | |
Drug resin complex from 2A | (g) | 65 |
Ethylcellulose (g) | 193 | |
(pre-plasticized, 25 wt% solids) | ||
Deionized water (g) | 128 | |
Coating conditions Nozzle diameter (mm) | 0.5 | |
Fluidizing air pressure (bar) | 0.25 | |
Fluidizing air température | (°C) | 70-75 |
Nozzle air pressure (bar) | 1.5 | |
Product température (°C) | 25 | |
Pump speed (g/min) | 3 | |
Yield (g) | 95 | |
Moisture content (wt.%,LOD) | 5 |
Ropinirole drug resin complex (RoDRC) was fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus analogous to Example IB.
- 43 3B) Coating A1DRC with a release modifying coating layer g of ethylcellulose was thoroughly mixed with 30 ml of 99% éthanol and 0.5 g glycerin used as a plasticizer. The obtained mixture was added to 40 g of the alendronate drug resin complex prepared in Example 3A and mixed until the mixture was homogeneous. The wet mass was forced through a 425 μ sieve and dried at 60 °C for 2 h. The obtained granulate was sieved through a 425 μ sieve.
C) Coating with a bioadhesive coating layer
Exemple | 2C | 3C | 4C | 5C |
Release modlfying material | 39% | 35% | - | - |
Bioadhesive material | 9% | 9% | 10.6% | 13% |
Drug resin complex (Example) | 2B | 3 B | 4A | 5A |
Drug resin complex (g) | 100 | 100 | 84 | 67 |
Coating dispersion | ||||
Carboxypolymethylene* (g) | 10 | 10 | 10 | 10 |
Ethanol 96 vol.% (g) | 90 | 90 | 90 | 120 |
Water (g) | 4 | 4 | 4 | 4 |
Coating conditions | ||||
Nozzle diameter (mm) | 0.5 | 0.5 | 0.5 | 0.5 |
0.2- | 0.2- | |||
Fluidizing air pressure (bar) | 0.22 | 0.22 | 0.3 | 0.25 |
Fluidizing air température (°C) | 60 | 60 | 60 | 60 |
Nozzle air pressure (bar) | 1.5 | 1.5 | 1.5 | 1.5 |
Product température (°C) | 38 | 36 | 30-38 | 23-40 |
Pump speed (g/min) | 1-3 | 3 | 3 | 3 |
Peristaltic pump hose internai | o | n | 9 | 9 |
diameter (mm) |
*High molecular weight polymer of acrylic acid crosslinked with allyl ethers and pentaerythritol
Drug resin complexes were fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus analogous to Example IC.
- 44 D) Coating with an enteric coating layer
Example | 2D | 3D | 4D | 5D |
Release modifying material | 28% | 25% | - | - |
Bioadhesive material | 6% | 6% | 7% | 9% |
Amount of enteric coating mat. | 29% | 29% | 31% | 31% |
Drug resin complex (Example) | 2C | 3C | 4C | 5C |
Drug resin complex (g) | 100 | 100 | 94 | 77 |
Coating dispersion Methacrylic acid copolymer* (g) | 35 | 35 | 35 | 35 |
Triethyl citrate (g) | 5 | 5 | 5 | 4 |
Ethanol 96 vol.% (g) | 300 | 300 | 300 | 300 |
Coating conditions Nozzle diameter (mm) | 0.5 | 0.5 | 0.5 | 0.5 |
Fluidizing air pressure (bar) | 0.3- 0.4 | 0.2 | 0.3 | 0.3 |
Fluidizing air température (°C) | 60 | 60 | 60 | 60 |
Nozzle air pressure (bar) | 1.5 | 1.2 | 1.5 | 1.5 |
Product température (°C) | 27-42 | 30-48 | 35-37 | 35-37 |
Pump speed (g/min) | 5 | 5 | 5 | 5 |
Peristaltic pump hose internai diameter (mm) Active agent content (wt.%,HPLC) | 2 9.3 | 2 22 | 2 20.3 | 2 10.8 |
*Commercially available methacrylic acid copolymer with dispersing agents formulated for easy dispersion in water
Drug resin complexes were fluidized and sprayed with coating dispersion using a Mini-Glatt coating apparatus analogous to Example ID.
Dissolution profiles of coated ropinirole drug resin complexes obtained in Example 2D before and after sieving in phosphate buffer (USP method #2, paddle rotation speed 75 rpm, 37 °C, dissolution medium 0-1 h: 500 ml 0.1 N HCl, 1-10 h: buffer mixture [500 ml 0.1 N HCl + 500 ml phosphate buffer], pH 5.6, ionic strength 0.075) are shown in Fig. 9.
Dissolution profiles in Examples 3D, 4D an
*
Amended daims (OAPI régional phase)
Claims (5)
1. Oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ion-exchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material, wherein the bioadhesive material is selected from the group consisting of optionally crosslinked homopolymers of acrylic acid or an alkylacrylic acid and optionally crosslinked copolymers of acrylic acid or methacrylic acid with a (C10-C30) alkyl acrylate.
2. Composition according to claim 1, wherein the coated particles further comprise an enteric coating layer which is placed over the bioadhesive layer and comprises at least one enteric coating material.
3. Composition according to claim 1 or 2, wherein at least a portion of the coated particles further comprises a release modifying coating layer which is placed between the complex and the bioadhesive layer and comprises at least one release modifying material.
4. Composition according to any one of daims 1 to 3, wherein the bioadhesive material has a weight average molecular weight of at least about 10,000 Daltons, preferably at least about 50,000 Daltons, more preferably at least about 100,000 Daltons, still more preferably at least about 1,000,000 Daltons, and most preferably from about 1,000,000 to about 10,000,000 Daltons.
5. Composition according to any one of claims 2 to 4, wherein the enteric coating material is selected from the group consisting of anionic cellulose dérivatives, anionic vinyl resins and anionic acrylic résina and preferably selected from the group consisting of cellulose acetate phthalate, cellulose diacetate phthalate, cellulose triacetate phthalate, methylcellulose phthalate, hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate hexahydrophthalate, hydroxypropyl methylcellulose hexahydrophthalate and pharmaceutically acceptable salts thereof, polyvinyl acetate phthalate, poly(methacrylic acid-co-ethylacrylate) and poly(methacrylic acid-co-methylmethacrylate).
6. Composition according to any one of daims 3 to 5, wherein the release modifying material is selected from delayed release materials and/or controlled release materials, in particular selected from the group consisting of 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), poly(methacrylic acid-co-methylmethacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co-vinylacetate) , silicone elastomers, shellac, zein, rosin esters and mixtures thereof and preferably selected from the group consisting of methyl cellulose, ethyl cellulose and mixtures thereof.
7. Composition according to any one of daims 1 to 6, wherein the ion exchange resin is selected from the group consisting of polymers and copolymers of acrylic acid, methacrylic acid and styrene modified with ionic groups, cellulose modified with ionic groups, dextran modified with ionic groups and silica gel modified with ionic groups, wherein said ionic groups are selected from sulfonate groups, tertiary amine groups and quaternary ammonium groups, and preferably is a crosslinked sulfonated copolymer of styrene and divinylbenzene.
Θ. Composition according to any one of daims 1 to 7, wherein the average particle size of the particles of the complex of the active agent with the ion-exchange resin is preferably about 10 to about 3000 pm, particularly about 30 to about 2000 pm, and most preferably about 50 to about 1000 pm, and/or wherein the average particle size of the coated particles is preferably about 20 to about 5000 pm, particularly about 50 to about 4 000 pm, and most preferably about 70 to about 3000 pm.
9. Composition according to any one of claims 1 to 8, wherein the coated particles hâve a spécifie gravity in the range from 1.1 to 2.0, preferably from 1.2 to 1.8, and/or wherein the coated particles exhibit a spécifie surface area in the range of from about 1 to 200 m2/g.
10.
Oral pharmaceutical composition comprising coated particles of a complex of at least one active agent with an ionexchange resin, wherein said particles are coated with a bioadhesive coating layer comprising at least one bioadhesive material, wherein the active agent is selected from the group consisting of ondansetron, tropisetron, dolasetron, palonosetron, sulfasalazine, doxazosin, atenolol, hydrochlorothiazide, carvedilol, amlodipine, nifedipine, verapamil, diltiazem, enalapril, granisetron, aprepitant, bisoprolol, felodipine, lisinopril, ramipril, quinapril, cilazapril, fosinopril, trandolapril, losartan, valsartan, simvastatin, lovastatin, fluvastatin, atorvastatin, rosuvastatin, gemfibrozil, choiestyramine, oxybutynin, propiverine, trospium, darifenacin, sildenafil, tamsulosin, finasteride, cyclophosphamide, fenofibrate, solifenacin, phentolamine, chlorambucil,
- 4Θ melphalan, busulfan, mercaptopurine, cytarabine, Vinblastine, paclitaxel, daunorubicin, mycin, temozolomide, cladribine, gemcitabine, vindesine, D, lomustin, thioguanine, 5-fluorouracil, vincristine, docetaxel, actinomycin epirubicin, idarubicin, mitomycin, cisplatin, carboplatin, methotrexate, fludarabine, capecitabine, etoposide, doxorubicin, mitoxantrone, bleooxaliplatin, procarbazine, rituximab, trastuzumab, cetuximab, bevacizumab, sunitinib, sorafenib, dasatinib, lapatinib, nilotinib, temsirolimus, amsacrine, asparaginase, hydroxyurea, estramustine, topotecan, irinotecan, imatinib, bortezomib, erlotinib, anagrelide, megestrol, tamoxifen, flutamide, nilutamide, bicalutamide, anastrazole, letrozole, exemestane, mycophenolate mofetil, sirolimus, everolimus, cyclosporine, tacrolimus, azathioprine, etidronic acid, clodronic acid, pamidronic acid, alendronic acid, tiludronic acid, ibandronic acid, risedronic acid, zoledronic acid, morphine, hydromorphone, oxycodone, pethidine, fentanyl, pentazocine, buprénorphine, tramadol, acetylsalicylic acid, metamizole, paracétamol, sumatriptan, methylphenobarbital, phénobarbital, primidone, phenytoin, ethosuximide, clonazepam, carbamazepine, oxcarbazepine, valproic acid, vigabatrin, progabide, tiagabine, sultiame, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, pheneturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, beclamide, trihexyphenidyl, biperiden, levodopa, carbidopa, benserazide, entacapone, amantadine, bromocriptine, pergolide, dihydroergocryptine, ropinirole, pramipexole, cabergoline, apomorphine, piribedil, rotigotine, selegiline, rasagiline, tolcapone, entacapone, budipine, levomepromazine, chlorpromazine, promazine, fluphenazine, perazine, haloperidol, sertindole, ziprazïdone, zuclopenthixol, clozapine, olanzapine, quetiapine, loxapine, sulpiride, amisulpride, lithium, prothipendyl, rispéridone, clotiapine, mosapramine, zotepine, aripiprazole, paliperidone, diazepam,
- 49 alprazolam, meprobamate, flurazepam, nitrazepam, midazolam, zolpidem, clomipramine, amitriptyline, maprotiline, fluoxetine, citalopram, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidon, escitalopram, mirtazapine, venlafaxine, methylphenidate, modafinil, neostigmine, pyridostigmine, disulfiram, naloxone, methadone, riluzole, abacavir, aciclovir, atropine, buspirone, caffeine, captopril, chloroquine, chlorphenamine, desipramine, diphenhydramine, disopyramide, doxepin, doxycycline, ephedrine, ergonovine, ethambutol, glucose, imipramine, ketorolac, ketoprofen, labetalol, levofloxacin, metoprolol, metronidazole, minocycline, misoprostol, phenazone, phenylalanine, prednisolone, primaquine, propranolol, quinidine, rosiglitazone, salicylic acid, theophylline, zidovudine, codeine, dextromethorphan, hydrocodone, hydralazine, metaproterenol, phenylpropanolamine, pseudoephedrine and mixtures thereof.
11. Composition according to claim 10, wherein the active agent is selected from the group consisting of levodopa, carbidopa, benserazide, entacapone and mixtures thereof.
12. Composition according to claim 10, wherein the active agent is selected from the group consisting of alendronate, olanzapine, rispéridone and ropinirole.
13. Composition according to any one of daims 1 to 12 comprising at least two groups of coated particles comprising different active agents.
14. Composition according to any one of daims 1 to 13 further comprising an active agent, or a pharmaceutically acceptable sait or solvaté thereof, outside the coated particles.
Λ
preferably 15 to 25 wt.% of said ion-exchange resin;
(c) 0 to 50 wt.%, particularly 1 to 50 wt.%, preferably 10 to 40 wt.% and more preferably 15 to 30 wt.% of said release modifying material;
(d) 0.5 to 30 wt.%, particularly 1 to 10 wt.% and preferably 2 to Θ wt.% of said bioadhesive material; and (e) 0 to 80 wt.%, particularly 1 to 80 wt.%, preferably 10 to 60 wt.% and more preferably 3 0 to 50 wt.% of said enteric coating material;
based on the total weight of the coated particles.
17. Process for preparing a composition according to any one of claims 1 to 16, said process comprising the steps of:
(i) contacting an active agent with an ion-exchange resin to obtain an active agent/ion exchange resin complex;
(ii) optionally coating the complex of step (i) with a coating layer comprising a release modifying material;
(iii) coating the complex of step (i) or the coated complex of step (ii) with a coating layer comprising a bioadhesive material; and (iv) optionally coating the coated complex of step (iii)
5 with a coating layer comprising an enteric coating material.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HR11161398.0 | 2011-04-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA16606A true OA16606A (en) | 2015-11-20 |
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