EP0862437A1 - Pharmaceutical formulations - Google Patents
Pharmaceutical formulationsInfo
- Publication number
- EP0862437A1 EP0862437A1 EP96938215A EP96938215A EP0862437A1 EP 0862437 A1 EP0862437 A1 EP 0862437A1 EP 96938215 A EP96938215 A EP 96938215A EP 96938215 A EP96938215 A EP 96938215A EP 0862437 A1 EP0862437 A1 EP 0862437A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formulation
- molecular weight
- polyethylene oxide
- range
- low molecular
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 68
- 238000009472 formulation Methods 0.000 claims abstract description 62
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 29
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 29
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 28
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 229920000642 polymer Polymers 0.000 claims abstract description 20
- 238000013270 controlled release Methods 0.000 claims abstract description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 15
- 229960001389 doxazosin Drugs 0.000 claims description 10
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 claims description 10
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 10
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 10
- 239000012736 aqueous medium Substances 0.000 claims description 9
- 239000011159 matrix material Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 239000002702 enteric coating Substances 0.000 claims description 3
- 238000009505 enteric coating Methods 0.000 claims description 3
- 230000003628 erosive effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims 3
- 239000001913 cellulose Substances 0.000 claims 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 1
- 229940125758 compound 15 Drugs 0.000 claims 1
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 7
- 238000010874 in vitro model Methods 0.000 abstract description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 16
- 239000004615 ingredient Substances 0.000 description 14
- 229960000220 doxazosin mesylate Drugs 0.000 description 13
- VJECBOKJABCYMF-UHFFFAOYSA-N doxazosin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 VJECBOKJABCYMF-UHFFFAOYSA-N 0.000 description 13
- 235000019359 magnesium stearate Nutrition 0.000 description 12
- 229920003091 Methocel™ Polymers 0.000 description 11
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 8
- 235000019700 dicalcium phosphate Nutrition 0.000 description 8
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 8
- 238000013268 sustained release Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000012730 sustained-release form Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 4
- 229960004884 fluconazole Drugs 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 2
- 229960002677 darifenacin Drugs 0.000 description 2
- 238000009506 drug dissolution testing Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 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 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- BFCDFTHTSVTWOG-YLJYHZDGSA-N (1S,2R)-2-(octylamino)-1-[4-(propan-2-ylthio)phenyl]-1-propanol Chemical compound CCCCCCCCN[C@H](C)[C@@H](O)C1=CC=C(SC(C)C)C=C1 BFCDFTHTSVTWOG-YLJYHZDGSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920002602 Polyethylene Oxide 200000 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-UHFFFAOYSA-N alpha-noscapine Natural products CN1CCC2=CC=3OCOC=3C(OC)=C2C1C1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-UHFFFAOYSA-N 0.000 description 1
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 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 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 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 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 description 1
- 229960002472 eletriptan Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229960003580 felodipine Drugs 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 1
- 229960002867 griseofulvin Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 229960003967 suloctidil Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
Definitions
- This invention relates to controlled-release oral pharmaceutical formulations
- Controlled-release oral pharmaceutical formulations are known Their purpose is to modify the rate of drug release, for example to produce a constant rate of release of a drug into the gastrointestinal tract of a patient, or to delay the release of a drug into the gastrointestinal tract of a patient (see 'Sustained and Controlled Release Drug Delivery Systems', pp 3-6, edited by J R Robinson, published by Marcel Dekker Inc)
- US Patent N° 4,765,989 discloses an osmotic delivery device for delivering inter alia nifedipi ⁇ e or doxazosin It has a perforated semipermeable wall enclosing a drug composition which includes an osmopolymer, and a pusher composition containing a second osmopolymer
- a drug composition which includes an osmopolymer
- a pusher composition containing a second osmopolymer The performance of this prior art device is satisfactory, but it has the disadvantage that it is very complicated, leading to high manufacturing costs
- UK Patent Application 2,123,291 discloses a sustained release formulation of suloctidil which is a two-part tablet a first part is a prompt-release portion and a second part is a slow-release portion, which must contain a surface-active agent to promote bio-erosion
- US Patent N° 5,393,765 discloses an erodibie pharmaceutical composition providing a zero order controlled release profile, comprising low viscosity hydroxypropylmethyl cellulose
- a controlled-release pharmaceutical formulation for oral administration consisting essentially of an active drug compound low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose tabletting excipients and optionally one or more enteric polymers
- formulations of the present invention may also be administered buccally (i e placed behind the top lip and allowed to dissolve) and the term includes such formulations "Consisting essentially of means that at least 95% by weight of the formulation is made up of the listed components. At least 99% by weight of uncoated formulations, and the cores of coated formulations, are preferably made up of the listed components.
- Polymerized ethylene oxide having a number average molecular weight less than 100,000 is sometimes referred to as "polyethylene glycol".
- polyethylene glycol Polyethylene glycol
- low molecular weight polyethylene oxide is used to refer to polymerized ethylene oxide in the number average molecular weight range of interest, namely 15,000 to 750,000.
- Tabletting excipients making up formulations according to the invention may be conven ⁇ tional tabletting excipients, for example dibasic calcium phosphate, lactose and magnesium stearate.
- the first class is weakly basic compounds. Examples of this class include dipyridamole, noscapine, papaverine, doxazosin, sildenafil and prazosin. Doxazosin and its pharmaceutically acceptable salts are of particular interest.
- the second class are compounds having high solubility in aqueous media.
- this class include salbutamol, metoprolol, propanolol, aminophylline, isosorbide mono- and dinitrate, glyceryl trinitrate, verapamil, captopril, diltiazem, morphine, chlorpheni- ramine, promethazine, eletriptan, darifenacin and fluconazole.
- the third class are compounds having low solubility in aqueous media.
- Examples of this class include nifedipine, griseofulvin, carbamazepine, felodipine, nimodipine and megestrol.
- solubility in aqueous media and “low solubility in aqueous media” will be understood by those skilled in the art. However, the former may be defined as a solubility
- Formulations according to the invention have the advantage that they produce a constant rate of release of drugs that are weakly basic and/or have a high solubility in aqueous media in in vitro models of the gastrointestinal tract, and so are expected to produce a constant rate of release of the drug in the gastrointestinal tract of a patient.
- the formulations of the invention have the advantage that they produce a delayed or pulsed release of the drug.
- the formulations are very simple and so can be manufactured at a compara ⁇ tively low cost.
- the hydroxypropylmethyl cellulose has a number average molecular weight in the range 80,000-250,000.
- the hydroxypropylmethyl cellulose has a degree of methyl substitution in the range 19-30 %.
- the hydroxypropylmethyl cellulose has a degree of hydroxy substitution in the range 4-12 %.
- a number of hydroxypropylme- thyl cellulose polymers are available commercially under the brand name Methocel®, and some of those suitable for use in formulations according to the invention are given in the table below:
- Methocel® K4M has characteristics of particular interest.
- the low molecular weight polyethylene oxide has a number average molecular weight in the range 20,000 to 500,000, more preferably 100,000-300,000.
- Polyethylene oxide with a number average molecular weight above 100,000 is a powder, which makes it easier to handle than lower molecular weight polyethylene oxide, which has a lower melting point.
- polyethylene oxide with a number average molecular weight of 6000 has a melting point of 60-63°C It will be apparent to those skilled in the art that the polyethylene oxide may consist of molecules of different chain lengths, but that the average chain length gives a molecular weight in the range stated. The same applies to the hydroxypropylmethyl cellulose.
- Formulations according to the invention may contain an enteric polymer admixed with the other components of the formulation.
- formulations according to the invention are preferably provided with a coating of an enteric polymer.
- Enteric polymers that may be mentioned are phthalate derivatives (including cellulose acetate phthalate, polyvinyiacetate phthalate and hydroxypropylmethyl cellulose phthalate), polyacrylic acid derivatives (including methacrylic acid copolymer), and vinyl acetate and crotonic acid copolymers. Methacrylic acid copolymer is of particular interest.
- the formulation contains up to 50% by weight of active drug compound, for example 1-20%.
- formulations of the invention contain 5-30% by weight of low molecular weight polyethylene oxide, for example 8-10%.
- the formulations of the invention contain 10-60% by weight of hydroxypropyl- methyl cellulose, for example 25-35%.
- Formulations having enteric polymer admixed with the other components of the formula ⁇ tion preferably have 10-40% by weight of admixed enteric polymer, for example 25-35%.
- the mass ratio of low molecular weight polyethylene oxide:hydroxypropylmethyl cellulose is in the range 2:1- 1 :5.
- the mass ratio of (low molecular weight polyethylene ox- ide+hydroxypropylmethyl cellulose):admixed enteric polymer is in the range 1 :2-6: 1 , more preferably 1 :2-2:1.
- the enteric coating (where present) makes up 2-15% by weight of the formulation, more preferably 5-10% by weight of the formulation.
- the use of low molecular weight polyethylene oxide in an oral controlled-release pharmaceutical formulation having a hydroxypropylmethyl cellulose matrix, to enhance the erosion of the matrix after a predetermined period of time following administration of the formulation to a patient
- the predetermined period of time is 6 hours In this way, a constant rate of drug release can be achieved in the gastrointestinal tract of a patient despite the varying conditions which exist along its length
- a process for the production of a pharmaceutical formulation as defined in claim 1 which comprises mixing an active drug compound, low molecular weight polyethylene oxide, hydroxypropylmethyl cellulose, tabletting excipients, and optionally one or more enteric polymers, followed by pressing into tablets
- formulations according to the present invention may be measured in a model of the gastrointestinal tract such as Apparatus 1 of USP 22, page
- Figure 1 shows the percentage of drug compound released v time from formulations according to the invention [as prepared in Examples 1 (a) and 1 (b)] in comparison with a control [as prepared in Example 6] using simple dissolution testing
- Figure 2 shows the percentage of drug compound released v time from a formulation according to the invention [as prepared in Example 2(a)] using dissolution testing with first an acidic and then a neutral dissolution medium
- Methacrylic acid copolymer type C a 6 500
- Example 5 Sustained release formulations of fluconazole (suitable for buccal administration.
- Example 1 The tablets of Examples 1 (a), 1 (b) and 6 were dissolved using Apparatus 1 of USP 22, page 1578, Method 1 (baskets)
- the dissolution fluid was 900ml of water at 37°C
- the rotation speed of the baskets was 100 rpm
- the drug compound released was detected by UV spectroscopy at a wavelength of 246 nm
- the percentage of drug compound released v time for each tablet type is shown in Figure 1
- Example 2(a) The tablets of Example 2(a) were dissolved using Apparatus 1 of USP 22, page 1578, Method 1 (baskets)
- the rotation speed of the baskets was 200 rpm, and the drug compound released was detected by UV spectros- copy at a wavelength of 246 nm
- the percentage of drug compound released v time is shown in Figure 2
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9523752.5A GB9523752D0 (en) | 1995-11-21 | 1995-11-21 | Pharmaceutical formulations |
| GB9523752 | 1995-11-21 | ||
| PCT/EP1996/005020 WO1997018814A1 (en) | 1995-11-21 | 1996-11-11 | Pharmaceutical formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0862437A1 true EP0862437A1 (en) | 1998-09-09 |
Family
ID=10784188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP96938215A Withdrawn EP0862437A1 (en) | 1995-11-21 | 1996-11-11 | Pharmaceutical formulations |
Country Status (29)
| Country | Link |
|---|---|
| EP (1) | EP0862437A1 (cs) |
| JP (1) | JPH10513481A (cs) |
| KR (1) | KR19990071505A (cs) |
| CN (1) | CN1215993A (cs) |
| AP (1) | AP718A (cs) |
| AR (1) | AR004335A1 (cs) |
| AU (1) | AU709560B2 (cs) |
| BG (1) | BG102438A (cs) |
| BR (1) | BR9611626A (cs) |
| CA (1) | CA2232715A1 (cs) |
| CO (1) | CO4480020A1 (cs) |
| CZ (1) | CZ155498A3 (cs) |
| GB (1) | GB9523752D0 (cs) |
| HR (1) | HRP960554A2 (cs) |
| HU (1) | HUP9903734A3 (cs) |
| IS (1) | IS4706A (cs) |
| MA (1) | MA26410A1 (cs) |
| MX (1) | MX9804008A (cs) |
| NO (1) | NO982302L (cs) |
| NZ (1) | NZ322053A (cs) |
| OA (1) | OA10687A (cs) |
| PE (1) | PE22898A1 (cs) |
| PL (1) | PL326981A1 (cs) |
| SK (1) | SK63098A3 (cs) |
| TN (1) | TNSN96141A1 (cs) |
| TR (1) | TR199800902T2 (cs) |
| WO (1) | WO1997018814A1 (cs) |
| YU (1) | YU62096A (cs) |
| ZA (1) | ZA969722B (cs) |
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| GT199900061A (es) * | 1998-05-15 | 2000-10-14 | Pfizer | Formulaciones farmaceuticas. |
| EP0987020A1 (en) * | 1998-09-04 | 2000-03-22 | Pharma Pass LLC | Metoprolol composition and processes for manufacturing the same |
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| UA67802C2 (uk) * | 1998-10-23 | 2004-07-15 | Пфайзер Рісьоч Енд Дівелепмент Компані, Н.В./С.А. | Фармацевтична композиція з контрольованим вивільненням інгібітора цгмф фде-5 (варіанти), спосіб її одержання та спосіб лікування еректильної дисфункції |
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-
1995
- 1995-11-21 GB GBGB9523752.5A patent/GB9523752D0/en active Pending
-
1996
- 1996-11-11 HU HU9903734A patent/HUP9903734A3/hu unknown
- 1996-11-11 CN CN96198486A patent/CN1215993A/zh active Pending
- 1996-11-11 TR TR1998/00902T patent/TR199800902T2/xx unknown
- 1996-11-11 KR KR1019980703777A patent/KR19990071505A/ko not_active Ceased
- 1996-11-11 SK SK630-98A patent/SK63098A3/sk unknown
- 1996-11-11 BR BR9611626A patent/BR9611626A/pt not_active Application Discontinuation
- 1996-11-11 EP EP96938215A patent/EP0862437A1/en not_active Withdrawn
- 1996-11-11 NZ NZ322053A patent/NZ322053A/xx unknown
- 1996-11-11 WO PCT/EP1996/005020 patent/WO1997018814A1/en not_active Application Discontinuation
- 1996-11-11 CA CA002232715A patent/CA2232715A1/en not_active Abandoned
- 1996-11-11 CZ CZ981554A patent/CZ155498A3/cs unknown
- 1996-11-11 AU AU75721/96A patent/AU709560B2/en not_active Ceased
- 1996-11-11 JP JP9519364A patent/JPH10513481A/ja active Pending
- 1996-11-11 PL PL96326981A patent/PL326981A1/xx unknown
- 1996-11-20 PE PE1996000831A patent/PE22898A1/es not_active Application Discontinuation
- 1996-11-20 TN TNTNSN96141A patent/TNSN96141A1/fr unknown
- 1996-11-20 AR ARP960105252A patent/AR004335A1/es unknown
- 1996-11-20 ZA ZA9609722A patent/ZA969722B/xx unknown
- 1996-11-20 MA MA24397A patent/MA26410A1/fr unknown
- 1996-11-20 YU YU62096A patent/YU62096A/sh unknown
- 1996-11-21 AP APAP/P/1996/000883A patent/AP718A/en active
- 1996-11-21 HR HR9523752.5A patent/HRP960554A2/hr not_active Application Discontinuation
- 1996-11-21 CO CO96061449A patent/CO4480020A1/es unknown
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1998
- 1998-03-31 IS IS4706A patent/IS4706A/is unknown
- 1998-05-08 BG BG102438A patent/BG102438A/xx unknown
- 1998-05-19 OA OA9800058A patent/OA10687A/en unknown
- 1998-05-20 NO NO982302A patent/NO982302L/no not_active Application Discontinuation
- 1998-05-20 MX MX9804008A patent/MX9804008A/es unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| PL326981A1 (en) | 1998-11-09 |
| PE22898A1 (es) | 1998-05-07 |
| MX9804008A (es) | 1998-09-30 |
| ZA969722B (en) | 1998-05-20 |
| TR199800902T2 (xx) | 1998-09-21 |
| MA26410A1 (fr) | 2004-12-20 |
| AP718A (en) | 1999-01-06 |
| NO982302L (no) | 1998-07-17 |
| HRP960554A2 (en) | 1998-02-28 |
| WO1997018814A1 (en) | 1997-05-29 |
| OA10687A (en) | 2002-11-27 |
| TNSN96141A1 (fr) | 2005-03-15 |
| CO4480020A1 (es) | 1997-07-09 |
| AU7572196A (en) | 1997-06-11 |
| BR9611626A (pt) | 1999-06-01 |
| KR19990071505A (ko) | 1999-09-27 |
| YU62096A (sh) | 1999-03-04 |
| BG102438A (en) | 1999-01-29 |
| HUP9903734A2 (hu) | 2000-03-28 |
| CN1215993A (zh) | 1999-05-05 |
| HUP9903734A3 (en) | 2000-04-28 |
| AP9600883A0 (en) | 1997-01-31 |
| CA2232715A1 (en) | 1997-05-29 |
| SK63098A3 (en) | 1999-05-07 |
| NO982302D0 (no) | 1998-05-20 |
| GB9523752D0 (en) | 1996-01-24 |
| AR004335A1 (es) | 1998-11-04 |
| JPH10513481A (ja) | 1998-12-22 |
| CZ155498A3 (cs) | 1999-03-17 |
| NZ322053A (en) | 1999-11-29 |
| AU709560B2 (en) | 1999-09-02 |
| IS4706A (is) | 1998-03-31 |
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