CA2617280A1 - Pharmaceutical form with sustained ph-independent active ingredient release for active ingredients having strong ph-dependent solubility - Google Patents
Pharmaceutical form with sustained ph-independent active ingredient release for active ingredients having strong ph-dependent solubility Download PDFInfo
- Publication number
- CA2617280A1 CA2617280A1 CA002617280A CA2617280A CA2617280A1 CA 2617280 A1 CA2617280 A1 CA 2617280A1 CA 002617280 A CA002617280 A CA 002617280A CA 2617280 A CA2617280 A CA 2617280A CA 2617280 A1 CA2617280 A1 CA 2617280A1
- Authority
- CA
- Canada
- Prior art keywords
- water
- solid pharmaceutical
- pharmaceutical formulation
- formulation according
- layer
- 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.)
- Abandoned
Links
- 239000004480 active ingredient Substances 0.000 title claims abstract description 80
- 230000001419 dependent effect Effects 0.000 title claims abstract description 30
- 230000002459 sustained effect Effects 0.000 title claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 40
- 239000007787 solid Substances 0.000 claims abstract description 38
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 33
- 229920003176 water-insoluble polymer Polymers 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims description 70
- 238000009472 formulation Methods 0.000 claims description 50
- 239000008188 pellet Substances 0.000 claims description 30
- 239000000126 substance Substances 0.000 claims description 30
- 229920000642 polymer Polymers 0.000 claims description 17
- 229920001577 copolymer Polymers 0.000 claims description 16
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- 239000011159 matrix material Substances 0.000 claims description 11
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 10
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Chemical compound [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 claims description 8
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 8
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 8
- 239000011118 polyvinyl acetate Substances 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 239000001103 potassium chloride Substances 0.000 claims description 5
- 235000011164 potassium chloride Nutrition 0.000 claims description 5
- 239000004254 Ammonium phosphate Substances 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 4
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical class CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 4
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 4
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 4
- 239000001166 ammonium sulphate Substances 0.000 claims description 4
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 4
- 229920002301 cellulose acetate Polymers 0.000 claims description 4
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 4
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 claims description 4
- 229910001386 lithium phosphate Inorganic materials 0.000 claims description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 4
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 4
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 4
- 239000001120 potassium sulphate Substances 0.000 claims description 4
- 235000011151 potassium sulphates Nutrition 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 4
- 235000011008 sodium phosphates Nutrition 0.000 claims description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 4
- 235000011152 sodium sulphate Nutrition 0.000 claims description 4
- 229920001897 terpolymer Polymers 0.000 claims description 4
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 claims description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920013820 alkyl cellulose Polymers 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- SSONCJTVDRSLNK-UHFFFAOYSA-N 2-methylprop-2-enoic acid;hydrochloride Chemical compound Cl.CC(=C)C(O)=O SSONCJTVDRSLNK-UHFFFAOYSA-N 0.000 claims description 2
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical compound OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- 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 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229920000084 Gum arabic Polymers 0.000 claims description 2
- 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 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 241000978776 Senegalia senegal Species 0.000 claims description 2
- 229920001800 Shellac Polymers 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 235000010489 acacia gum Nutrition 0.000 claims description 2
- 239000000205 acacia gum Substances 0.000 claims description 2
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- POKMOYDXOVENEF-UHFFFAOYSA-N butanedioic acid;ethenyl acetate Chemical compound CC(=O)OC=C.OC(=O)CCC(O)=O POKMOYDXOVENEF-UHFFFAOYSA-N 0.000 claims description 2
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- LUJQXGBDWAGQHS-UHFFFAOYSA-N ethenyl acetate;phthalic acid Chemical class CC(=O)OC=C.OC(=O)C1=CC=CC=C1C(O)=O LUJQXGBDWAGQHS-UHFFFAOYSA-N 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- IWVKTOUOPHGZRX-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.COC(=O)C(C)=C IWVKTOUOPHGZRX-UHFFFAOYSA-N 0.000 claims description 2
- NZEXUPLJXSDMCK-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;methyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound COC(=O)C=C.CC(=C)C(O)=O.COC(=O)C(C)=C NZEXUPLJXSDMCK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005498 phthalate group Chemical class 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 claims description 2
- 239000004208 shellac Substances 0.000 claims description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 2
- 229940113147 shellac Drugs 0.000 claims description 2
- 235000013874 shellac Nutrition 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000230 xanthan gum Substances 0.000 claims description 2
- 235000010493 xanthan gum Nutrition 0.000 claims description 2
- 229920001285 xanthan gum Polymers 0.000 claims description 2
- 229940082509 xanthan gum Drugs 0.000 claims description 2
- 239000002609 medium Substances 0.000 description 15
- 239000012528 membrane Substances 0.000 description 14
- 230000003204 osmotic effect Effects 0.000 description 14
- 239000003826 tablet Substances 0.000 description 12
- 239000011248 coating agent Substances 0.000 description 9
- 238000000576 coating method Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000013543 active substance Substances 0.000 description 8
- 238000009498 subcoating Methods 0.000 description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 7
- 239000008108 microcrystalline cellulose Substances 0.000 description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 7
- 239000011148 porous material Substances 0.000 description 7
- 239000012907 medicinal substance Substances 0.000 description 6
- 239000012736 aqueous medium Substances 0.000 description 5
- 239000012982 microporous membrane Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 238000007792 addition Methods 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- -1 Cl-PVP) Chemical compound 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- XQYASZNUFDVMFH-CQSZACIVSA-N [5-chloro-2-[2-[(2r)-4-[(4-fluorophenyl)methyl]-2-methylpiperazin-1-yl]-2-oxoethoxy]phenyl]urea Chemical group C([C@H](N(CC1)C(=O)COC=2C(=CC(Cl)=CC=2)NC(N)=O)C)N1CC1=CC=C(F)C=C1 XQYASZNUFDVMFH-CQSZACIVSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002357 osmotic agent Substances 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 241000206607 Porphyra umbilicalis Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002778 chronopharmacological effect Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002706 hydrostatic effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 229920005597 polymer membrane Polymers 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
Solid pharmaceutical formulation for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers, at least one layer of one or more pH-dependently water-soluble polymers and an active ingredient-containing core, having strong pH-dependent water solubility and comprises at least one osmagent.
Description
PHARMACEUTICAL FORM WITH SUSTAINED pH-INDEPENDENT
ACTIVE INGREDIENT RELEASE FOR ACTIVE INGREDIENTS HAVING
STRONG pH-DEPENDENT SOLUBILITY
Technical field The invention relates to a solid pharmaceutical formulation for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers, at least one layer of one or more pH-dependent water-soluble polymers and an active ingredient-containing core, where the core comprises an active ingredient having strong pH-dependent water solubility and at least one osmotically active ingredient.
Active ingredients having strong pH-dependent water solubility are for example substances which have very poor solubility at basic pH values, normally having a solubility in water of less than 0.1 mg/ml, whereas the solubility at acidic pH values (pH < 4) extends up to values of 1 mg/ml or higher.
Generally pH-dependent water-soluble active ingredients can also be defined as substances having a difference of at least 10-fold in the water solubility at acidic and basic pH values.
One example of an active ingredient having strong pH-dependent solubility in water is (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluoro-benzyl)piperazine or a salt thereof.
(2R) -1- ( (4-chloro-2- (ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine is called piperazineurea hereinafter and has the following structure:
GHa F
N
. ~~~~ 1~.: ~=.,~~=~:
Cl" NH
ii=II~.NN
pz (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-mathvl -a- /a-flõu~v"'~v~i-.u iic.yc~"".,'t/~1 ~_...-1r1CLd"G--- --=
l... ~. 1i1C and its SaltS are prepared by the method described in Example 2 in WO 98/56771.
Salts thereof are, for example, the hydrochloride, dihydrogen phosphate, hydrogen sulphate, sulphate, mesylate, ethylsulphonate, malate, fumarate and tartrate.
The following invention further relates to a matrix pellet for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers in which the pore-forming substances are present and are dissolved out after contact with the aqueous medium and thus form a microporous membrane, and comprising at least one layer of one or more pH-dependently water-soluble polymers, and an active ingredient-containing core, where the core comprises piperazineurea and at least one water-soluble ionic substance from the group of magnesium chloride, magnesium sulphate, lithium chloride, sodium chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium chloride, ammonium sulphate, ammonium phosphate as osmager.t.
Further solid pharmaceutical formulations within the meaning of the invention are single-unit systems such as, for example, tablets and multiparticulate systems.
Multiparticulate systems may be for example granular particles, pellets or mini tablets. These may be packed into hard or soft gelatin capsules, and compressed to tablets. The original forrri-ulation usually disintegrates into many subunits in the stomach. The minidepots then gradually pass from the stomach into the intestine. The minidepots are moreover normally able to pass through the pylorus when the sphincter is closed.
Sustained release formulations are medicaments which can be administered orally anu have a longer-lasting effect of the medicament. In these cases, the active pharmaceutical ingredient is released slowly.
Prior art Various pharmaceutical formulations for controlled active ingredient release are present in the literature.
An elementary osmotic pump (EOP) for example, are tablets which consist of an osmotically active tablet core which is coated with a semipermeable membrane which comprises a release orifice.
The tablet core may comprise an osmotically active medicinal substance or, in the case of a medicinal substance of low osmotic activity, osmotically active additives, also generally defined as osmagents. Water flowing through the semipermeable membrane (SPM) into the pharmaceutical form generates a hydrostatic pressure which forces the dissolved medicinal substance through the release aperture.
The object of an EOP is controlled active ingredient release, achieving 0 order release kinetics. Thus, the amount of medicinal substance released from the pharmaceutical form per unit time remains the same.
A precondition for an EOP is a moderately water-soluble active ingredient.
ACTIVE INGREDIENT RELEASE FOR ACTIVE INGREDIENTS HAVING
STRONG pH-DEPENDENT SOLUBILITY
Technical field The invention relates to a solid pharmaceutical formulation for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers, at least one layer of one or more pH-dependent water-soluble polymers and an active ingredient-containing core, where the core comprises an active ingredient having strong pH-dependent water solubility and at least one osmotically active ingredient.
Active ingredients having strong pH-dependent water solubility are for example substances which have very poor solubility at basic pH values, normally having a solubility in water of less than 0.1 mg/ml, whereas the solubility at acidic pH values (pH < 4) extends up to values of 1 mg/ml or higher.
Generally pH-dependent water-soluble active ingredients can also be defined as substances having a difference of at least 10-fold in the water solubility at acidic and basic pH values.
One example of an active ingredient having strong pH-dependent solubility in water is (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluoro-benzyl)piperazine or a salt thereof.
(2R) -1- ( (4-chloro-2- (ureido)phenoxy)methyl)carbonyl-2-methyl-4-(4-fluorobenzyl)piperazine is called piperazineurea hereinafter and has the following structure:
GHa F
N
. ~~~~ 1~.: ~=.,~~=~:
Cl" NH
ii=II~.NN
pz (2R)-1-((4-chloro-2-(ureido)phenoxy)methyl)carbonyl-2-mathvl -a- /a-flõu~v"'~v~i-.u iic.yc~"".,'t/~1 ~_...-1r1CLd"G--- --=
l... ~. 1i1C and its SaltS are prepared by the method described in Example 2 in WO 98/56771.
Salts thereof are, for example, the hydrochloride, dihydrogen phosphate, hydrogen sulphate, sulphate, mesylate, ethylsulphonate, malate, fumarate and tartrate.
The following invention further relates to a matrix pellet for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers in which the pore-forming substances are present and are dissolved out after contact with the aqueous medium and thus form a microporous membrane, and comprising at least one layer of one or more pH-dependently water-soluble polymers, and an active ingredient-containing core, where the core comprises piperazineurea and at least one water-soluble ionic substance from the group of magnesium chloride, magnesium sulphate, lithium chloride, sodium chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium chloride, ammonium sulphate, ammonium phosphate as osmager.t.
Further solid pharmaceutical formulations within the meaning of the invention are single-unit systems such as, for example, tablets and multiparticulate systems.
Multiparticulate systems may be for example granular particles, pellets or mini tablets. These may be packed into hard or soft gelatin capsules, and compressed to tablets. The original forrri-ulation usually disintegrates into many subunits in the stomach. The minidepots then gradually pass from the stomach into the intestine. The minidepots are moreover normally able to pass through the pylorus when the sphincter is closed.
Sustained release formulations are medicaments which can be administered orally anu have a longer-lasting effect of the medicament. In these cases, the active pharmaceutical ingredient is released slowly.
Prior art Various pharmaceutical formulations for controlled active ingredient release are present in the literature.
An elementary osmotic pump (EOP) for example, are tablets which consist of an osmotically active tablet core which is coated with a semipermeable membrane which comprises a release orifice.
The tablet core may comprise an osmotically active medicinal substance or, in the case of a medicinal substance of low osmotic activity, osmotically active additives, also generally defined as osmagents. Water flowing through the semipermeable membrane (SPM) into the pharmaceutical form generates a hydrostatic pressure which forces the dissolved medicinal substance through the release aperture.
The object of an EOP is controlled active ingredient release, achieving 0 order release kinetics. Thus, the amount of medicinal substance released from the pharmaceutical form per unit time remains the same.
A precondition for an EOP is a moderately water-soluble active ingredient.
Push and pull osmotic pumps (PPOPs) have been established also to allow controlled release of slightly soluble medicinal substances.
These comprise multichamber tablet systems whose core comprises an osmotic active ingredient compartment and a swellable osmotically active polymer, with the two compartments being separated by an elastic diaphragm.
The entire tablet core is in turn enveloped by an SPM
which comprises a release orifice on the active ingredient containing side.
Water penetrates into both compartments, whereupon the polymer swells and thus forces the diaphragm into the active ingredient compartment. The active ingredient is then delivered through the release aperture. The aim in this case too is to create plasma levels which remain the same owing to the 0 order active ingredient release.
Hence, systems which operate osmotically, such as the elementary osmotic pump (EOP) and push and pull osmotic pumps (PPOP) release at least moderately water-soluble active ingredients from tablets which consist of a semipermeable membrane around an osmotically active core which comprises at least one substance having an osmotic effect (osmagent) and, in the case of the PPOP, an expanding polymer push compartment.
Since semipermeable membranes are permeable only by the medium but not by the active ingredient, the active constituent is released through at least one orifice in the semipermeable membrane.
The essential aim of osmotic pi?mps as known in the state of the art is 0 order active ingredient release.
In contrast to EOP and PPOP, pharmaceutical forms without semipermeable membranes have also been described, for example: Controlled Porosity Osmotic Pumps (CPOP).
CPOPs were also developed in order to replace the elaborate manufacture of the above-described systems in which release orifices must be bored by drilling machines or lasers.
These CPOP formulations have a water-insoluble polymer membrane into which water-soluble ingredients are incorporated and, after contact with the aqueous medium, are dissolved out and thus form a microporous membrane which is now permeable by medium and active ingredient.
In these systems, in detail the osmotic tablet core is enveloped by an insoluble polymer membrane into which water-soluble substances have been incorporated. After the pharmaceutical form is introduced into the medium, these water-soluble substances are dissolved out.
This results in pores through which the active ingredient release takes place. These systems also comprise tablets which show controlled release.
In these cases, the active ingredient release depends in particular on the water-solubility of the medicinal substance and thus shows a pH-dependent release for pH-dependently soluble active ingredients.
Delayed release pellet formulations have been described for ~vsiTiageiit-CoiLtaiiiiiig iTiatrix peiiet cores whiCh have been coated with a semipermeable membrane. This membrane is stretched owing to the swelling of the core, resultinq after a laq time in pores which make the membrane permeable by medium and active ingredient and thus bring about a delayed active ingredient release. Such delayed release formulations are utilized for accurately targeted active ingredient release in the GI tracL or release according to chrono-pharmacological aspects or are used when the kinetics of absorption of a medicinal substance are non-linear.
Asymmetric membranes which can be applied to tablets and also to pellet cores bring about an improved release of active ingredients of low solubility.
j.uv we vo ,.i- +- L. ,-. .. .~, r------ -' ~, 111C.7C Lc.,~~~iuiaLions also do not show pH-independent active ingredient release for pH-dependently soluble substances. A pH-independent release has been described for such systems when pH
adjusters have been incorporated in the core formulation for buffering. Such excipients either acids or bases alter the pH within the formulation to such an extent that the active ingredient solubility is improved, even in pH-unfavourable media.
Further systems described in the literature for pH-independent active ingredient release by means of pH
adjusters in the core of tablets or pellets are also described for systems which do not operate osmotically.
Multilayer coating combinations have been described for the combination of water-soluble and water-insoluble polymer layers, where the water-soluble polymers do not show pH-dependent solubility and thus any control of the release of pH-dependently soluble active constituents either.
There have furthermore been descriptions of combinations of water-insoluble and pH-dependently soluble polymer layers and polymer mixtures, a pH-independent active ingredient release being achieved solely on the basis of differences in the permeability of the polymer coating. The permeabilities of the polymer film can be adjusted accurately in these cases.
The pH-dependently soluble polymer component always shows a contrary solubility to the active ingredient.
These comprise multichamber tablet systems whose core comprises an osmotic active ingredient compartment and a swellable osmotically active polymer, with the two compartments being separated by an elastic diaphragm.
The entire tablet core is in turn enveloped by an SPM
which comprises a release orifice on the active ingredient containing side.
Water penetrates into both compartments, whereupon the polymer swells and thus forces the diaphragm into the active ingredient compartment. The active ingredient is then delivered through the release aperture. The aim in this case too is to create plasma levels which remain the same owing to the 0 order active ingredient release.
Hence, systems which operate osmotically, such as the elementary osmotic pump (EOP) and push and pull osmotic pumps (PPOP) release at least moderately water-soluble active ingredients from tablets which consist of a semipermeable membrane around an osmotically active core which comprises at least one substance having an osmotic effect (osmagent) and, in the case of the PPOP, an expanding polymer push compartment.
Since semipermeable membranes are permeable only by the medium but not by the active ingredient, the active constituent is released through at least one orifice in the semipermeable membrane.
The essential aim of osmotic pi?mps as known in the state of the art is 0 order active ingredient release.
In contrast to EOP and PPOP, pharmaceutical forms without semipermeable membranes have also been described, for example: Controlled Porosity Osmotic Pumps (CPOP).
CPOPs were also developed in order to replace the elaborate manufacture of the above-described systems in which release orifices must be bored by drilling machines or lasers.
These CPOP formulations have a water-insoluble polymer membrane into which water-soluble ingredients are incorporated and, after contact with the aqueous medium, are dissolved out and thus form a microporous membrane which is now permeable by medium and active ingredient.
In these systems, in detail the osmotic tablet core is enveloped by an insoluble polymer membrane into which water-soluble substances have been incorporated. After the pharmaceutical form is introduced into the medium, these water-soluble substances are dissolved out.
This results in pores through which the active ingredient release takes place. These systems also comprise tablets which show controlled release.
In these cases, the active ingredient release depends in particular on the water-solubility of the medicinal substance and thus shows a pH-dependent release for pH-dependently soluble active ingredients.
Delayed release pellet formulations have been described for ~vsiTiageiit-CoiLtaiiiiiig iTiatrix peiiet cores whiCh have been coated with a semipermeable membrane. This membrane is stretched owing to the swelling of the core, resultinq after a laq time in pores which make the membrane permeable by medium and active ingredient and thus bring about a delayed active ingredient release. Such delayed release formulations are utilized for accurately targeted active ingredient release in the GI tracL or release according to chrono-pharmacological aspects or are used when the kinetics of absorption of a medicinal substance are non-linear.
Asymmetric membranes which can be applied to tablets and also to pellet cores bring about an improved release of active ingredients of low solubility.
j.uv we vo ,.i- +- L. ,-. .. .~, r------ -' ~, 111C.7C Lc.,~~~iuiaLions also do not show pH-independent active ingredient release for pH-dependently soluble substances. A pH-independent release has been described for such systems when pH
adjusters have been incorporated in the core formulation for buffering. Such excipients either acids or bases alter the pH within the formulation to such an extent that the active ingredient solubility is improved, even in pH-unfavourable media.
Further systems described in the literature for pH-independent active ingredient release by means of pH
adjusters in the core of tablets or pellets are also described for systems which do not operate osmotically.
Multilayer coating combinations have been described for the combination of water-soluble and water-insoluble polymer layers, where the water-soluble polymers do not show pH-dependent solubility and thus any control of the release of pH-dependently soluble active constituents either.
There have furthermore been descriptions of combinations of water-insoluble and pH-dependently soluble polymer layers and polymer mixtures, a pH-independent active ingredient release being achieved solely on the basis of differences in the permeability of the polymer coating. The permeabilities of the polymer film can be adjusted accurately in these cases.
The pH-dependently soluble polymer component always shows a contrary solubility to the active ingredient.
Weak active ingredient bases are coated with an acid-insoluble polymer, whereas an alkali-insoluble polymer is used as pH-dependently soluble component in the case of weak active ingredient acids. The result is a thinner or more porous coating in the medium in which the active substance is less soluble. The diffusion barrier in the medium having lower active ingredient solubility is thus reduced, resulting in an improved active ingredient liberation.
The present invention relates to a solid pharmaceutical formulation for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers, at least one layer of one or more pH-dependent water-soluble polymers and an active ingredient-containing core, where the core comprises an active ingredient having strong pH-dependent solubility in water and at least one osmagent.
In a preferred form of the present invention, the layer of one or more water-insoluble polymers comprises pore-forming substances which are dissolved out after contact with the aqueous medium and thus form a microporous membrane.
In a further embodiment of the invention, the layer of one or more pH-dependent water-soluble polymers is the outer layer on the solid pharmaceutical formulation, and the layer of one or more water-insoluble polymers is the inner one.
The present invention further relates to a~~atrix pellet for a sustained pH-independent active ingredient release comprising at least one inner layer of one or more water-insoluble polymers in which pore-forming substances are present and, after contact with the aqueous medium, are dissolved out and thus form a microporous membrane, and comprising at least one outer layer of one or more pH-dependent water-soluble polymers, and an active ingredient-containing core, where the core comprises piperazineurea and at least one water-soluble ionic substance from the group of magnesium chloride, magnesium sulphate, lithium chloride, sodium chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium chloride, ammonium sulphate, ammonium phosphate.
Surprisingly, simply mixing water-insoluble with pH-dependently soluble polymers and application of layers thereof is insufficient for sustained pH-independent active ingredient release.
This phenomenon was observable even on application of very small amounts of pH-dependently water-soluble polymer, for example 2.5 and 5% (w/w) based on the total mass of the formulation.
Only by use of osmotically active substances according to the present invention was a pH-independent active ingredient release achieved. Only an osmotically active addition to the core formulation with a high active ingredient loading, for example up to 90% w/w, preferably up to 60% w/w, based on the mass of the core formulation brings about rapid penetration of medium into the core, followed by the formation of a saturated active ingredient solution which, driven by the osmotic pressure, is forced out of the solid pharmaceutical formulation.
It is possible in this way to increase significantly the release of the active substance in the medium with low active ingredient solubility.
Only there is the pH-dependently soluble polymer layer stretched, owing to the increased penetration in of medium, to such an extent that a significant emergence of active ingredient is in fact achieved.
According to the present invention, a pH-dependently water-soluble polymer layer is necessary even for a core with osmagent.
Additionally, according to a further preferred embodiment of the invention, pore-torming substances may be an addition to the water-insoluble membrane.
Owing to incorporated pore formers, the membrane rapidly becomes permeable not only by medium but also by the active ingredient. The rapid permeability of the water-insoluble membrane is very important in particular for active ingredients having a very low solubility in water.
It is now possible to adjust a pH-independent release of the active substance in the solid pharmaceutical formulation according to the present invention through the combination of water-insoluble polymer with or without further water-soluble substances for pore formation and a pH-dependently water-soluble polymer.
In addition, the release of the active substance from the solid pharmaceutical formulation according to the present invention is not only pH-independent but also substantially increased by comparison with known pharmaceutical formulations without osmagent in the core.
Brief description of the drawings The invention is explained in more detail below by means of the drawing. This shows in:
Figure 1 a preferred embodiment of the solid pharmaceutical formulation according to the present invention.
Figure 2 a solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble polymer layer without osmagent in the core. Formulations with pH-dependently water-soluble polymer layer without osmagent in the core show a very greatly reduced active ingredient release in the medium with the actually highest active ingredient solubility.
Figures 3a-3c show release investigations on a solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble polymer layer without osmagent in the core. The release investigations were carried out in a USPXXV basket apparatus at 100 revolutions per minute and with a medium temperature of 37 C ( 0.5 C). The media used were 0.1 N HC1 and phosphate buffer of pH 6.8. Quantification took place by HPLC.
Figure 4 a solid pharmaceutical formulation of Figure 1 without pH-dependently water-soluble polymer layer with osmagent in the core.
Figure 5 a solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble polymer layer and osmagent in the core. A pH-independent active ingredient release was achieved through the introduction of osmotically active substances.
Figures 6a-6c and 7a-7c show release investigations on the solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble poly<<<er layer with osmagent in the core (Figure 6a-6c for Examples 2 and Figures 7a-7c for Examples 3). The release investigations were carried out in a USPXXV basket apparatus at 100 revolutions per minute and with a medium temperature of 37 C ( 0.5 C). The media used were 0.1 N HC1 and phosphate buffer of pH 6.8.
The present invention relates to a solid pharmaceutical formulation for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers, at least one layer of one or more pH-dependent water-soluble polymers and an active ingredient-containing core, where the core comprises an active ingredient having strong pH-dependent solubility in water and at least one osmagent.
In a preferred form of the present invention, the layer of one or more water-insoluble polymers comprises pore-forming substances which are dissolved out after contact with the aqueous medium and thus form a microporous membrane.
In a further embodiment of the invention, the layer of one or more pH-dependent water-soluble polymers is the outer layer on the solid pharmaceutical formulation, and the layer of one or more water-insoluble polymers is the inner one.
The present invention further relates to a~~atrix pellet for a sustained pH-independent active ingredient release comprising at least one inner layer of one or more water-insoluble polymers in which pore-forming substances are present and, after contact with the aqueous medium, are dissolved out and thus form a microporous membrane, and comprising at least one outer layer of one or more pH-dependent water-soluble polymers, and an active ingredient-containing core, where the core comprises piperazineurea and at least one water-soluble ionic substance from the group of magnesium chloride, magnesium sulphate, lithium chloride, sodium chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium chloride, ammonium sulphate, ammonium phosphate.
Surprisingly, simply mixing water-insoluble with pH-dependently soluble polymers and application of layers thereof is insufficient for sustained pH-independent active ingredient release.
This phenomenon was observable even on application of very small amounts of pH-dependently water-soluble polymer, for example 2.5 and 5% (w/w) based on the total mass of the formulation.
Only by use of osmotically active substances according to the present invention was a pH-independent active ingredient release achieved. Only an osmotically active addition to the core formulation with a high active ingredient loading, for example up to 90% w/w, preferably up to 60% w/w, based on the mass of the core formulation brings about rapid penetration of medium into the core, followed by the formation of a saturated active ingredient solution which, driven by the osmotic pressure, is forced out of the solid pharmaceutical formulation.
It is possible in this way to increase significantly the release of the active substance in the medium with low active ingredient solubility.
Only there is the pH-dependently soluble polymer layer stretched, owing to the increased penetration in of medium, to such an extent that a significant emergence of active ingredient is in fact achieved.
According to the present invention, a pH-dependently water-soluble polymer layer is necessary even for a core with osmagent.
Additionally, according to a further preferred embodiment of the invention, pore-torming substances may be an addition to the water-insoluble membrane.
Owing to incorporated pore formers, the membrane rapidly becomes permeable not only by medium but also by the active ingredient. The rapid permeability of the water-insoluble membrane is very important in particular for active ingredients having a very low solubility in water.
It is now possible to adjust a pH-independent release of the active substance in the solid pharmaceutical formulation according to the present invention through the combination of water-insoluble polymer with or without further water-soluble substances for pore formation and a pH-dependently water-soluble polymer.
In addition, the release of the active substance from the solid pharmaceutical formulation according to the present invention is not only pH-independent but also substantially increased by comparison with known pharmaceutical formulations without osmagent in the core.
Brief description of the drawings The invention is explained in more detail below by means of the drawing. This shows in:
Figure 1 a preferred embodiment of the solid pharmaceutical formulation according to the present invention.
Figure 2 a solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble polymer layer without osmagent in the core. Formulations with pH-dependently water-soluble polymer layer without osmagent in the core show a very greatly reduced active ingredient release in the medium with the actually highest active ingredient solubility.
Figures 3a-3c show release investigations on a solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble polymer layer without osmagent in the core. The release investigations were carried out in a USPXXV basket apparatus at 100 revolutions per minute and with a medium temperature of 37 C ( 0.5 C). The media used were 0.1 N HC1 and phosphate buffer of pH 6.8. Quantification took place by HPLC.
Figure 4 a solid pharmaceutical formulation of Figure 1 without pH-dependently water-soluble polymer layer with osmagent in the core.
Figure 5 a solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble polymer layer and osmagent in the core. A pH-independent active ingredient release was achieved through the introduction of osmotically active substances.
Figures 6a-6c and 7a-7c show release investigations on the solid pharmaceutical formulation of Figure 1 with pH-dependently water-soluble poly<<<er layer with osmagent in the core (Figure 6a-6c for Examples 2 and Figures 7a-7c for Examples 3). The release investigations were carried out in a USPXXV basket apparatus at 100 revolutions per minute and with a medium temperature of 37 C ( 0.5 C). The media used were 0.1 N HC1 and phosphate buffer of pH 6.8.
Quantification took place by HPLC.
Embodiment(s) of the invention The solid pharmaceutical formulation 1 according to the invention (Fig. 1) comprises at least one layer 3 of one or more water-insoluble polymers, at least one layer 2 of one or more pH-dependently water-soluble polymers.
The formulation core 5 according to the invention is loaded with a strong pH-dependent water-soluble active ingredient 6 and at least one osmagent 7.
In a preferred embodiment of the invention, the layer 3 of one or more water-insoluble polymers comprises pore-forming substances 4 which are dissolved out after contact with the aqueous medium 8 and thus form a microporous membrane.
The one or more pore-forming substances 4 may be water-soluble polymers or other water-soluble additions such as salts or sugars.
The one or more pore-forming substances 4 may be selected from the group comprising for example poly-vinylpyrrolidone (PVP), crospovidone (crosslinked N-vinyl-2-pyrrolidone, Cl-PVP), hydroxypropylmethyl-cellulose (HPMC), polyethylene glycol (PEG), hydroxy-propylcellulose (HPC) and mixtures thereof.
Formulations of an active ingredient-containing core wltiiGut GSllageilt and Gf twG iayers of pGi'y'iT'ier (F1g. 2) , where the inner layer consisted of a water-insoluble and the outer layer of a pH-dependently water-soluble polymer, still showed a strong pH-dependent release of the active substance.
The very greatly reduced active ingredient release in the medium with the actually highest active ingredient solubility was particularly noteworthy.
For example, a piperazineurea-containing core without osmagent according to Figure 2 with higher solubility at acidic pH values (pH < 4) was unable to achieve an efficient active ingredient release (Fig. 3a-c) . The active ingredient release of piperazineurea in medium of pH 1 was less than expected.
A pH-independently active ingredient release is not achieved even with a formulation without pH-dependently water-soluble polymer film (Fig. 4).
Efficient sustained pH-independent active ingredient releases of 0 or lst order can easily be achieved by the solid pharmaceutical formulation according to the invention.
An example of the production of the solid pharmaceutical formulation for a sustained pH-independent active ingredient release according to the present invention is described below.
A dry powder mixture was prepared by introducing the sieved ingredients into a Muller drum with subsequent mixing in a Turbula mixer.
The dry powder mixture was subsequently moistened in a high-speed mixer, the amount of binder solution necessary for extrusion and spheronization having been determined by preliminary tests. The resulting moist granules .vere tiien eXtruded in an extruder and rounded in a spheronizer.
The produced pellets in a preferred embodiment of the invention were then dried in a fluidized bed (GPCGl from Glatt).
Embodiment(s) of the invention The solid pharmaceutical formulation 1 according to the invention (Fig. 1) comprises at least one layer 3 of one or more water-insoluble polymers, at least one layer 2 of one or more pH-dependently water-soluble polymers.
The formulation core 5 according to the invention is loaded with a strong pH-dependent water-soluble active ingredient 6 and at least one osmagent 7.
In a preferred embodiment of the invention, the layer 3 of one or more water-insoluble polymers comprises pore-forming substances 4 which are dissolved out after contact with the aqueous medium 8 and thus form a microporous membrane.
The one or more pore-forming substances 4 may be water-soluble polymers or other water-soluble additions such as salts or sugars.
The one or more pore-forming substances 4 may be selected from the group comprising for example poly-vinylpyrrolidone (PVP), crospovidone (crosslinked N-vinyl-2-pyrrolidone, Cl-PVP), hydroxypropylmethyl-cellulose (HPMC), polyethylene glycol (PEG), hydroxy-propylcellulose (HPC) and mixtures thereof.
Formulations of an active ingredient-containing core wltiiGut GSllageilt and Gf twG iayers of pGi'y'iT'ier (F1g. 2) , where the inner layer consisted of a water-insoluble and the outer layer of a pH-dependently water-soluble polymer, still showed a strong pH-dependent release of the active substance.
The very greatly reduced active ingredient release in the medium with the actually highest active ingredient solubility was particularly noteworthy.
For example, a piperazineurea-containing core without osmagent according to Figure 2 with higher solubility at acidic pH values (pH < 4) was unable to achieve an efficient active ingredient release (Fig. 3a-c) . The active ingredient release of piperazineurea in medium of pH 1 was less than expected.
A pH-independently active ingredient release is not achieved even with a formulation without pH-dependently water-soluble polymer film (Fig. 4).
Efficient sustained pH-independent active ingredient releases of 0 or lst order can easily be achieved by the solid pharmaceutical formulation according to the invention.
An example of the production of the solid pharmaceutical formulation for a sustained pH-independent active ingredient release according to the present invention is described below.
A dry powder mixture was prepared by introducing the sieved ingredients into a Muller drum with subsequent mixing in a Turbula mixer.
The dry powder mixture was subsequently moistened in a high-speed mixer, the amount of binder solution necessary for extrusion and spheronization having been determined by preliminary tests. The resulting moist granules .vere tiien eXtruded in an extruder and rounded in a spheronizer.
The produced pellets in a preferred embodiment of the invention were then dried in a fluidized bed (GPCGl from Glatt).
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The polymer dispersions were applied in a fluidized bed granulator with Wurster insert, with application of the first layer being followed by a brief drying pause and then application of the second layer.
The formulation layer of one or more water-insoluble polymers (subcoating formulation) is for example from 1% to 40% w/w, preferably from 1% to 10% w/w, preferably from 2% to 5% w/w based on the total mass of formulation. The water-insoluble polymers may be selected from the group comprising polyvinyl acetate;
alkylcelluloses, acrylate-methacrylate copolymers, vinyl acetate-methacrylate copolymers and -acrylate copolymers; ethylcellulose, ethyl acrylate-methyl methacrylate copolymer and ethyl acrylate-methyl acrylate-trimethylammoniummethyl methacrylate chloride terpolymer and mixtures thereof.
In a preferred embodiment of the invention, pore-forming substances were used in the formulation layer of one or more water-insoluble polymers (subcoating formulation). The one or more pore-forming substances may be water-soluble polymers or other water-soluble additions such as salts or sugars. In a preferred embodiment of the invention, the one or more pore-forming substances may be selected from the group comprising for example polyvinylpyrrolidone (PVP), crospovidone (crosslinked N-vinyl-2-pyrrolidone, Cl-PVP), hydroxypropylmethylcellulose (HPMC), ol='eth ==lene 1'-col ~PE~v' droxY-~ceiliiiose l'HPC'! Y Y ~ Y ~ I, ~'ly P-~-uPYl 1 and mixtures thereof.
The formulation laver of one or more pH-dependent water-soluble polymers (topcoating formulation) is for example from 1% to 40 % w/w, preferably from 1% to 10%
w/w, preferably from 2% to 5% w/w, based on the total mass of formulation.
The acid-insoluble polymers may be selected from the group comprising acrylate-methacrylic acid copolymers, carboxyalkylcelluloses, cellulose acetate phthalates, cellulose acetate succinates, cellulose acetate trimelliates, hydroxyalkylcellulose phthalates, hydroxyalkylcellulose acetate succinates, vinyl acetate phthalates, vinyl acetate succinate; ethylacrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, methyl methacrylate-methyl acrylate-methacrylic acid copolymer, carboxymethyl-cellulose, cellulose acetate phthalate; hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and mixtures thereof.
Alkali-insoluble polymers which can be used are acrylate-methacrylate copolymers, basic natural polysaccharides, dimethylaminoethyl methacrylate-methyl methacrylate-butyl methacrylate terpolymer, chitosan and mixtures thereof.
Osmotically active substances (osmagents) which can be used for targeted pH-independent active ingredient release are water-soluble ionic or nonionic substances and hydrophilic polymers, alone or as mixture.
The water-soluble ionic substance may be selected from the group comprising magnesium chloride, magnesium sulphate, lithium chloride, sodium, chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, sodium carbonate, ammonium chloride, ammonium sulphate, ammonium phosphate alone or as mixture.
The content of water-soluble ionic osmotic substance in the core may be from 2% to 50% w/w based on the total mass of cores and in particular from 2% to 20% w/w based on the total mass of cores.
A water-soluble nonionic substance may be selected from the group comprising for example sucrose, mannitol, lactose, dextrose, sorbitol, alone or as mixture.
The content of water-soluble nonionic osmotic substance in the core may be from 2% to 50% w/w based on the total mass of cores and in particular from 10% to 40%
w/w based on the total mass of cores.
The hydrophilic polymers may be selected from the group comprising hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), xanthan gum, alginate, sodium carboxylmethylcellulose, polyvinylpyrrolidone (PVP), Cl-polyvinylpyrrolidone (Cl-PVP), polyethylene oxide, carbopols, polyacrylamides, gum arabic and mixtures thereof.
Water-soluble ionic substances preferably used according to the present invention are those which achieve a high osmotic effect with relatively small amounts.
It is possible to use cellulose or cellulose derivatives as additional formulating agent for influencing the mechanical strength of the pharmaceutical form. Microcrystalline cellulose is particularly advantageous.
The polymer dispersions were applied in a fluidized bed granulator with Wurster insert, with application of the first layer being followed by a brief drying pause and then application of the second layer.
The formulation layer of one or more water-insoluble polymers (subcoating formulation) is for example from 1% to 40% w/w, preferably from 1% to 10% w/w, preferably from 2% to 5% w/w based on the total mass of formulation. The water-insoluble polymers may be selected from the group comprising polyvinyl acetate;
alkylcelluloses, acrylate-methacrylate copolymers, vinyl acetate-methacrylate copolymers and -acrylate copolymers; ethylcellulose, ethyl acrylate-methyl methacrylate copolymer and ethyl acrylate-methyl acrylate-trimethylammoniummethyl methacrylate chloride terpolymer and mixtures thereof.
In a preferred embodiment of the invention, pore-forming substances were used in the formulation layer of one or more water-insoluble polymers (subcoating formulation). The one or more pore-forming substances may be water-soluble polymers or other water-soluble additions such as salts or sugars. In a preferred embodiment of the invention, the one or more pore-forming substances may be selected from the group comprising for example polyvinylpyrrolidone (PVP), crospovidone (crosslinked N-vinyl-2-pyrrolidone, Cl-PVP), hydroxypropylmethylcellulose (HPMC), ol='eth ==lene 1'-col ~PE~v' droxY-~ceiliiiose l'HPC'! Y Y ~ Y ~ I, ~'ly P-~-uPYl 1 and mixtures thereof.
The formulation laver of one or more pH-dependent water-soluble polymers (topcoating formulation) is for example from 1% to 40 % w/w, preferably from 1% to 10%
w/w, preferably from 2% to 5% w/w, based on the total mass of formulation.
The acid-insoluble polymers may be selected from the group comprising acrylate-methacrylic acid copolymers, carboxyalkylcelluloses, cellulose acetate phthalates, cellulose acetate succinates, cellulose acetate trimelliates, hydroxyalkylcellulose phthalates, hydroxyalkylcellulose acetate succinates, vinyl acetate phthalates, vinyl acetate succinate; ethylacrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, methyl methacrylate-methyl acrylate-methacrylic acid copolymer, carboxymethyl-cellulose, cellulose acetate phthalate; hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and mixtures thereof.
Alkali-insoluble polymers which can be used are acrylate-methacrylate copolymers, basic natural polysaccharides, dimethylaminoethyl methacrylate-methyl methacrylate-butyl methacrylate terpolymer, chitosan and mixtures thereof.
Osmotically active substances (osmagents) which can be used for targeted pH-independent active ingredient release are water-soluble ionic or nonionic substances and hydrophilic polymers, alone or as mixture.
The water-soluble ionic substance may be selected from the group comprising magnesium chloride, magnesium sulphate, lithium chloride, sodium, chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, sodium carbonate, ammonium chloride, ammonium sulphate, ammonium phosphate alone or as mixture.
The content of water-soluble ionic osmotic substance in the core may be from 2% to 50% w/w based on the total mass of cores and in particular from 2% to 20% w/w based on the total mass of cores.
A water-soluble nonionic substance may be selected from the group comprising for example sucrose, mannitol, lactose, dextrose, sorbitol, alone or as mixture.
The content of water-soluble nonionic osmotic substance in the core may be from 2% to 50% w/w based on the total mass of cores and in particular from 10% to 40%
w/w based on the total mass of cores.
The hydrophilic polymers may be selected from the group comprising hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), xanthan gum, alginate, sodium carboxylmethylcellulose, polyvinylpyrrolidone (PVP), Cl-polyvinylpyrrolidone (Cl-PVP), polyethylene oxide, carbopols, polyacrylamides, gum arabic and mixtures thereof.
Water-soluble ionic substances preferably used according to the present invention are those which achieve a high osmotic effect with relatively small amounts.
It is possible to use cellulose or cellulose derivatives as additional formulating agent for influencing the mechanical strength of the pharmaceutical form. Microcrystalline cellulose is particularly advantageous.
Examples Example 1: Production of coated matrix pellets with pH-dependent water-soluble polymer layer without osmagent in the core (Fig. 3a-c; state of the art) Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Microcrystalline cellulose 40%
Formulation layer of one or more water-insoluble polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the subcoating formulation: 5% w/w based on total mass of pellets.
Formulation layer of one or more pH-dependent water-soluble polymers (topcoating formulation) (% w/w):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating formulation (% w/w) :
0% (Fig. 3a); 2.5% (Fig. 3b); 5% (Fig. 3c) w/w based on total mass of pellets.
Microcrystalline cellulose and active ingredient are sieved and mixed in a Turbula mixer for 20 minutes.
The dry powder mixture is mixed with the required amount of binder solution (water) in a high-speed mixer. The resulting moist granules are -subsequently extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a spheronizer at 400 rpm. The pellets are subsequently dried in a GPCG1 fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a GPCG1 fluidized bed granulator with Wurster insert for 10 minutes. Then a 15% (w/w) polyvinyl acetate dispersion which comprises the water-soluble pore former polyvinylpyrrolidone is applied at an inlet air temperature of 50 C.
After intermediate drying for 10 min, the pH-dependently soluble methacrylic acid-ethyl acrylate copolymer (15% w/w) is sprayed on at an inlet air temperature of 50 C.
After the polymer has been applied, the coated matrix pellets are equilibrated at 40 C for 24 h.
Example 2: Production of coated matrix pellets with pH-dependent water-soluble polymer layer with osmagent (KC1) in the core (Fig. 6a-c) Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Osmotically active substance (KC1) 15%
Microcrystalline cellulose 25%
Formulation layer of one or more water-insoluble polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the subcoating formulation: 5% w/w based on total mass of pellets.
Formulation layer of one or more pH-dependent water-soluble polymers (topcoating formulation) (% w/w):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating formulation (% w/w) :
Active ingredient (piperazineurea) 60%
Microcrystalline cellulose 40%
Formulation layer of one or more water-insoluble polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the subcoating formulation: 5% w/w based on total mass of pellets.
Formulation layer of one or more pH-dependent water-soluble polymers (topcoating formulation) (% w/w):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating formulation (% w/w) :
0% (Fig. 3a); 2.5% (Fig. 3b); 5% (Fig. 3c) w/w based on total mass of pellets.
Microcrystalline cellulose and active ingredient are sieved and mixed in a Turbula mixer for 20 minutes.
The dry powder mixture is mixed with the required amount of binder solution (water) in a high-speed mixer. The resulting moist granules are -subsequently extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a spheronizer at 400 rpm. The pellets are subsequently dried in a GPCG1 fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a GPCG1 fluidized bed granulator with Wurster insert for 10 minutes. Then a 15% (w/w) polyvinyl acetate dispersion which comprises the water-soluble pore former polyvinylpyrrolidone is applied at an inlet air temperature of 50 C.
After intermediate drying for 10 min, the pH-dependently soluble methacrylic acid-ethyl acrylate copolymer (15% w/w) is sprayed on at an inlet air temperature of 50 C.
After the polymer has been applied, the coated matrix pellets are equilibrated at 40 C for 24 h.
Example 2: Production of coated matrix pellets with pH-dependent water-soluble polymer layer with osmagent (KC1) in the core (Fig. 6a-c) Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Osmotically active substance (KC1) 15%
Microcrystalline cellulose 25%
Formulation layer of one or more water-insoluble polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the subcoating formulation: 5% w/w based on total mass of pellets.
Formulation layer of one or more pH-dependent water-soluble polymers (topcoating formulation) (% w/w):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating formulation (% w/w) :
0% (Fig. 6a) ; 2.5% (Fig. 6b) ; 5% (Fig. 6c) based on total mass of pellets.
Microcrystalline cellulose and active ingredient are sieved and mixed in a Turbula mixer for 10 minutes.
Sieved potassium chloride is added and mixed in the Turbula mixer for a further 10 minutes.
The dry Yowder mixture is mixed with the required amount of binder solution (water) in a high-speed mixer. The resulting moist granules are subsequently extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a spheronizer at 400 rpm. The pellets are subsequently dried in a GPCGl fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a GPCG1 fluidized bed granulator with Wurster insert for 10 minutes. Then a 15% (w/w) polyvinyl acetate dispersion which comprises the water-soluble pore former polyvinylpyrrolidone is applied at an inlet air temperature of 50 C.
After intermediate drying for 10 min, the pH-dependently soluble methacrylic acid-ethyl acrylate copolymer (15% w/w) is sprayed on at an inlet air temperature of 50 C.
After the pollTmer has been applied, the coated matrix pellets are equilibrated at 40 C for 24 h.
Example 3: Production of coated matrix pellets with pH-dependent water-soluble polymer layer with osmagent (NaCl) in the core (Fig. 7a-c) Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Osmotically active substance (NaCl) 15%
Microcrystalline cellulose 25%
Formulation layer of one or more water-insoluble polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the subcoating formulation: 5% w/w based on total mass of pellets.
Formulation layer of one or more pH-dependent water-soluble polymers (topcoating formulation):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating formulation (% w/w) :
0% (Fig. 7a) ; 3% (Fig. 7b) ; 4% (Fig. 7c) based on total mass of pellets.
Microcrystalline cellulose and active ingredient are sieved and mixed in a Turbula mixer for 10 minutes.
Sieved sodium chloride is added and mixed in the Turbula mixer for a further 10 minutes.
The dry powder mixture is mixed with the required amount of binder solution (water) in a high-speed mixer. The resulting moist granules are subsequently extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a spheronizer at 400 rpm. The pellets are subsequently dried in a GPCG1 fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a GPCG1 fluidized bed granulator with Wurster insert for minutes. Then a 15% (w/w) polyvinyl acetate dispersion which comprises the water-soluble pore former polyvinylpyrrolidone is applied at an inlet air 5 temperature of 50 C.
After intermediate drying for 10 min, the pH-dependently soluble methacrylic acid-ethyl acrylate copolymer (15% w/w) is sprayed on at an inlet air 10 temperature of 50 C.
After the polymer has been applied, the coated matrix pellets are equilibrated at 40 C for 24 h.
Microcrystalline cellulose and active ingredient are sieved and mixed in a Turbula mixer for 10 minutes.
Sieved potassium chloride is added and mixed in the Turbula mixer for a further 10 minutes.
The dry Yowder mixture is mixed with the required amount of binder solution (water) in a high-speed mixer. The resulting moist granules are subsequently extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a spheronizer at 400 rpm. The pellets are subsequently dried in a GPCGl fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a GPCG1 fluidized bed granulator with Wurster insert for 10 minutes. Then a 15% (w/w) polyvinyl acetate dispersion which comprises the water-soluble pore former polyvinylpyrrolidone is applied at an inlet air temperature of 50 C.
After intermediate drying for 10 min, the pH-dependently soluble methacrylic acid-ethyl acrylate copolymer (15% w/w) is sprayed on at an inlet air temperature of 50 C.
After the pollTmer has been applied, the coated matrix pellets are equilibrated at 40 C for 24 h.
Example 3: Production of coated matrix pellets with pH-dependent water-soluble polymer layer with osmagent (NaCl) in the core (Fig. 7a-c) Core formulation (% w/w):
Active ingredient (piperazineurea) 60%
Osmotically active substance (NaCl) 15%
Microcrystalline cellulose 25%
Formulation layer of one or more water-insoluble polymers (subcoating formulation) (% w/w):
Polyvinyl acetate 70%
Polyvinylpyrrolidone 30%
Coating level of the subcoating formulation: 5% w/w based on total mass of pellets.
Formulation layer of one or more pH-dependent water-soluble polymers (topcoating formulation):
Methacrylic acid-ethyl acrylate copolymer 100%
Coating level of the topcoating formulation (% w/w) :
0% (Fig. 7a) ; 3% (Fig. 7b) ; 4% (Fig. 7c) based on total mass of pellets.
Microcrystalline cellulose and active ingredient are sieved and mixed in a Turbula mixer for 10 minutes.
Sieved sodium chloride is added and mixed in the Turbula mixer for a further 10 minutes.
The dry powder mixture is mixed with the required amount of binder solution (water) in a high-speed mixer. The resulting moist granules are subsequently extruded through a 1 mm screen in an extruder.
The produced extrudate is rounded in portions in a spheronizer at 400 rpm. The pellets are subsequently dried in a GPCG1 fluidized bed granulator at 60 C.
After sieving, the pellet fraction from 0.8 mm to 1.25 mm diameter was used for further production.
The matrix pellet cores are equilibrated at 50 C in a GPCG1 fluidized bed granulator with Wurster insert for minutes. Then a 15% (w/w) polyvinyl acetate dispersion which comprises the water-soluble pore former polyvinylpyrrolidone is applied at an inlet air 5 temperature of 50 C.
After intermediate drying for 10 min, the pH-dependently soluble methacrylic acid-ethyl acrylate copolymer (15% w/w) is sprayed on at an inlet air 10 temperature of 50 C.
After the polymer has been applied, the coated matrix pellets are equilibrated at 40 C for 24 h.
Claims (20)
1. Solid pharmaceutical formulation for a sustained pH-independent active ingredient release comprising at least one layer of one or more water-insoluble polymers at least one layer of one or more pH-dependent water-soluble polymers, and an active ingredient-containing core, where the core comprises an active ingredient having strong pH-dependent water solubility and at least one osmagent.
2. Solid pharmaceutical formulation according to Claim 1, where the layer of one or more pH-dependent water-soluble polymers is the outer layer of the solid pharmaceutical formulation, and the layer of one or more water-insoluble polymers is the inner one.
3. Solid pharmaceutical formulation according to Claim 1 and 2, where the layer of one or more water-insoluble polymers is from 1% to 40% w/w based on the total mass of the formulation.
4. Solid pharmaceutical formulation according to Claim 1-3, where the layer of one or more water-insoluble polymers is from 1% to 10% w/w based on the total mass of the formulation.
5. Solid pharmaceutical formulation according to Claim 1-4, where the layer of one or more water-insoluble polymers is from 2% to 5% w/w based on the total mass of the formulation.
6. Solid pharmaceutical formulation according to Claim 1-5, where one or more water-insoluble polymers from the group comprising polyvinyl acetate, alkylcelluloses, acrylate-methacrylate copolymers, vinyl acetate-methacrylate copolymers and acrylate copolymers, ethylcellulose, ethyl acrylate-methyl methacrylate copolymer and ethyl acrylate-methyl acrylate-trimethylammoniummethyl methacrylate chloride terpolymer and mixtures thereof are selected.
7. Solid pharmaceutical formulation according to Claim 1-6, where the layer of one or more water-insoluble polymers comprises one or more pore-forming substances.
8. Solid pharmaceutical formulation according to Claim 1-7, where the pore-forming substance is selected from the group comprising polyvinyl-pyrrolidone, crospovidone, hydroxypropylmethyl-cellulose, polyethylene glycol, hydroxypropyl-cellulose and mixtures thereof.
9. Solid pharmaceutical formulation according to Claim 1-8, where the layer of one or more pH-dependent water-soluble polymers is from 1% to 40% w/w based on the total mass of the formulation.
10. Solid pharmaceutical formulation according to Claim 1-9, where the layer of one or more pH-dependent water-soluble polymers is from 1% to 10% w/w based on the total mass of the formulation.
11. Solid pharmaceutical formulation according to Claim 1-10, where the layer of one or more pH-dependent water-soluble polymers is from 2% to 5% w/w based on the total mass of the formulation.
12. Solid pharmaceutical formulation according to Claim 1-11, where one or more acid-insoluble polymers are selected from the group comprising acrylate-methacrylic acid copolymers, carboxy-alkylcelluloses, cellulose acetate phthalates, cellulose acetate succinates, cellulose acetate trimelliates, hydroxyalkylcellulose phthalates, hydroxyalkylcellulose acetate succinates, vinyl acetate phthalates, vinyl acetate succinate;
ethylacrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, methyl methacrylate-methyl acrylate-methacrylic acid copolymer, carboxymethylcellulose, cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and mixtures thereof.
ethylacrylate-methacrylic acid copolymer, methyl methacrylate-methacrylic acid copolymer, methyl methacrylate-methyl acrylate-methacrylic acid copolymer, carboxymethylcellulose, cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac and mixtures thereof.
13. Solid pharmaceutical formulation according to Claim 1-12, where one or more alkali-insoluble polymers are selected from the group comprising acrylate-methacrylate copolymers, basic natural polysaccharides, dimethylaminoethyl methacrylate-methyl methacrylate-butyl methacrylate terpolymer, chitosan and mixtures thereof.
14. Solid pharmaceutical formulation according to Claim 1-13, where the core is loaded with up to 90% w/w, based on the mass of the core formulation, of an active ingredient having strong pH-dependent water solubility.
15. Solid pharmaceutical formulation according to Claim 1-14, where the core is loaded with up to 60% w/w, based on the mass of the core formulation, of an active ingredient having strong pH-dependent water solubility.
16. Solid pharmaceutical formulation according to Claim 1-15, where the core is loaded with piperazineurea.
17. Solid pharmaceutical formulation according to Claim 1-16, where the osmagent in the core is selected from the group comprising water-soluble ionic substances, water-soluble nonionic substances, hydrophilic polymers and mixtures thereof.
18. Solid pharmaceutical formulation according to Claim 1-17, where the osmagent in the core is selected from the group comprising magnesium chloride, magnesium sulphate, lithium chloride, sodium chloride, potassium chloride, lithium sulphate, sodium sulphate, potassium sulphate, lithium phosphate, sodium phosphate, potassium phosphate, ammonium chloride, ammonium sulphate, ammonium phosphate, sucrose, mannitol, lactose, dextrose, sorbitol, hydroxypropylmethylcellulose, hydroxypropylcellulose, xanthan gum, alginate, sodium carboxylmethylcellulose, polyvinyl-pyrrolidone, Cl-polyvinylpyrrolidone, polyethylene oxide, carbopols, polyacrylamides, gum arabic and mixtures thereof.
19. Solid pharmaceutical formulation according to Claim 1-18, which is a matrix pellet.
20. Solid pharmaceutical formulation according to Claim 1-19, where the core has a diameter of from 0.8 mm to 1.25 mm.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05090228A EP1749519A1 (en) | 2005-08-05 | 2005-08-05 | Dosage form with pH-independent sustained release for active substances with pH-dependent solubility |
| EP05090228.7 | 2005-08-05 | ||
| US70642805P | 2005-08-09 | 2005-08-09 | |
| US60/706,428 | 2005-08-09 | ||
| PCT/EP2006/007783 WO2007017219A2 (en) | 2005-08-05 | 2006-08-02 | Pharmaceutical form with sustained ph-independent active ingredient release for active ingredients having strong ph-dependent solubility |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2617280A1 true CA2617280A1 (en) | 2007-02-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA002617280A Abandoned CA2617280A1 (en) | 2005-08-05 | 2006-08-02 | Pharmaceutical form with sustained ph-independent active ingredient release for active ingredients having strong ph-dependent solubility |
Country Status (11)
| Country | Link |
|---|---|
| EP (2) | EP1749519A1 (en) |
| JP (1) | JP2009503011A (en) |
| CN (1) | CN101257895A (en) |
| AR (1) | AR055110A1 (en) |
| CA (1) | CA2617280A1 (en) |
| DO (1) | DOP2006000184A (en) |
| GT (1) | GT200600353A (en) |
| PE (1) | PE20070464A1 (en) |
| TW (1) | TW200738285A (en) |
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| WO (1) | WO2007017219A2 (en) |
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| CN101374497A (en) * | 2006-05-08 | 2009-02-25 | 麦克内尔-Ppc股份有限公司 | Penetrating formulation |
| JP5228359B2 (en) * | 2007-04-12 | 2013-07-03 | ニプロ株式会社 | Active ingredient particles, process for producing the same and orally disintegrating tablets |
| WO2012013928A1 (en) * | 2010-07-27 | 2012-02-02 | Norgine Bv | Compositions |
| CN103093211B (en) * | 2013-01-27 | 2015-09-30 | 西安电子科技大学 | Based on the human body motion tracking method of deep nuclear information image feature |
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| US4627851A (en) * | 1984-10-26 | 1986-12-09 | Alza Corporation | Colonic-therapeutic delivery system |
| SE460945B (en) * | 1987-01-15 | 1989-12-11 | Lejus Medical Ab | A MULTIPLE-UNIT DOS COMPOSITION OF FUROSEMID |
| DK0758244T4 (en) * | 1994-05-06 | 2008-06-16 | Pfizer | Controlled-release azithromycin dosage forms |
| US6207665B1 (en) | 1997-06-12 | 2001-03-27 | Schering Aktiengesellschaft | Piperazine derivatives and their use as anti-inflammatory agents |
| WO2001076557A1 (en) * | 2000-04-10 | 2001-10-18 | Sumitomo Pharmaceuticals Co., Ltd. | Sustained release preparations |
| DE10152351B4 (en) * | 2001-10-18 | 2005-09-22 | Schering Ag | Solid drug formulation for a piperazine urea derivative |
| DE10211289A1 (en) * | 2002-03-14 | 2003-09-25 | Basf Ag | Combination of polyvinyl acetate from water-insoluble, acid-insoluble or alkali-insoluble polymers for the production of film coatings with very controlled release and high stability |
-
2005
- 2005-08-05 EP EP05090228A patent/EP1749519A1/en not_active Withdrawn
-
2006
- 2006-08-02 CN CNA2006800288421A patent/CN101257895A/en active Pending
- 2006-08-02 EP EP06776644A patent/EP1926482A2/en not_active Withdrawn
- 2006-08-02 CA CA002617280A patent/CA2617280A1/en not_active Abandoned
- 2006-08-02 WO PCT/EP2006/007783 patent/WO2007017219A2/en active Application Filing
- 2006-08-02 JP JP2008524453A patent/JP2009503011A/en not_active Ceased
- 2006-08-04 UY UY29728A patent/UY29728A1/en not_active Application Discontinuation
- 2006-08-04 PE PE2006000945A patent/PE20070464A1/en not_active Application Discontinuation
- 2006-08-04 AR ARP060103409A patent/AR055110A1/en not_active Application Discontinuation
- 2006-08-04 DO DO2006000184A patent/DOP2006000184A/en unknown
- 2006-08-04 TW TW095128584A patent/TW200738285A/en unknown
- 2006-08-04 GT GT200600353A patent/GT200600353A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1926482A2 (en) | 2008-06-04 |
| PE20070464A1 (en) | 2007-06-07 |
| JP2009503011A (en) | 2009-01-29 |
| UY29728A1 (en) | 2007-02-28 |
| GT200600353A (en) | 2007-03-14 |
| WO2007017219A3 (en) | 2007-06-28 |
| AR055110A1 (en) | 2007-08-08 |
| WO2007017219A2 (en) | 2007-02-15 |
| TW200738285A (en) | 2007-10-16 |
| DOP2006000184A (en) | 2007-05-31 |
| EP1749519A1 (en) | 2007-02-07 |
| CN101257895A (en) | 2008-09-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |
Effective date: 20140509 |