CN117717533B - Epalrestat sustained-release composition, preparation method and application thereof - Google Patents
Epalrestat sustained-release composition, preparation method and application thereof Download PDFInfo
- Publication number
- CN117717533B CN117717533B CN202311738680.2A CN202311738680A CN117717533B CN 117717533 B CN117717533 B CN 117717533B CN 202311738680 A CN202311738680 A CN 202311738680A CN 117717533 B CN117717533 B CN 117717533B
- Authority
- CN
- China
- Prior art keywords
- epalrestat
- gastric floating
- hypromellose
- floating tablet
- weight
- 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.)
- Active
Links
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 title claims abstract description 245
- 229950010170 epalrestat Drugs 0.000 title claims abstract description 245
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 title claims abstract description 244
- 239000000203 mixture Substances 0.000 title abstract description 215
- 238000002360 preparation method Methods 0.000 title description 68
- 238000013268 sustained release Methods 0.000 title description 65
- 239000012730 sustained-release form Substances 0.000 title description 65
- 239000000463 material Substances 0.000 claims abstract description 58
- 239000003814 drug Substances 0.000 claims abstract description 49
- 239000000945 filler Substances 0.000 claims abstract description 28
- 239000000017 hydrogel Substances 0.000 claims abstract description 27
- 239000000314 lubricant Substances 0.000 claims abstract description 26
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 239000000853 adhesive Substances 0.000 claims abstract description 12
- 230000001070 adhesive effect Effects 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 178
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 162
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 160
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 160
- 229960003943 hypromellose Drugs 0.000 claims description 116
- 230000002496 gastric effect Effects 0.000 claims description 113
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 100
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 100
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 100
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 100
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 99
- 239000001856 Ethyl cellulose Substances 0.000 claims description 98
- 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 98
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 97
- 229920001249 ethyl cellulose Polymers 0.000 claims description 97
- 235000019359 magnesium stearate Nutrition 0.000 claims description 89
- 229960000913 crospovidone Drugs 0.000 claims description 86
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 86
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 86
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 63
- 239000008187 granular material Substances 0.000 claims description 57
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 45
- 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 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 38
- 238000002156 mixing Methods 0.000 claims description 35
- 239000012530 fluid Substances 0.000 claims description 29
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 26
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 26
- 238000005303 weighing Methods 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 23
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 16
- 239000011230 binding agent Substances 0.000 claims description 15
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 229950005770 hyprolose Drugs 0.000 claims description 13
- 229940069328 povidone Drugs 0.000 claims description 13
- 235000010980 cellulose Nutrition 0.000 claims description 10
- 229920002678 cellulose Polymers 0.000 claims description 10
- 239000001913 cellulose Substances 0.000 claims description 10
- 239000007884 disintegrant Substances 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 9
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 9
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 239000011159 matrix material Substances 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 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 6
- 235000010443 alginic acid Nutrition 0.000 claims description 6
- 229920000615 alginic acid Polymers 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- -1 polysaccharide glycoside Chemical class 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- 235000010356 sorbitol Nutrition 0.000 claims description 6
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 239000008055 phosphate buffer solution Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- 238000007907 direct compression Methods 0.000 claims description 4
- 229930182470 glycoside Natural products 0.000 claims description 4
- 229920002674 hyaluronan Polymers 0.000 claims description 4
- 229960003160 hyaluronic acid Drugs 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 239000005017 polysaccharide Substances 0.000 claims description 4
- 238000005550 wet granulation Methods 0.000 claims description 4
- 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 3
- 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 3
- 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 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 235000010216 calcium carbonate Nutrition 0.000 claims description 3
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- 235000011132 calcium sulphate Nutrition 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 231100000862 numbness Toxicity 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 239000002002 slurry Substances 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims 3
- 239000002953 phosphate buffered saline Substances 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 208000012902 Nervous system disease Diseases 0.000 claims 1
- 208000025966 Neurological disease Diseases 0.000 claims 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 claims 1
- 229920003087 methylethyl cellulose Polymers 0.000 claims 1
- 230000002093 peripheral effect Effects 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000003937 drug carrier Substances 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000012453 solvate Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 230000005496 eutectics Effects 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 166
- 239000012634 fragment Substances 0.000 description 29
- 210000004369 blood Anatomy 0.000 description 15
- 239000008280 blood Substances 0.000 description 15
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 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 description 10
- 239000008103 glucose Substances 0.000 description 10
- 239000008119 colloidal silica Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 6
- 239000003405 delayed action preparation Substances 0.000 description 5
- 238000011835 investigation Methods 0.000 description 5
- 229920000058 polyacrylate Polymers 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 208000013016 Hypoglycemia Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 238000004061 bleaching Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000000422 nocturnal effect Effects 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 230000000291 postprandial effect Effects 0.000 description 4
- 229920000178 Acrylic resin Polymers 0.000 description 3
- 239000004925 Acrylic resin Substances 0.000 description 3
- 229920002907 Guar gum Polymers 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
- 239000000665 guar gum Substances 0.000 description 3
- 229960002154 guar gum Drugs 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920001285 xanthan gum Polymers 0.000 description 3
- 235000010493 xanthan gum Nutrition 0.000 description 3
- 239000000230 xanthan gum Substances 0.000 description 3
- 229940082509 xanthan gum Drugs 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- 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 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000282887 Suidae Species 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229940072056 alginate Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229960005168 croscarmellose Drugs 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 229920002689 polyvinyl acetate Polymers 0.000 description 2
- 239000011118 polyvinyl acetate Substances 0.000 description 2
- 229910021487 silica fume Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- 239000001496 (E)-2-methyl-3-phenylprop-2-enal Substances 0.000 description 1
- VLUMOWNVWOXZAU-VQHVLOKHSA-N (e)-2-methyl-3-phenylprop-2-enal Chemical compound O=CC(/C)=C/C1=CC=CC=C1 VLUMOWNVWOXZAU-VQHVLOKHSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 1
- RFRMMZAKBNXNHE-UHFFFAOYSA-N 6-[4,6-dihydroxy-5-(2-hydroxyethoxy)-2-(hydroxymethyl)oxan-3-yl]oxy-2-(hydroxymethyl)-5-(2-hydroxypropoxy)oxane-3,4-diol Chemical compound CC(O)COC1C(O)C(O)C(CO)OC1OC1C(O)C(OCCO)C(O)OC1CO RFRMMZAKBNXNHE-UHFFFAOYSA-N 0.000 description 1
- 102000016912 Aldehyde Reductase Human genes 0.000 description 1
- 108010053754 Aldehyde reductase Proteins 0.000 description 1
- 229940118148 Aldose reductase inhibitor Drugs 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- QANDQRKVQCIBES-WLHGVMLRSA-N OC(=O)\C=C\C(O)=O.CCCCCCCCCCCCCCCCCC(O)=O Chemical compound OC(=O)\C=C\C(O)=O.CCCCCCCCCCCCCCCCCC(O)=O QANDQRKVQCIBES-WLHGVMLRSA-N 0.000 description 1
- 206010041662 Splinter Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000003288 aldose reductase inhibitor Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Molecular Biology (AREA)
- Endocrinology (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to an epalrestat slow-release composition, which comprises 20-50% by weight of epalrestat or derivatives thereof and a pharmaceutically acceptable carrier, wherein the derivatives are selected from any one or combination of eutectic, salt, free acid, prodrug, ester, polymorphic substance and solvate, and the pharmaceutically acceptable carrier is selected from any one or combination of hydrogel materials, framework materials, filling agents, disintegrating agents, adhesives, solvents, lubricants and glidants. The epalrestat slow release composition has the advantages of good floatability, long-acting slow release, good quality uniformity, good stability, small variability, high bioavailability and the like, and the medication compliance and the safety and effectiveness of the medication of patients are obviously improved.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to an epalrestat slow-release composition, a preparation method and application thereof.
Background
Epalrestat (5- [ (1 z,2 e) -2-methyl-3-phenyl-2-propenylidene ] -4-oxo-2-thioxo-3-thiazolidineacetic acid) is an aldose reductase inhibitor class of drugs that act to reversibly inhibit the aldose reductase enzyme that converts glucose to sorbitol in the polyol metabolism associated with the pathogenesis of diabetic complications. Sorbitol can affect nerve cell function and accumulate within neurons causing symptoms of peripheral neuropathy that innervate sensory motor in diabetes. Epalrestat is clinically used for inhibiting sorbitol accumulation in erythrocytes of patients with peripheral neuropathy of diabetes, improving subjective symptoms and nerve dysfunction of the patients, and preventing, improving and treating diabetes and peripheral nerve dysfunction (numbness and pain) accompanied by diabetes. However, the patient needs to take the epalrestat tablet or epalrestat capsule three times per day. The compliance of the patient is reduced by taking the medicine for multiple times every day, the patient is easy to miss the medicine to cause the rise of blood sugar, even the problems of Diabetes Ketoacidosis (DKA) and the like are caused, and the occurrence rate of hypoglycemia caused by poor fasting blood sugar control, postprandial blood sugar control and nocturnal blood sugar control exist, so that the treatment effect of the medicine and the safety and effectiveness of the medicine are influenced. The epalrestat gastric floating tablet reported in the literature needs to be added with a gas generating agent (such as sodium bicarbonate and the like) and a bleaching aid (such as stearyl alcohol and the like), and has the defects of high cost, complex preparation and the like. For this reason, it is required to develop a safe and effective sustained-release preparation of epalrestat to meet clinical treatment requirements.
Disclosure of Invention
The invention aims to provide an epalrestat slow-release composition, which comprises 20-50% by weight of epalrestat or derivatives thereof and a pharmaceutically acceptable carrier, wherein the derivatives are selected from any one or combination of co-crystals, salts, free acids, prodrugs, esters, polymorphs and solvates, and the pharmaceutically acceptable carrier is selected from any one or combination of hydrogel materials, framework materials, fillers, disintegrants, adhesives, lubricants and glidants.
According to the preferred technical scheme, the epalrestat or the derivatives thereof in the composition accounts for 25-45% by weight, and preferably 30-40% by weight.
In a preferred embodiment of the invention, the hydrogel material in the composition is 5-20%, preferably 8-18%, more preferably 9-15% by weight.
In a preferred embodiment of the present invention, the hydrogel material is selected from any one of polyvinyl alcohol, water-swellable cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose K4M, hydroxyethyl cellulose, alginate, polyoxyethylene, carboxymethyl cellulose, povidone, chitosan, or a combination thereof.
In a preferred embodiment of the present invention, the matrix material in the composition is 5-20%, preferably 8-18%, more preferably 10-15% by weight.
In a preferred embodiment of the present invention, the framework material is selected from any one of water-insoluble cellulose, polyvinylpyrrolidone, acrylic resin, polyacrylate, ethylcellulose N10, or a combination thereof.
In a preferred embodiment of the present invention, the filler in the composition is 5-40%, preferably 10-35%, more preferably 15-30% by weight.
In a preferred embodiment of the present invention, the filler is selected from any one of starch, sucrose, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose SH-101, microcrystalline cellulose 102, or a combination thereof.
In a preferred embodiment of the present invention, the disintegrant in the composition is 10-35%, preferably 12-30%, more preferably 15-20% by weight.
In a preferred embodiment of the present invention, the disintegrating agent is selected from one or a combination of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and croscarmellose calcium.
In a preferred embodiment of the invention, the binder in the composition is 0-5%, preferably 0.5-2.5%, more preferably 1.5-2% by weight.
In a preferred embodiment of the present invention, the binder is selected from any one of low viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharide glycoside, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, starch slurry, methylcellulose, ethylcellulose, povidone, or a combination thereof.
In a preferred embodiment of the invention, the lubricant in the composition is 0.1-2%, preferably 0.15-1.8%, more preferably 0.2-0.5% by weight.
In a preferred embodiment of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, sodium lauryl sulfate, or a combination thereof.
In a preferred embodiment of the present invention, the glidant in the composition is 0-1%, preferably 0.2-0.8%, more preferably 0.4-0.6% by weight.
In a preferred embodiment of the present invention, the glidant is selected from any one of colloidal silicon dioxide, talcum powder and micro silica gel or a combination thereof.
In the preferred technical scheme of the invention, the composition comprises, by weight, 20-50% of epalrestat, 5-20% of a hydrogel material, 5-20% of a framework material, 5-40% of a filler, 10-35% of a disintegrating agent, 0-5% of an adhesive, 0.1-2% of a lubricant and 0-1% of a glidant.
In the preferred technical scheme of the invention, according to weight percentage, the epalrestat in the composition comprises 25-45%, hydrogel material 8-18%, framework material 8-18%, filler 10-35%, disintegrating agent 12-30%, adhesive 0.5-2.5%, lubricant 0.15-1.8% and glidant 0.2-0.8%.
In the preferred technical scheme of the invention, 30-40% of epalrestat, 9-15% of hydrogel material, 10-15% of framework material, 15-30% of filler, 15-20% of disintegrating agent, 1.5-2% of adhesive, 0.2-0.5% of lubricant and 0.4-0.6% of glidant in the composition by weight percentage.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 20-50%, microcrystalline cellulose 5-40%, hypromellose 5-20%, ethylcellulose 5-20%, crospovidone 10-35%, magnesium stearate or sodium stearate fumarate 0.1-2% and colloidal silicon dioxide 0-1% in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 25-45%, microcrystalline cellulose 10-35%, hypromellose 8-18%, ethylcellulose 8-18%, crospovidone 12-30%, magnesium stearate or sodium stearyl fumarate 0.15-1.8% and colloidal silicon dioxide 0.2-0.8% in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 30-40%, microcrystalline cellulose 15-30%, hypromellose 9-15%, ethylcellulose 10-15%, crospovidone 15-20%, magnesium stearate or sodium stearate fumarate 0.2-0.5% and colloidal silicon dioxide 0.4-0.6% are contained in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of epalrestat 20-50%, microcrystalline cellulose 5-40%, hypromellose 5-20%, ethylcellulose 5-20%, hypromellose 1-5%, crospovidone 10-35%, magnesium stearate or fumaric acid stearate is 0.1-2% and colloidal silicon dioxide 0.1-1%.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 25-45%, the microcrystalline cellulose 10-35%, the hypromellose 8-18%, the ethylcellulose 8-18%, the hypromellose 1-5%, the crospovidone 12-30%, the magnesium stearate or the sodium stearate fumarate 0.15-1.8% and the colloidal silicon dioxide 0.2-0.8% in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, the composition comprises 30-40% of epalrestat, 15-30% of microcrystalline cellulose, 9-15% of hypromellose, 10-15% of ethylcellulose, 1-5% of hypromellose, 15-20% of crospovidone, 0.2-0.5% of any one or combination of magnesium stearate and sodium stearate fumarate, and 0.4-0.6% of colloidal silicon dioxide.
In a preferred technical scheme of the invention, 34.88% of epalrestat, 9.30% of microcrystalline cellulose, 13.95% of hypromellose K4M, 16.28% of ethylcellulose, 5.81% of hypromellose E, 23.26% of crospovidone and 1.51% of magnesium stearate are contained in the composition in percentage by weight.
In a preferred technical scheme of the invention, 34.88% of epalrestat, 11.63% of microcrystalline cellulose, 12.79% of hypromellose K4M, 15.12% of ethylcellulose, 5.81% of hypromellose E, 23.26% of crospovidone and 1.51% of magnesium stearate are contained in the composition in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 6.98% of microcrystalline cellulose, 12.79% of hypromellose K4M, 15.12% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 11.62% of microcrystalline cellulose, 10.47% of hypromellose K4M, 12.79% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, according to weight percentage, the composition comprises 34.88% of epalrestat, 9.30% of microcrystalline cellulose, 13.95% of hypromellose K4M, 16.28% of ethylcellulose, 5.81% of hypromellose E, 23.26% of crospovidone and 1.51% of sodium stearyl fumarate.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 13.95% of microcrystalline cellulose, 9.30% of hypromellose K4M, 11.63% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 15.12% of microcrystalline cellulose, 8.72% of hypromellose K4M, 11.05% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 13.60% of microcrystalline cellulose, 10.47% of hypromellose K4M, 11.63% of ethylcellulose E, 27.91% of crospovidone and 1.51% of magnesium stearate by weight percent.
In a preferred embodiment of the invention, the composition comprises, by weight, 31.25% of epalrestat, 30.31% of microcrystalline cellulose, 9.9% of hypromellose K4M, 10.42% of ethylcellulose, 0.73% of hypromellose E, 16.67% of crospovidone, 0.52% of magnesium stearate, and 0.21% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 27.9% of microcrystalline cellulose, 4M 9% of hypromellose, 11% of ethylcellulose, 5.5% of hypromellose E, 20% of crospovidone, 0.2% of magnesium stearate and 0.4% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 27.4% of microcrystalline cellulose, 9% of hypromellose, 11% of ethylcellulose, 2% of hyprolose, 20% of crospovidone, 0.2% of magnesium stearate and 0.4% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 22.4% of microcrystalline cellulose, 11% of hypromellose, 14% of ethylcellulose, 2% of hyprolose, 20% of crospovidone, 0.2% of magnesium stearate and 0.4% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 26.6% of microcrystalline cellulose, 12% of hypromellose, 14% of ethylcellulose, 1% of hyprolose, 16% of crospovidone, 0.2% of magnesium stearate and 0.2% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 31.3% of epalrestat, 27.7% of microcrystalline cellulose, 12.5% of hypromellose, 14.6% of ethylcellulose, 1% of hydroxypropyl cellulose, 12.5% of crospovidone, 0.2% of magnesium stearate and 0.2% of colloidal silicon dioxide.
In a preferred embodiment of the present invention, the sustained release composition optionally contains a solvent, preferably a solvent selected from any one of water, ethanol or a combination thereof.
In a preferred embodiment of the present invention, the sustained-release composition is a gastric floating tablet.
In a preferred embodiment of the present invention, the gastric floating tablet immediately floats in simulated gastric fluid (pH 1.2).
In the preferable technical scheme of the invention, the floating time of the gastric floating tablet in simulated gastric fluid (pH 1.2) is more than or equal to 8 hours, preferably more than or equal to 24 hours, and more preferably more than or equal to 72 hours.
In the preferable technical scheme of the invention, the dissolution rate of the gastric floating tablet in phosphate buffer solution (pH 6.8) for 8 hours is more than or equal to 80%, preferably more than or equal to 90%.
In the preferable technical scheme of the invention, the dissolution rate of the gastric floating tablet in phosphate buffer solution (pH 6.8) for 12h is more than or equal to 90%, preferably more than or equal to 95%.
The invention further aims to provide a preparation method of the epalrestat slow-release composition, which comprises 20-50% of epalrestat or derivatives thereof and a pharmaceutically acceptable carrier in percentage by weight, wherein the derivatives are selected from any one or combination of co-crystals, salts, free acids, prodrugs, esters, polymorphs and solvates, the pharmaceutically acceptable carrier is selected from any one or combination of hydrogel materials, framework materials, fillers, disintegrants, adhesives, lubricants and glidants, and the preparation of the composition is selected from any one of a powder direct compression method and a wet granulation method.
According to the preferred technical scheme, the epalrestat or the derivatives thereof in the composition accounts for 25-45% by weight, and preferably 30-40% by weight.
In a preferred embodiment of the invention, the hydrogel material in the composition is 5-20%, preferably 8-18%, more preferably 9-15% by weight.
In a preferred embodiment of the present invention, the hydrogel material is selected from any one of polyvinyl alcohol, water-swellable cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose K4M, hydroxyethyl cellulose, alginate, polyoxyethylene, carboxymethyl cellulose, povidone, chitosan, or a combination thereof.
In a preferred embodiment of the present invention, the matrix material in the composition is 5-20%, preferably 8-18%, more preferably 10-15% by weight.
In a preferred embodiment of the present invention, the framework material is selected from any one of water-insoluble cellulose, polyvinylpyrrolidone, acrylic resin, polyacrylate, ethylcellulose N10, or a combination thereof.
In a preferred embodiment of the present invention, the filler in the composition is 5-40%, preferably 10-35%, more preferably 15-30% by weight.
In a preferred embodiment of the present invention, the filler is selected from any one of starch, sucrose, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose SH-101, microcrystalline cellulose 102, or a combination thereof.
In a preferred embodiment of the present invention, the disintegrant in the composition is 10-35%, preferably 12-30%, more preferably 15-20% by weight.
In a preferred embodiment of the present invention, the disintegrating agent is selected from one or a combination of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and croscarmellose calcium.
In a preferred embodiment of the invention, the binder in the composition is 0-5%, preferably 0.5-2.5%, more preferably 1.5-2% by weight.
In a preferred embodiment of the present invention, the binder is selected from any one of low viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharide glycoside, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, starch slurry, methylcellulose, ethylcellulose, povidone, or a combination thereof.
In a preferred embodiment of the invention, the lubricant in the composition is 0.1-2%, preferably 0.15-1.8%, more preferably 0.2-0.5% by weight.
In a preferred embodiment of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, sodium lauryl sulfate, or a combination thereof.
In a preferred embodiment of the present invention, the glidant in the composition is 0-1%, preferably 0.2-0.8%, more preferably 0.4-0.6% by weight.
In a preferred embodiment of the present invention, the glidant is selected from any one of colloidal silicon dioxide, talcum powder and micro silica gel or a combination thereof.
In the preferred technical scheme of the invention, the composition comprises, by weight, 20-50% of epalrestat, 5-20% of a hydrogel material, 5-20% of a framework material, 5-40% of a filler, 10-35% of a disintegrating agent, 0-5% of an adhesive, 0.1-2% of a lubricant and 0-1% of a glidant.
In the preferred technical scheme of the invention, according to weight percentage, the epalrestat in the composition comprises 25-45%, hydrogel material 8-18%, framework material 8-18%, filler 10-35%, disintegrating agent 12-30%, adhesive 0.5-2.5%, lubricant 0.15-1.8% and glidant 0.2-0.8%.
In the preferred technical scheme of the invention, 30-40% of epalrestat, 9-15% of hydrogel material, 10-15% of framework material, 15-30% of filler, 15-20% of disintegrating agent, 1.5-2% of adhesive, 0.2-0.5% of lubricant and 0.4-0.6% of glidant in the composition by weight percentage.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 20-50%, microcrystalline cellulose 5-40%, hypromellose 5-20%, ethylcellulose 5-20%, crospovidone 10-35%, magnesium stearate or sodium stearate fumarate 0.1-2% and colloidal silicon dioxide 0-1% in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 25-45%, microcrystalline cellulose 10-35%, hypromellose 8-18%, ethylcellulose 8-18%, crospovidone 12-30%, magnesium stearate or sodium stearyl fumarate 0.15-1.8% and colloidal silicon dioxide 0.2-0.8% in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 30-40%, microcrystalline cellulose 15-30%, hypromellose 9-15%, ethylcellulose 10-15%, crospovidone 15-20%, magnesium stearate or sodium stearate fumarate 0.2-0.5% and colloidal silicon dioxide 0.4-0.6% are contained in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or the combination of the epalrestat 20-50%, the microcrystalline cellulose 5-40%, the hypromellose 5-20%, the ethylcellulose 5-20%, the hypromellose 1-5%, the crospovidone 10-35%, the magnesium stearate or the sodium stearate fumarate 0.1-2% and the colloidal silicon dioxide 0.1-1% are contained in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, any one or combination of the epalrestat 25-45%, the microcrystalline cellulose 10-35%, the hypromellose 8-18%, the ethylcellulose 8-18%, the hypromellose 1-5%, the crospovidone 12-30%, the magnesium stearate or the sodium stearate fumarate 0.15-1.8% and the colloidal silicon dioxide 0.2-0.8% in the composition.
In the preferred technical scheme of the invention, according to the weight percentage, the composition comprises 30-40% of epalrestat, 15-30% of microcrystalline cellulose, 9-15% of hypromellose, 10-15% of ethylcellulose, 1-5% of hypromellose, 15-20% of crospovidone, 0.2-0.5% of any one or combination of magnesium stearate and sodium stearate fumarate, and 0.4-0.6% of colloidal silicon dioxide.
In a preferred technical scheme of the invention, 34.88% of epalrestat, 9.30% of microcrystalline cellulose, 13.95% of hypromellose K4M, 16.28% of ethylcellulose, 5.81% of hypromellose E, 23.26% of crospovidone and 1.51% of magnesium stearate are contained in the composition in percentage by weight.
In a preferred technical scheme of the invention, 34.88% of epalrestat, 11.63% of microcrystalline cellulose, 12.79% of hypromellose K4M, 15.12% of ethylcellulose, 5.81% of hypromellose E, 23.26% of crospovidone and 1.51% of magnesium stearate are contained in the composition in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 6.98% of microcrystalline cellulose, 12.79% of hypromellose K4M, 15.12% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 11.62% of microcrystalline cellulose, 10.47% of hypromellose K4M, 12.79% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, according to weight percentage, the composition comprises 34.88% of epalrestat, 9.30% of microcrystalline cellulose, 13.95% of hypromellose K4M, 16.28% of ethylcellulose, 5.81% of hypromellose E, 23.26% of crospovidone and 1.51% of sodium stearyl fumarate.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 13.95% of microcrystalline cellulose, 9.30% of hypromellose K4M, 11.63% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 15.12% of microcrystalline cellulose, 8.72% of hypromellose K4M, 11.05% of ethylcellulose, 5.81% of hypromellose E, 27.91% of crospovidone and 1.51% of magnesium stearate in percentage by weight.
In a preferred technical scheme of the invention, the composition comprises 34.88% of epalrestat, 13.60% of microcrystalline cellulose, 10.47% of hypromellose K4M, 11.63% of ethylcellulose E, 27.91% of crospovidone and 1.51% of magnesium stearate by weight percent.
In a preferred embodiment of the invention, the composition comprises, by weight, 31.25% of epalrestat, 30.31% of microcrystalline cellulose, 9.9% of hypromellose K4M, 10.42% of ethylcellulose, 0.73% of hypromellose E, 16.67% of crospovidone, 0.52% of magnesium stearate, and 0.21% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 27.9% of microcrystalline cellulose, 4M 9% of hypromellose, 11% of ethylcellulose, 5.5% of hypromellose E, 20% of crospovidone, 0.2% of magnesium stearate and 0.4% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 27.4% of microcrystalline cellulose, 9% of hypromellose, 11% of ethylcellulose, 2% of hyprolose, 20% of crospovidone, 0.2% of magnesium stearate and 0.4% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 22.4% of microcrystalline cellulose, 11% of hypromellose, 14% of ethylcellulose, 2% of hyprolose, 20% of crospovidone, 0.2% of magnesium stearate and 0.4% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 30% of epalrestat, 26.6% of microcrystalline cellulose, 12% of hypromellose, 14% of ethylcellulose, 1% of hyprolose, 16% of crospovidone, 0.2% of magnesium stearate and 0.2% of colloidal silicon dioxide.
In a preferred embodiment of the invention, the composition comprises, by weight, 31.3% of epalrestat, 27.7% of microcrystalline cellulose, 12.5% of hypromellose, 14.6% of ethylcellulose, 1% of hydroxypropyl cellulose, 12.5% of crospovidone, 0.2% of magnesium stearate and 0.2% of colloidal silicon dioxide.
In a preferred embodiment of the present invention, the sustained-release composition is a gastric floating tablet.
In a preferred embodiment of the present invention, the gastric floating tablet immediately floats in simulated gastric fluid (pH 1.2).
In the preferable technical scheme of the invention, the floating time of the gastric floating tablet in simulated gastric fluid (pH 1.2) is more than or equal to 8 hours, preferably more than or equal to 24 hours, and more preferably more than or equal to 72 hours.
In the preferable technical scheme of the invention, the dissolution rate of the gastric floating tablet in phosphate buffer solution (pH 6.8) for 8 hours is more than or equal to 80%, preferably more than or equal to 90%.
In the preferable technical scheme of the invention, the dissolution rate of the gastric floating tablet in phosphate buffer solution (pH 6.8) for 12h is more than or equal to 90%, preferably more than or equal to 95%.
In a preferred technical scheme of the invention, the powder direct compression method comprises the following steps of: weighing any one or combination of epalrestat, hydrogel material, skeleton material, filler, disintegrating agent, adhesive, lubricant and glidant, mixing, and tabletting.
In a preferred embodiment of the present invention, the sustained release composition optionally contains a solvent, preferably a solvent selected from any one of water, ethanol or a combination thereof.
In a preferred technical scheme of the invention, the wet granulation method comprises the following steps: 1) Weighing any one or combination of epalrestat, filler, hydrogel material, skeleton material and disintegrating agent, mixing, adding solvent, granulating, and drying to obtain dry granule; 2) Uniformly mixing the prepared dry particles with any one or combination of a binding agent, a lubricant and a glidant in required amount, and tabletting, wherein the solvent is selected from any one or combination of water and ethanol.
In a preferred embodiment of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying, spray drying, and fluidized bed drying.
In a preferred embodiment of the present invention, the drying temperature is 55-75deg.C, preferably 60-70deg.C.
In a preferred embodiment of the present invention, the moisture content of the dry particles is less than or equal to 5.0%, preferably less than or equal to 3.0%.
The invention further aims at an epalrestat slow-release preparation which at least comprises a slow-release floating layer, wherein the slow-release floating layer contains a hydrogel material and a framework material, and the hydrogel material in the slow-release preparation comprises the following components: the mass ratio of epalrestat is 0.25-0.4:1, framework material: the mass ratio of epalrestat is 0.2-0.5:1, the hydrogel material is selected from any one or combination of polyvinyl alcohol, water swelling cellulose, carrageenan, xanthan gum, guar gum, acacia gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose K4M, and the framework material is selected from any one or combination of water insoluble cellulose, polyvinylpyrrolidone, acrylic resin, polyacrylate and ethylcellulose N10.
In a preferred technical scheme of the invention, the matrix material in the sustained-release preparation is as follows: the mass ratio of epalrestat is 0.3-0.5:1.
In a preferred embodiment of the present invention, the sustained release preparation further comprises a filler, and the filler is selected from any one of microcrystalline cellulose, microcrystalline cellulose SH-101, microcrystalline cellulose 102, or a combination thereof.
In a preferred embodiment of the present invention, the filler in the sustained-release preparation: the mass ratio of epalrestat is 0.2-1:1, preferably 0.3-0.4:1, more preferably 0.7-1:1.
In a preferred embodiment of the present invention, the sustained release preparation optionally contains any one of a disintegrant, a binder, a solvent, a glidant, a lubricant, or a combination thereof.
In a preferred embodiment of the present invention, the disintegrant is crospovidone.
In a preferred embodiment of the present invention, the disintegrating agent in the sustained release formulation: the mass ratio of epalrestat is 0.5-0.8:1.
In a preferred embodiment of the present invention, the binder is selected from any one of low viscosity cellulose, acrylic acid polymer, hyaluronic acid, alginic acid, polysaccharide glycoside, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, or a combination thereof.
In a preferred embodiment of the present invention, the binder in the sustained release formulation: the mass ratio of epalrestat is 1:50-1:15.
In a preferred embodiment of the present invention, the lubricant is magnesium stearate.
In a preferred embodiment of the present invention, the lubricant in the sustained release formulation: the mass ratio of epalrestat is 0.005-0.05:1.
In a preferred embodiment of the present invention, the glidant is colloidal silicon dioxide.
In a preferred technical scheme of the invention, the glidant in the slow-release preparation comprises the following components: the mass ratio of epalrestat is 0.005-0.05:1.
The invention also aims to provide the application of the epalrestat slow release composition or the slow release preparation in preparing medicines for preventing and treating diabetes and complications thereof.
In a preferred embodiment of the present invention, the complication is any one or a combination of peripheral nerve disorder, numbness and pain associated with diabetes.
According to the preferable technical scheme, proper dosage and treatment course are selected according to factors such as illness state, medication, age, sex, illness type and the like of a patient. The adult patient takes one tablet (dosage of 150 mg) once a day.
The immediate bleaching as used herein, unless otherwise indicated, refers to bleaching within 5 minutes of placing the gastric-floating tablets in simulated gastric fluid (pH 1.2).
The impurity content detection according to the invention, unless otherwise indicated, uses a high performance liquid chromatograph with chromatographic conditions of: octadecylsilane chemically bonded silica is used as a filler, a mobile phase A is disodium hydrogen phosphate solution- (pH is regulated to 6.0 by phosphoric acid) -acetonitrile (75:25), a mobile phase B is acetonitrile, gradient elution is carried out (the volume ratio of the mobile phase A to the mobile phase B is respectively 100:0, 85:15, 80:20, 20:80 and 0:100, and elution is carried out for 0-60 min), the flow rate is 1.0ml/min, the column temperature is 35 ℃, the detection wavelength is 280nm, and the sample injection volume is 10 mu l.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial technical effects:
1. The invention scientifically screens the components and the proportion of the epalrestat slow-release composition, omits the use of a gas generating agent (such as sodium bicarbonate and the like) and a bleaching aid (such as stearyl alcohol and the like), and the prepared gastric floating tablet has the advantages of good floating performance, long-acting slow release, better quality (including good quality uniformity, complete tablet, no splinter or fragments, smaller tablet weight and the like), good stability, small variability, high bioavailability, safety, effectiveness and the like, is beneficial to fasting blood glucose control, postprandial blood glucose control and nocturnal blood glucose control, obviously reduces the incidence of hypoglycemia, obviously improves the medication compliance, treatment compliance and persistence of patients, and obviously improves the safety and effectiveness of clinical medication.
2. The preparation of the epalrestat slow-release composition has the advantages of simplicity and convenience in operation, better cost, environment friendliness, suitability for industrial production and the like.
Drawings
FIG. 1 in vitro release profile study of the epalrestat slow release composition of the invention.
Figure 2 in vivo absorption studies of epalrestat slow release compositions of the invention.
Detailed Description
The following detailed description of the invention is provided in connection with specific embodiments, but is not intended to limit the scope of the invention.
Related substances (impurities) of the embodiment are numbered and composition:
| Numbering device | Impurity composition |
| Impurity A | Epalrestat 1E,2Z isomer |
| Impurity B | Epalrestat 1E,2E isomer |
| Impurity C | Epalrestat 1Z,2Z isomer |
| Impurity D | Alpha-methyl cinnamaldehyde |
| Impurity F | Epalrestat dimer |
| Impurity H | Epalrestat ethyl ester |
EXAMPLE 1 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 5.75 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 8h.
EXAMPLE 2 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 50 |
| Hydroxypropyl methylcellulose K4M | 55 |
| Ethylcellulose N10 | 65 |
| Hydroxypropyl methylcellulose E5 | 3.5 |
| Crospovidone KCL | 100 |
| Magnesium stearate | 6.5 |
| Totalizing | 430 |
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 5.58 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 8h.
EXAMPLE 3 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 5.6 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 8h.
EXAMPLE 4 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 50 |
| Hydroxypropyl methylcellulose K4M | 45 |
| Ethylcellulose N10 | 55 |
| Hydroxypropyl methylcellulose E5 | 3.5 |
| Crospovidone KCL | 120 |
| Magnesium stearate | 6.5 |
| Totalizing | 430 |
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 5.68 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 5 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH102 | 40 |
| Hydroxypropyl methylcellulose K4M | 60 |
| Ethylcellulose N10 | 70 |
| Hydroxypropyl methylcellulose E5 | 3.5 |
| Crospovidone KCL | 100 |
| Stearyl sodium fumarate | 6.5 |
| Totalizing | 430 |
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 6.08 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 6 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 60 |
| Hydroxypropyl methylcellulose K4M | 40 |
| Ethylcellulose N10 | 50 |
| Hydroxypropyl methylcellulose E5 | 3.5 |
| Crospovidone KCL | 120 |
| Magnesium stearate | 6.5 |
| Totalizing | 430 |
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 5.78 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 7 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 65 |
| Hydroxypropyl methylcellulose K4M | 37.5 |
| Ethylcellulose N10 | 47.5 |
| Hydroxypropyl methylcellulose E5 | 3.5 |
| Crospovidone KCL | 120 |
| Magnesium stearate | 6.5 |
| Totalizing | 430 |
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 6.15 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 8 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 58.5 |
| Hydroxypropyl methylcellulose K4M | 45 |
| Ethylcellulose N10 | 50 |
| Crospovidone KCL | 120 |
| Magnesium stearate | 6.5 |
| Totalizing | 430 |
The preparation of the epalrestat slow release composition comprises the following steps: weighing the components with required amount, uniformly mixing, and directly tabletting to obtain the tablet (the tablet thickness is 6.08 mm). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 9 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 145.5 |
| Hydroxypropyl methylcellulose K4M | 47.5 |
| Ethylcellulose N10 | 50 |
| Hydroxypropyl methylcellulose E5 | 3.5 |
| Crospovidone KCL | 80 |
| Magnesium stearate | 2.5 |
| Colloidal silica | 1 |
| Totalizing | 480 |
The preparation of the epalrestat slow release composition comprises the following steps:
1. Weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded, agglomerated and scattered when touched') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the moisture is less than or equal to 3.0 percent);
2. uniformly mixing the prepared particles with required amount of hypromellose E5, magnesium stearate and colloidal silicon dioxide, and tabletting to obtain the final product (tablet thickness 6.42 mm).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 10 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (batch 600 tablets):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 139.5 |
| Hydroxypropyl methylcellulose K4M | 45 |
| Ethylcellulose N10 | 55 |
| Hydroxypropyl methylcellulose E5 | 7.5 |
| Crospovidone KCL | 100 |
| Magnesium stearate | 1 |
| Colloidal silica | 2 |
| Totalizing | 500 |
The preparation of the epalrestat slow release composition comprises the following steps:
1. Weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded, agglomerated and scattered when touched') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the moisture is less than or equal to 3.0 percent);
2. The granules were uniformly mixed with the required amounts of hypromellose E5, magnesium stearate, and colloidal silica, and then tabletted (tablet thickness 6.59 mm).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 11 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (batch 600 tablets):
The preparation of the epalrestat slow release composition comprises the following steps:
1. Weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded, agglomerated and scattered when touched') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the moisture is less than or equal to 3.0 percent);
2. uniformly mixing the prepared particles with the required amount of hypromellose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting to obtain the tablet (the tablet thickness is 6.56 mm).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 12 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (batch 600 tablets):
The preparation of the epalrestat slow release composition comprises the following steps:
1. Weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded, agglomerated and scattered when touched') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the moisture is less than or equal to 3.0 percent);
2. uniformly mixing the prepared particles with the required amount of hypromellose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting to obtain the tablet (the tablet thickness is 6.57 mm).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art.
EXAMPLE 13 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 133 |
| Hydroxypropyl methylcellulose K4M | 60 |
| Ethylcellulose N10 | 70 |
| Hydroxypropyl methylcellulose EXF | 5 |
| Crospovidone KCL | 80 |
| Magnesium stearate | 1 |
| Colloidal silica | 1 |
| Totalizing | 500 |
The preparation of the epalrestat slow release composition comprises the following steps:
1. Weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL, uniformly mixing, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded, agglomerated and scattered when touched') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the moisture is less than or equal to 3.0 percent);
2. Uniformly mixing the prepared particles with the required amount of hypromellose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting to obtain the tablet (the tablet thickness is 6.28 mm).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 8h.
EXAMPLE 14 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat sustained release composition (400 tablets in batch):
| Component (A) | Each tablet is composed (mg) |
| Epalrestat | 150 |
| Microcrystalline cellulose SH101 | 133 |
| Hydroxypropyl methylcellulose K4M | 60 |
| Ethylcellulose N10 | 70 |
| Hydroxypropyl methylcellulose EXF | 5 |
| Crospovidone KCL | 60 |
| Magnesium stearate | 1 |
| Colloidal silica | 1 |
| Totalizing | 480 |
The preparation of the epalrestat slow release composition comprises the following steps:
1. Weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL, uniformly mixing, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded, agglomerated and scattered when touched') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the moisture is less than or equal to 3.0 percent);
2. uniformly mixing the prepared particles with the required amount of hydroxypropyl methylcellulose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting to obtain the finished product (the tablet thickness is 6.04 mm).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 8h.
EXAMPLE 15 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 16 |
| Hydroxypropyl methylcellulose K4M | 24 |
| Ethylcellulose N10 | 28 |
| Hydroxypropyl methylcellulose E5 | 1.4 |
| Crosslinked povidone KCL-F | 40 |
| Magnesium stearate | 2.6 |
| Totalizing | 172 |
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 16 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 17 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 12 |
| Hydroxypropyl methylcellulose K4M | 22 |
| Ethylcellulose N10 | 26 |
| Hydroxypropyl methylcellulose E5 | 1.4 |
| Crosslinked povidone KCL-F | 48 |
| Magnesium stearate | 2.6 |
| Totalizing | 172 |
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 18 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 20 |
| Hydroxypropyl methylcellulose K4M | 18 |
| Ethylcellulose N10 | 22 |
| Hydroxypropyl methylcellulose E5 | 1.4 |
| Crosslinked povidone KCL-F | 48 |
| Magnesium stearate | 2.6 |
| Totalizing | 172 |
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 19 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH102 | 16 |
| Hydroxypropyl methylcellulose K4M | 24 |
| Ethylcellulose N10 | 28 |
| Hydroxypropyl methylcellulose E5 | 1.4 |
| Crosslinked povidone KCL-F | 40 |
| Stearyl sodium fumarate | 2.6 |
| Totalizing | 172 |
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 20 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 24 |
| Hydroxypropyl methylcellulose K4M | 16 |
| Ethylcellulose N10 | 20 |
| Hydroxypropyl methylcellulose E5 | 1.4 |
| Crosslinked povidone KCL-F | 48 |
| Magnesium stearate | 2.6 |
| Totalizing | 172 |
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 21 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 22 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 23.4 |
| Hydroxypropyl methylcellulose K4M | 18 |
| Ethylcellulose N10 | 20 |
| Crosslinked povidone KCL-F | 48 |
| Magnesium stearate | 2.6 |
| Totalizing | 172 |
The preparation of the epalrestat slow release composition comprises the following steps: the components with the required amount are weighed, evenly mixed and directly pressed into tablets, thus obtaining the medicine (each tablet weighs 430 mg). The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 23 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 58.2 |
| Hydroxypropyl methylcellulose K4M | 19 |
| Ethylcellulose N10 | 20 |
| Hydroxypropyl methylcellulose E5 | 1.4 |
| Crosslinked povidone KCL-F | 32 |
| Magnesium stearate | 1 |
| Colloidal silica | 0.4 |
| Totalizing | 192 |
The preparation of the epalrestat slow release composition comprises the following steps:
1. weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL-F, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded into clusters and dispersed immediately after touching') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the water content is less than or equal to 3.0 percent);
2. The granules were uniformly mixed with the required amounts of hypromellose E5, magnesium stearate, and colloidal silica, and then tabletted (weight of 480mg per tablet).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 24 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
The preparation of the epalrestat slow release composition comprises the following steps:
1. weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL-F, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded into clusters and dispersed immediately after touching') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the water content is less than or equal to 3.0 percent);
2. Uniformly mixing the prepared granules with required amount of hypromellose E5, magnesium stearate and colloidal silicon dioxide, and tabletting (each tablet weighs 500 mg).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 25 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
The preparation of the epalrestat slow release composition comprises the following steps:
1. weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL-F, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded into clusters and dispersed immediately after touching') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the water content is less than or equal to 3.0 percent);
2. Uniformly mixing the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting (each tablet weighs 500 mg).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The resulting tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for 48h.
EXAMPLE 26 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
The preparation of the epalrestat slow release composition comprises the following steps:
1. weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL-F, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded into clusters and dispersed immediately after touching') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the water content is less than or equal to 3.0 percent);
2. Uniformly mixing the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting (each tablet weighs 500 mg).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The resulting tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for 72h.
EXAMPLE 27 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
The preparation of the epalrestat slow release composition comprises the following steps:
1. weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL-F, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded into clusters and dispersed immediately after touching') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the water content is less than or equal to 3.0 percent);
2. Uniformly mixing the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and tabletting (each tablet weighs 500 mg).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
EXAMPLE 28 preparation of the Epalrestat sustained-release composition of the present invention
Composition of epalrestat slow release composition:
| Component (A) | Dosage (g) |
| Epalrestat | 60 |
| Microcrystalline cellulose SH101 | 53.2 |
| Hydroxypropyl methylcellulose K4M | 24 |
| Ethylcellulose N10 | 28 |
| Hydroxypropyl cellulose EXF | 2 |
| Crosslinked povidone KCL-F | 24 |
| Magnesium stearate | 0.4 |
| Colloidal silica | 0.4 |
| Totalizing | 192 |
The preparation of the epalrestat slow release composition comprises the following steps:
1. weighing required amounts of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethylcellulose N10 and crospovidone KCL-F, uniformly mixing the materials, adding a proper amount of water (the water dosage is proper for the granules to be 'kneaded into clusters and dispersed immediately after touching') under the stirring condition of 450rpm to prepare medicine-containing wet granules, and drying the medicine-containing wet granules in a fluidized bed (60 ℃) to prepare granules (the water content is less than or equal to 3.0 percent);
2. the obtained granules were uniformly mixed with the required amounts of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silica, and then tabletted (weight of each tablet: 480 mg).
The quality of the tablets obtained is stable, the tablets are complete and free of splits and fragments, as measured by methods conventional in the art. The prepared tablets were placed in simulated gastric fluid (pH 1.2) which floated immediately for > 12h.
Test example 1 stability investigation of the epalrestat slow-release composition of the invention
Taking the sustained-release composition of example 26 as an example, the stability of the sustained-release composition of the present invention was examined by leaving it at 40℃under a Relative Humidity (RH) of 75% for 6 months, and the results are shown in Table 1. The sustained release composition of the present invention has complete tablet shape and no discoloration, pitting, cracking, chipping, etc. in the investigation period of 6 months.
Table 1 investigation of stability of the sustained-release composition of example 26
The sustained-release composition of the remaining examples of the present invention was examined by this method, and exhibited similarly excellent stability.
Test example 2 investigation of in vitro Release degree of Epalrestat sustained-release composition of the invention
According to the dissolution and release rate measurement method of the second method of the four general rules 0931 of the Chinese pharmacopoeia (2020 edition), 900ml of phosphate buffer (pH6.8+0.5% Tween 80) is taken as a dissolution medium, and the slurry method (100 revolutions/min) is taken as an example, and the sustained release compositions of examples 1-2, 21-23 and 25-26 are taken as examples, and the in vitro release rate of the epalrestat sustained release composition of the invention is measured for 1h, 2h, 4h, 6h, 8h and 12h, and the result is shown in FIG. 1.
Experimental example 3 quality uniformity investigation of the epalrestat sustained-release composition of the invention
Taking the sustained-release compositions prepared in example 25 and example 26 as examples, the mass uniformity of the epalrestat sustained-release composition of the present invention was examined, and the results are shown in table 2. The epalrestat slow release composition has good quality uniformity.
TABLE 2
Experimental example 4 in vivo absorption study of Epalrestat sustained-release composition of the present invention
The absorption condition of the epalrestat slow release preparation in vivo is studied. The epalrestat sustained release tablets prepared in the example 2 and the example 6 and the original ground common tablet are subjected to biological experimental tests, and a small pig animal model is adopted for oral administration. The sustained-release tablets prepared in example 2 and example 6 were administered once, the amount of epalrestat administered once was 150mg, and the conventional tablet of epalrestat which was ground was administered once every 8 hours, and the result was shown in fig. 2A.
The epalrestat slow release composition of the invention has long-acting slow release, is favorable for fasting blood glucose control, postprandial blood glucose control and nocturnal blood glucose control, obviously reduces the incidence of hypoglycemia, improves the medication compliance and the treatment persistence of patients, and ensures the safety and effectiveness of clinical medication.
Experimental example 5 in vivo absorption study of epalrestat slow release composition of the present invention
6 Pigs (male and female halves) with weight of 9-15kg and month age of 3-6 months are selected, and divided into 3 groups of 2 pigs (male and female halves) for gastric administration. The test animals were fasted prior to dosing.
Control group: the formulation (trade name: KINEDAK) was administered by gavage, each dose being 50mg, 3 times per day at 8h intervals.
Test group 1: the sustained-release composition of example 25 was administered by gavage at a dose of 150mg 1 time per day.
Test group 2: the sustained-release composition of example 26 was administered by gavage at a dose of 150mg 1 time per day.
Control group before and after administration blood samples are collected for detection at 0.25h,0.5h,1h,2h,4h,8h,8.25h,8.5h,9h,10h,12h,16h,16.25h,16.5h,17h,18h,20h and 24 h; test groups before and after administration blood samples were collected for testing at 0.25h,0.5h,1h,2h,4h,6h,8h,12h,16h,24 h. The results are shown in FIG. 2B.
The epalrestat slow release composition of the invention has long-acting slow release, is favorable for fasting blood glucose control, postprandial blood glucose control and nocturnal blood glucose control, obviously reduces the incidence of hypoglycemia, improves the medication compliance and the treatment persistence of patients, and ensures the safety and effectiveness of clinical medication.
The above description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art can make various changes or modifications according to the present invention without departing from the spirit of the present invention, and shall fall within the scope of the claims of the present invention.
Claims (64)
1. The epalrestat gastric floating tablet comprises, by weight, 20-50% of epalrestat, 5-20% of a hydrogel material, 5-20% of a framework material, 5-40% of a filling agent, 10-35% of a disintegrating agent, 0-5% of an adhesive, 0.1-2% of a lubricant and 0-1% of a glidant, wherein the epalrestat gastric floating tablet does not contain a glidant and a gas generating agent, the hydrogel material is hypromellose, and the framework material is ethylcellulose;
the filler is selected from any one or combination of starch, sucrose, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol and microcrystalline cellulose;
The disintegrating agent is crospovidone;
The binder is selected from any one or combination of low-viscosity cellulose, acrylic acid polymer, hyaluronic acid, alginic acid, polysaccharide glycoside, hydroxypropyl methyl cellulose, starch slurry, methyl cellulose, ethyl cellulose and povidone;
The lubricant is any one or combination of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols and sodium dodecyl sulfate;
The glidant is selected from any one or combination of colloidal silicon dioxide, talcum powder and micro powder silica gel.
2. The gastric floating tablet of claim 1 wherein the epalrestat is 25-45% by weight of the gastric floating tablet.
3. The gastric floating tablet of claim 2 wherein the epalrestat is 30-40% by weight.
4. A gastric floating sheet according to any one of claims 1 to 3 wherein the hydrogel material is 8 to 18% by weight of the gastric floating sheet.
5. The gastric floating tablet of claim 4 wherein the hydrogel material is 9-15% by weight.
6. A gastric floating tablet according to any one of claims 1 to 3 wherein the hydrogel material is selected from hypromellose K4M.
7. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the matrix material is 8 to 18% by weight.
8. A gastric floating tablet as claimed in claim 7 wherein the matrix material is 10-15% by weight.
9. A gastric floating tablet according to any one of claims 1 to 3 wherein the matrix material is selected from ethylcellulose N10.
10.A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the filler is present in the gastric floating tablet in a weight percentage of 10 to 35%.
11. A gastric floating tablet as claimed in claim 10 wherein the filler is 15-30% by weight.
12. A gastric floating tablet according to any one of claims 1-3 wherein the filler is selected from any one of microcrystalline cellulose SH-101, microcrystalline cellulose 102 or a combination thereof.
13. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the disintegrant is 12 to 30% by weight.
14. A gastric floating tablet as claimed in claim 13 wherein the disintegrant is 15-20% by weight.
15. A gastric floating sheet as claimed in any one of claims 1 to 3 wherein the binder is present in the gastric floating sheet in a weight percentage of 0.5 to 2.5%.
16. A gastric floating sheet as claimed in claim 15 wherein the binder is 1.5-2% by weight.
17. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the binder is selected from any one of hypromellose E5, hypromellose EXF, or a combination thereof.
18. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the lubricant is present in the gastric floating tablet in a weight percentage of 0.15 to 1.8%.
19. A gastric floating tablet as claimed in claim 18 wherein the lubricant is present in the gastric floating tablet in a weight percentage of 0.2 to 0.5%.
20. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the glidant is 0.2 to 0.8% by weight of the gastric floating tablet.
21. A gastric floating tablet as claimed in claim 20 wherein the glidant is 0.4-0.6% by weight.
22. A gastric floating tablet as claimed in any one of claims 1 to 3, wherein the gastric floating tablet comprises, by weight, epalrestat 25-45%, hydrogel material 8-18%, matrix material 8-18%, filler 10-35%, disintegrant 12-30%, binder 0.5-2.5%, lubricant 0.15-1.8% and glidant 0.2-0.8%.
23. A gastric floating tablet as claimed in claim 22, wherein the gastric floating tablet comprises, by weight, 30-40% epalrestat, 9-15% hydrogel material, 10-15% framework material, 15-30% filler, 15-20% disintegrant, 1.5-2% binder, 0.2-0.5% lubricant and 0.4-0.6% glidant.
24. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the weight percent of epalrestat 20 to 50%, microcrystalline cellulose 5 to 40%, hypromellose 5 to 20%, ethylcellulose 5 to 20%, crospovidone 10 to 35%, any one of magnesium stearate or sodium stearate fumarate or a combination thereof and colloidal silicon dioxide 0 to 1%.
25. A gastric floating tablet as claimed in claim 24, wherein the gastric floating tablet comprises, by weight, from 25 to 45% of epalrestat, from 10 to 35% of microcrystalline cellulose, from 8 to 18% of hypromellose, from 8 to 18% of ethylcellulose, from 12 to 30% of crospovidone, from 0.15 to 1.8% of any one of magnesium stearate or sodium stearyl fumarate, or a combination thereof, and from 0.2 to 0.8% of colloidal silicon dioxide.
26. A gastric floating tablet as claimed in claim 25, wherein the gastric floating tablet comprises, by weight, about 30-40% epalrestat, about 15-30% microcrystalline cellulose, about 9-15% hypromellose, about 10-15% ethylcellulose, about 15-20% crospovidone, about 0.2-0.5% magnesium stearate or sodium stearate fumarate, or a combination thereof, and about 0.4-0.6% colloidal silicon dioxide.
27. A gastric floating tablet as claimed in any one of claims 1 to 3, wherein the gastric floating tablet comprises, by weight, from 20 to 50% of epalrestat, from 5 to 40% of microcrystalline cellulose, from 5 to 20% of hypromellose, from 5 to 20% of ethylcellulose, from 1 to 5% of hyprolose, from 10 to 35% of crospovidone, from 0.1 to 2% of any one of magnesium stearate or sodium stearate fumarate, or a combination thereof, and from 0.1 to 1% of colloidal silicon dioxide.
28. A gastric floating tablet as claimed in claim 27, wherein the gastric floating tablet comprises, by weight, from 25 to 45% of epalrestat, from 10 to 35% of microcrystalline cellulose, from 8 to 18% of hypromellose, from 8 to 18% of ethylcellulose, from 1 to 5% of hyprolose, from 12 to 30% of crospovidone, from 0.15 to 1.8% of any one of magnesium stearate or sodium stearate fumarate, or a combination thereof, and from 0.2 to 0.8% of colloidal silicon dioxide.
29. A gastric floating tablet as claimed in claim 28, wherein the gastric floating tablet comprises, by weight, about 30-40% epalrestat, about 15-30% microcrystalline cellulose, about 9-15% hypromellose, about 10-15% ethylcellulose, about 1-5% hyprolose, about 15-20% crospovidone, about 0.2-0.5% magnesium stearate or sodium stearate fumarate, or a combination thereof, and about 0.4-0.6% colloidal silicon dioxide.
30. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, by weight, epalrestat 34.88%, microcrystalline cellulose 9.30%, hypromellose K4M 13.95%, ethylcellulose 16.28%, hypromellose E5.81%, crospovidone 23.26% and magnesium stearate 1.51%.
31. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, by weight, epalrestat 34.88%, microcrystalline cellulose 11.63%, hypromellose K4M 12.79%, ethylcellulose 15.12%, hypromellose E5.81%, crospovidone 23.26% and magnesium stearate 1.51%.
32. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the weight percentages of epalrestat 34.88%, microcrystalline cellulose 6.98%, hypromellose K4M 12.79%, ethylcellulose 15.12%, hypromellose E5.81%, crospovidone 27.91% and magnesium stearate 1.51%.
33. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the weight percentages of epalrestat 34.88%, microcrystalline cellulose 11.62%, hypromellose K4M 10.47%, ethylcellulose 12.79%, hypromellose E5.81%, crospovidone 27.91% and magnesium stearate 1.51%.
34. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the weight percentages of epalrestat 34.88%, microcrystalline cellulose 9.30%, hypromellose K4M 13.95%, ethylcellulose 16.28%, hypromellose E5.81%, crospovidone 23.26% and sodium stearyl fumarate 1.51%.
35. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the weight percentages of epalrestat 34.88%, microcrystalline cellulose 13.95%, hypromellose K4M 9.30%, ethylcellulose 11.63%, hypromellose E5.81%, crospovidone 27.91% and magnesium stearate 1.51%.
36. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the weight percentages of epalrestat 34.88%, microcrystalline cellulose 15.12%, hypromellose K4M 8.72%, ethylcellulose 11.05%, hypromellose E5.81%, crospovidone 27.91% and magnesium stearate 1.51%.
37. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, by weight, epalrestat 34.88%, microcrystalline cellulose 13.60%, hypromellose K4M 10.47%, ethylcellulose E5.63%, crospovidone 27.91% and magnesium stearate 1.51%.
38. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, by weight, epalrestat 31.25%, microcrystalline cellulose 30.31%, hypromellose K4M 9.9%, ethylcellulose 10.42%, hypromellose E5.73%, crospovidone 16.67%, magnesium stearate 0.52% and colloidal silicon dioxide 0.21%.
39. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, in weight percent, epalrestat 30%, microcrystalline cellulose 27.9%, hypromellose K4M 9%, ethylcellulose 11%, hypromellose E5.5%, crospovidone 20%, magnesium stearate 0.2% and colloidal silicon dioxide 0.4%.
40. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, in weight percent, epalrestat 30%, microcrystalline cellulose 27.4%, hypromellose 9%, ethylcellulose 11%, hyprolose 2%, crospovidone 20%, magnesium stearate 0.2% and colloidal silicon dioxide 0.4%.
41. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, in weight percent, epalrestat 30%, microcrystalline cellulose 22.4%, hypromellose 11%, ethylcellulose 14%, hyprolose 2%, crospovidone 20%, magnesium stearate 0.2% and colloidal silicon dioxide 0.4%.
42. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, in weight percent, epalrestat 30%, microcrystalline cellulose 26.6%, hypromellose 12%, ethylcellulose 14%, hyprolose 1%, crospovidone 16%, magnesium stearate 0.2% and colloidal silicon dioxide 0.2%.
43. A gastric floating tablet as claimed in any one of claims 1 to 3 wherein the tablet comprises, by weight, epalrestat 31.3%, microcrystalline cellulose 27.7%, hypromellose 12.5%, ethylcellulose 14.6%, hyprolose 1%, crospovidone 12.5%, magnesium stearate 0.2% and colloidal silicon dioxide 0.2%.
44. A gastric floating tablet as claimed in any one of claims 1 to 3 further comprising a solvent.
45. A gastric floating tablet according to claim 44 wherein the solvent is selected from any one of water, ethanol or a combination thereof.
46. A gastric floating tablet as claimed in any one of claims 1 to 3 which immediately floats in simulated gastric fluid ph 1.2.
47. The gastric floating tablet of claim 46 having a floating time of 8h or longer in simulated gastric fluid pH 1.2.
48. The gastric floating tablet of claim 47 which floats for a period of not less than 24 hours in simulated gastric fluid pH 1.2.
49. The gastric floating tablet of claim 48 which floats for a period of time of > 72 hours in simulated gastric fluid pH 1.2.
50. A gastric floating tablet as claimed in any one of claims 1 to 3 having a dissolution rate of greater than or equal to 80% in phosphate buffer solution at ph6.8 for 8 hours.
51. The gastric floating tablet of claim 50 having a dissolution rate of 90% or more in phosphate buffered saline at pH6.8 for 8 hours.
52. The gastric floating tablet of claim 51 having a dissolution rate of 90% or more in phosphate buffered saline at pH6.8 for 12 hours.
53. The gastric floating tablet of claim 52 having a dissolution rate of 95% or more in phosphate buffered saline at pH6.8 for 12 hours.
54. The method for producing an epalrestat gastric floating tablet of any one of claims 1 to 53, wherein the production of the gastric floating tablet is selected from any one of a powder direct compression method and a wet granulation method.
55. The process of claim 54, wherein said powder direct compression process comprises the steps of: weighing any one or combination of epalrestat, hydrogel material, skeleton material, filler, disintegrating agent, adhesive, lubricant and glidant, mixing, and tabletting.
56. The process of claim 54, wherein said wet granulation comprises the steps of: 1) Weighing any one or combination of epalrestat, filler, hydrogel material, skeleton material and disintegrating agent, mixing, adding solvent, granulating, and drying to obtain dry granule; 2) Uniformly mixing the prepared dry particles with any one or combination of a binding agent, a lubricant and a glidant in required amount, and tabletting, wherein the solvent is selected from any one or combination of water and ethanol.
57. The process of claim 56, wherein said drying is selected from the group consisting of reduced pressure drying, vacuum drying, spray drying, and fluid bed drying.
58. The process of claim 56, wherein the drying temperature is 55-75deg.C.
59. The process of claim 58, wherein the drying temperature is 60-70deg.C.
60. The process of claim 56, wherein the dry particles have a moisture content of less than or equal to 5.0%.
61. The process of claim 60, wherein the dry particles comprise less than or equal to 3.0% water.
62. Use of epalrestat gastric floating tablet according to any one of claims 1 to 53 or epalrestat gastric floating tablet prepared by the method according to any one of claims 54 to 61 for preparing a medicament for preventing and treating diabetes and complications thereof.
63. The use of claim 62, wherein the complication is any one or a combination of peripheral neurological disorders, numbness, pain associated with diabetes.
64. The use according to any one of claims 62-63, wherein the appropriate dosage and course of treatment is selected according to the condition, administration, age, sex, type of illness of the patient, and is administered once a day to an adult patient, one at a time, in a dose of 150mg.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211623293X | 2022-12-16 | ||
| CN202211623293.XA CN115721621A (en) | 2022-12-16 | 2022-12-16 | Epalrestat sustained-release preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117717533A CN117717533A (en) | 2024-03-19 |
| CN117717533B true CN117717533B (en) | 2024-08-27 |
Family
ID=85301486
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211623293.XA Pending CN115721621A (en) | 2022-12-16 | 2022-12-16 | Epalrestat sustained-release preparation |
| CN202311736464.4A Pending CN117717532A (en) | 2022-12-16 | 2023-12-15 | Epalrestat gastric floating tablet, and preparation method and application thereof |
| CN202311738680.2A Active CN117717533B (en) | 2022-12-16 | 2023-12-15 | Epalrestat sustained-release composition, preparation method and application thereof |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211623293.XA Pending CN115721621A (en) | 2022-12-16 | 2022-12-16 | Epalrestat sustained-release preparation |
| CN202311736464.4A Pending CN117717532A (en) | 2022-12-16 | 2023-12-15 | Epalrestat gastric floating tablet, and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN115721621A (en) |
| WO (1) | WO2024125654A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115721621A (en) * | 2022-12-16 | 2023-03-03 | 杭州剂泰医药科技有限责任公司 | Epalrestat sustained-release preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102440976A (en) * | 2011-12-21 | 2012-05-09 | 南京海陵中药制药工艺技术研究有限公司 | Epalrestat sustained-release tablet and preparation method thereof |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4994570B2 (en) * | 2001-07-04 | 2012-08-08 | サン・ファーマ・アドバンスド・リサーチ・カンパニー・リミテッド | Stomach retention control drug delivery system |
| JP2005132803A (en) * | 2003-10-31 | 2005-05-26 | Ono Pharmaceut Co Ltd | Solid pharmaceutical preparation staying in stomach |
| US9566269B2 (en) * | 2011-01-20 | 2017-02-14 | Bionevia Pharmaceuticals Inc. | Modified release compositions of epalrestat or a derivative thereof and methods for using the same |
| CN104940156B (en) * | 2015-06-09 | 2018-06-12 | 扬子江药业集团南京海陵药业有限公司 | Epalrestat enteric-coated sustained-release tablet and preparation method thereof |
| KR20220048341A (en) * | 2020-10-12 | 2022-04-19 | 뉴지랩테라퓨틱스 주식회사 | Controlled release formulations comprising nafamostat or pharmaceutically acceptable salts thereof and a preparation method thereof |
| CN113143880B (en) * | 2021-03-10 | 2022-07-12 | 河北化工医药职业技术学院 | Sustained-release tablet for treating diabetic complications and preparation method thereof |
| CN115444831B (en) * | 2022-10-25 | 2023-08-22 | 南京康川济医药科技有限公司 | Epalrestat gastric floating tablet and preparation method thereof |
| CN115721621A (en) * | 2022-12-16 | 2023-03-03 | 杭州剂泰医药科技有限责任公司 | Epalrestat sustained-release preparation |
-
2022
- 2022-12-16 CN CN202211623293.XA patent/CN115721621A/en active Pending
-
2023
- 2023-12-15 CN CN202311736464.4A patent/CN117717532A/en active Pending
- 2023-12-15 WO PCT/CN2023/139300 patent/WO2024125654A1/en unknown
- 2023-12-15 CN CN202311738680.2A patent/CN117717533B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102440976A (en) * | 2011-12-21 | 2012-05-09 | 南京海陵中药制药工艺技术研究有限公司 | Epalrestat sustained-release tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117717532A (en) | 2024-03-19 |
| CN115721621A (en) | 2023-03-03 |
| WO2024125654A1 (en) | 2024-06-20 |
| CN117717533A (en) | 2024-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN117717533B (en) | Epalrestat sustained-release composition, preparation method and application thereof | |
| KR101316773B1 (en) | Stabilized pharmaceutical compositions comprising fesoterodine | |
| CN107951853B (en) | Pramipexole dihydrochloride sustained-release pharmaceutical composition and preparation method thereof | |
| CN104758265B (en) | A kind of ranolazine sustained release tablet medicament composition and preparation method thereof | |
| CN103156819A (en) | Benzoic acid alogliptin composition troche and preparation method thereof | |
| CN103006600B (en) | Benzenesulfonate amlodipine tablet and preparation method thereof | |
| CN117547534B (en) | Nicorandil sustained release preparation and preparation method thereof | |
| CN102764254B (en) | A kind of levetiracetam medicinal composition and preparation method thereof | |
| CN112294770A (en) | Isosorbide mononitrate compound preparation and application and preparation method thereof | |
| Okafo et al. | Design and in vitro evaluation of sustained release matrix tablets of metformin produced using Detarium microcarpum gum | |
| CN108888602A (en) | A kind of montelukast preparation of sodium and preparation method thereof | |
| CN111617048B (en) | Erlotinib sustained release preparation for treating non-small cell lung cancer | |
| CN115671061A (en) | Linagliptin tablet and preparation method thereof | |
| CN111568873A (en) | Cyclobenzaprine solid oral preparation and preparation method thereof | |
| CN101244068B (en) | Hemsleyadin sustained-release preparation | |
| CN114917213B (en) | Mental disorder therapeutic agent comprising amitriptyline and method for treating mental disorder | |
| CN117562864B (en) | Nicorandil sustained release tablet and preparation method thereof | |
| CN111494329A (en) | Cyclobenzaprine sustained release preparation | |
| CN108721239A (en) | A kind of sustained release preparation and preparation method thereof for treating Alzheimer disease | |
| CN101780094B (en) | Slow-release preparation of cucurbitacin | |
| CN115300472A (en) | Pharmaceutical composition and preparation method thereof | |
| CN111494336A (en) | Cyclobenzaprine capsule | |
| WO2024060048A1 (en) | Saccharide sustained-release composition and preparation method therefor | |
| CN118717744A (en) | Non-urethane sustained release preparation and preparation method and application thereof | |
| Jooriah | Modified release tablets containing carnauba wax |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |