EP3661488A1 - Tablet comprising ezetimibe - Google Patents
Tablet comprising ezetimibeInfo
- Publication number
- EP3661488A1 EP3661488A1 EP18752437.6A EP18752437A EP3661488A1 EP 3661488 A1 EP3661488 A1 EP 3661488A1 EP 18752437 A EP18752437 A EP 18752437A EP 3661488 A1 EP3661488 A1 EP 3661488A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tablet
- tablet according
- ezetimibe
- starch
- silica
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title claims abstract description 29
- 229960000815 ezetimibe Drugs 0.000 title claims abstract description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 26
- 229920003023 plastic Polymers 0.000 claims abstract description 22
- 239000004033 plastic Substances 0.000 claims abstract description 22
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 18
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 18
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000008117 stearic acid Substances 0.000 claims abstract description 18
- 239000011230 binding agent Substances 0.000 claims abstract description 13
- 239000007884 disintegrant Substances 0.000 claims abstract description 12
- 229920002472 Starch Polymers 0.000 claims abstract description 10
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 10
- 235000019698 starch Nutrition 0.000 claims abstract description 10
- 239000008107 starch Substances 0.000 claims abstract description 10
- 239000003085 diluting agent Substances 0.000 claims abstract description 8
- 239000004094 surface-active agent Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 14
- 239000008119 colloidal silica Substances 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 11
- 238000005550 wet granulation Methods 0.000 claims description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 229940032147 starch Drugs 0.000 claims description 8
- 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 claims description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 229920000858 Cyclodextrin Polymers 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 235000012211 aluminium silicate Nutrition 0.000 claims description 2
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 229940097362 cyclodextrins Drugs 0.000 claims description 2
- 238000009826 distribution Methods 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 235000001055 magnesium Nutrition 0.000 claims description 2
- 229940091250 magnesium supplement Drugs 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229920003124 powdered cellulose Polymers 0.000 claims description 2
- 235000019814 powdered cellulose Nutrition 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 description 93
- 239000000203 mixture Substances 0.000 description 46
- 238000009472 formulation Methods 0.000 description 33
- 238000003475 lamination Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000008187 granular material Substances 0.000 description 11
- 238000007906 compression Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 6
- 239000004141 Sodium laurylsulphate Substances 0.000 description 6
- 230000006835 compression Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 229940069328 povidone Drugs 0.000 description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940051223 zetia Drugs 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 235000019759 Maize starch Nutrition 0.000 description 3
- -1 carbopol) Chemical class 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920002125 Sokalan® Polymers 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
- 238000004458 analytical method Methods 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960005168 croscarmellose Drugs 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000009477 fluid bed granulation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000005325 percolation Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000011800 void material Substances 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical group OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000009478 high shear granulation Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 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 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229960001708 magnesium carbonate Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229940068065 phytosterols Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012776 robust process Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 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 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- Tablet comprising ezetimibe
- Ezetimibe belongs to a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols.
- the chemical name of ezetimibe is l-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)- 2-azetidinone.
- Ezetimibe is sold under the brand name Zetia®, which is marketed by Merck/Schering-Plough Pharmaceuticals. Zetia® is available as a tablet for oral administration and is said to contain 10 mg of ezetimibe.
- the inactive ingredients of Zetia are reported to be croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulphate.
- the recommended dose is 10 mg once daily, administered with or without food, according to the Zetia label.
- Ezetimibe is reported to be practically insoluble in water.
- a solid dosage form comprising ezetimibe When a solid dosage form comprising ezetimibe is taken orally, the drug must dissolve in aqueous gastrointestinal fluids, e.g., in the patient's stomach, before it can exert a therapeutic effect.
- a recurring problem with compressed solid oral dosage forms, such as tablets, is that the dissolution rate of the drug limits its biological availability. Since T max for ezetimibe (in glucuronate form) is relatively short, 1 to 2 hours, it is of utmost importance to assure very fast disintegration of the tablet.
- Water entry promoters are substances that promote water entry into a dosage form such as a tablet. This occurs mostly by the transmission of water along the fibres of the promoters. When water reaches the disintegrant, it causes it to swell and the result is the disintegration of the tablet.
- plastic excipients characterised by plastic deformation during the compression process. During compression their particles deform plastically to accommodate induced stress. Density of the tablet bed increases with increasing pressure because deforming materials distort to fill void spaces between particles and may also exhibit a tendency to fill the gaps by percolation when the limit of plastic deformation is reached. Plastic excipients have another advantage. They are added to tablets in order to increase their resistance. However, they may worsen tablet blend flowability, and, in consequence, the reproducibility of tableting.
- Tablet resistance can be characterised by several parameters such as the absence of tablet capping, tablet lamination or tablet friability. Also robust processes can be achieved by ensuring low tablet ejection force.
- Tablet capping and lamination are unacceptable attributes of the formulation, and it is critical to the dose available to the patient (failure to administer a whole dose) and during the processing of the product in a production plant. Therefore, it is necessary to carry out the compression process at lower speeds, which is disadvantageous from an economic point of view.
- defective tablets can impair blistering by jamming in the channels, additionally prolonging the manufacturing process.
- Laminated or capped tablets can be classified as correct by automatic video control of incorrectly filled blisters and then undetected, released and given to the patient. Tablet friability is of similar importance. High tablet friability can generate significant dust during the blistering process, impairing the adhesive properties of the adhesive layer of the cover foil, causing stability issues.
- Tablet ejection force is associated with the lubricating properties of some excipients. Additionally, high ejection force can cause sticking to the punches or the undesirable adhesion of the tablet blend to punches, and in consequence, an inappropriate appearance, capping or lamination.
- prior art there are many patents and applications covering ezetimibe in several different pharmaceutical compositions; for example EP 0720599 B, EP 1353696 B, EP 1849459 A, US 2007/0275052 A, EP 2 229 938 B, EP 2 965 752 A, and EP 2 217 214 A2. But none of them address the problem of tablet capping, lamination and friability, as well as increasing tableting yield without an increase in tablet capping, lamination and friability. The problem of dose uniformity is also not addressed.
- the subject of the invention is a tablet comprising: a) 5 to 20%wt. of ezetimibe, b) 5 to 20%wt. of a plastic excipient, c) 3 to 10 %wt. of a disintegrant, d) 1 to 12%wt. of a starch, e) 0.5 to 1.5%wt. of a silica, and f) 0.5 to 2.5%wt.
- the tablet of the invention comprises a further diluent and binder, and optionally a surfactant.
- the tablet comprises a further diluent, a binder and a surfactant.
- the tablet of the invention comprises 5 to 20 %wt. of ezetimibe.
- the ezetimibe present in the tablet of the invention can have any particle distribution parameter d90.
- ezetimibe since ezetimibe has very low solubility in water, it is preferable in a micronized form to achieve proper bioavailability. Therefore, ezetimibe can have a d90 of less than 25 microns, more preferably less than 20, and even more preferably less than 10 microns. In its most preferable embodiment, ezetimibe has a d90 in a range of 3 to 9 ⁇ to achieve correct bioavailability.
- a Malvern Laser Diffraction instrument, equipped with a Hydro 2000S dispersion unit is used to characterise the particle size of ezetimibe.
- the suspension of the substance is prepared in 1.0% (w/v) Tween 80 water solution by vortex for 10 seconds and by sonication for 45 seconds.
- the measurement is started after 120 seconds of recirculation after suspension addition into the measurement cell at the speed of 2000 rpm.
- the other parameters of analysis are as follows: measuring range - 0.02 to 2000 ⁇ , analysis model - general purpose, sensitivity - normal and particle shape - irregular.
- the tablet of the invention comprises 5 to 20% wt. of a plastic excipient.
- the 'plastic excipient' is characterised by plastic deformation during the compression process. During compression particles deform plastically to accommodate induced stress. Density of the tablet bed will increase with increasing pressure because deforming materials will distort to fill void spaces between particles and may also exhibit a tendency to fill the gaps by percolation when the limit of plastic deformation is reached.
- the plastic excipient is selected from microcrystalline cellulose, powdered cellulose, cyclodextrins, preferably beta and gamma cyclodextrins, low-substituted hydroxypropyl cellulose, and maltodextrin. In its most preferable embodiment, the plastic excipient is selected from microcrystalline cellulose and low-substituted hydroxypropyl cellulose.
- the tablet of the invention also comprises 3 to 10 %wt. of disintegrant.
- the disintegrant is selected from carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, magnesium aluminium silicate, polacrillin potassium, cross-linked polyvinylpyrrolidone, sodium alginate and sodium starch glycolate.
- the disintegrant is croscarmellose sodium or cross-linked polyvinylpyrrolidone.
- the tablet of the invention comprises 1 to 12%wt. of starch.
- the starch contained in the tablet is a pregelatinised starch.
- the pregelatinised starch can be for example pregelatinised maize starch or pregelatinised potato starch.
- the tablet of the invention comprises 0.5 to 1.5%wt. of a silica.
- the silica is a colloidal silica.
- the colloidal silica has a specific surface area in the range of 200 to 300 m2/g. The use of a colloidal silica with a specific surface area below 200 m2/g leads to the deterioration of the properties of the final tablets.
- the tablet of the invention can comprise 20 to 80 %wt. of a further diluent.
- the diluent is selected from calcium carbonate, calcium sulphate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, lactose anhydrous, sorbitol and talc.
- the further diluent is lactose or mannitol.
- the tablet of the invention can comprise 1 to 10 %wt. of binder.
- the binder is selected from acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, copovidone (Plasdone® S-630), dextrin, ethyl cellulose, gelatine, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, liquid glucose, maltodextrin, methylcellulose, polymethacrylates, polyvinylpyrrolidone (PVP, e.g., povidone), pregelatinised starch, sodium alginate and starch.
- PVP polyvinylpyrrolidone
- the binder is polyvinylpyrrolidone and hydroxypropylcellulose.
- the tablet of the invention can comprise 0-5 %wt., of surfactant.
- the surfactant selected is sodium lauryl sulphate (SLS).
- wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water or an aqueous binder solution, which causes the powders to clump up into granules.
- a liquid typically water or an aqueous binder solution
- the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
- the granulate can then be tableted or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
- Another wet granulation technique involves the production of granules by spraying water or an aqueous binder solution onto the fluidising powder bed in an atmosphere of dry air at an elevated temperature. The resulting granules can be screened and/or milled and blended with other excipients and tableted.
- wet granulation is often preferred over direct compression because it is more likely that wet granulation overcomes the problems associated with the physical properties of the individual components in the formulation, such as a low solubility, poor flowing or sticking to the punches.
- Wet granulation provides a material that has the required flow and cohesive properties necessary to obtain an acceptable solid dosage form, i.e. tablet. Tablet uniformity is generally improved with wet granulation because all of the granules usually contain the same amount of drug. It also avoids separation of the drug from the excipients.
- the tablet of the invention is obtained using a wet granulation method. It was shown that the use of a wet granulation method in connection with the tablet of the invention results in tablets with not only very good resistance to capping and lamination, but it can also ensure good tablet friability and high reproducibility. Applied formulation gives the product uniformity, by reducing mass variation between tablets without having to compromise it with the reduction of tableting process efficacy.
- Parameters used in the context of the characterisation of a tablet of the invention can be measured as follows: a) Tablet friability. Test conducted on tablet friability apparatus, in accordance with Ph. Eur. 2.9.7 'Friability of uncoated tablets'. b) Tablet hardness.
- Ezetimibe was added to a high shear granulator together with excipients and half of the disintegrant.
- the plastic excipient i.e. microcrystalline cellulose was added in one portion (Formulation Nos. 2, 5, or 6) or was divided between intragranular and extragranular fractions (Formulation Nos. 1 or 4).
- the blend was granulated using a water solution of a binder (e.g., Povidone).
- the resulting granulate was screened, and then the remaining components (from the extragranular phase) were added. Separated blending was used before the lubricant was added, and after adding it.
- Formulation 3 was manufactured by the granulation of ezetimibe with lactose; 2/3 part of the maize starch and half of the disintegrant, using a binder solution and subsequently other excipients were admixtured before tableting. Tableting was performed using a rotary tablet press and tablets were formed as capsule- shaped tablets with dimensions of 8x5 mm.
- Formulations with a significant amount of excipients with plastic characteristics due to their composition have very high mechanical resistance, which is a direct result of the properties of the raw materials used.
- Reference Formulations 1 and 2 which contain at least 20% of plastic excipients have relatively high ejection forces which may adversely affect the tableting process during the production of a larger volume with, for example, the undesirable adhesion of the tablet blend to tablet punches and dies and faster tool wear.
- the tablet blends prepared according to the aforementioned compositions have worse flow characteristics, which results in a greater tablet mass RSD. This translates directly into a greater fluctuation in the amount of active substance in individual doses. This effect increases with higher tableting performance.
- Formulation 4 of the invention is characterised by high resistance to damage and low ejection forces. Good flow properties of the tableting blend result in a much more homogeneous product. It is thus possible to conduct the tableting process at the higher operating ranges, reducing time and costs.
- Reference Formulation 5, and Formulation 6 of the invention illustrate the effect of the lubricant used (magnesium stearate vs. stearic acid).
- the result was that the replacement of magnesium stearate with stearic acid significantly improves tablet resistance to capping/lamination. This effect reduces the ejection force and thus friction of the compressed tablet against the matrix walls.
- formulations of the invention compressed with lower or higher compression forces result in a robust product in terms of the reproducibility of dissolution profiles.
- Formulations with higher level of plastically deforming excipients are compression dependent (Formulation 1 and 2), and their dissolution profiles vary in accordance to the pressure applied during compression.
- Formulations of the invention (Formulation 4 and 6) represent very high similarity factor, which guarantees the same release of the API in the human body.
- Example 2 Composition containing more colloidal silica than stearic acid
- Reference Formulation 7 was prepared in order to investigate the effect of a quantitative excess of colloidal silica over stearic acid.
- the example has a stearic acid to silica ratio of 0.6:1.
- Ezetimibe was added to a high shear granulator together with SLS, a half of the croscarmellose and a half of the mannitol and microcrystalline cellulose. After preblending, the mixture was granulated using an aqueous solution of Povidone. The resulting granulate was dried and homogenised, and then mixed with the rest of the components, i.e. croscarmellose, mannitol, microcrystalline cellulose, starch, colloidal silica and stearic acid. Separated blending was used before the lubricant was added, and after adding it.
- Tableting was done using a rotary tablet press and tablets were formed as capsule shaped tablets with dimensions of 8x5 mm.
- the ratio of stearic acid to colloidal silica is important. It was shown that the ratio of stearic acid to colloidal silica should be in a range of 1 : 1 to 3 : 1 in favour of stearic acid.
- Reference Formulation 7 shows an example where the above ratio is outside of that range. In the aforementioned example, the ejection forces increase dramatically, making it impossible to conduct the process. Formulations with a higher excess of stearic acid are undesirable.
- Ezetimibe was added to a high shear granulator, together with SLS, and a half of the disintegrant and diluents.
- the plastic excipient is in the extragranular fraction, while in both Formulation 10 and 11, a half of the plastic excipient is in the extragranular fraction, and the other half is in the intragranular fraction.
- the blend was granulated using a water solution of a binder (e.g., Povidone or Hydroxypropylcellulose). The resulting granulate was homogenised, and then the remaining components (of the extragranular fraction) were added. Separated blending was used before the lubricant was added, and after adding it.
- a binder e.g., Povidone or Hydroxypropylcellulose
- Formulation 9 was prepared using fluid bed granulation. All granulate ingredients were introduced into the chamber of the device and granulated using a binder solution during fluidisation. SLS, half of the lactose, colloidal silica and starch were added to the resulting granulate, and after blending, stearic acid.
- Tableting was done using a rotary tablet press and tablets were formed as capsule shaped tablets with dimensions of 8x5 mm.
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Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17461579.9A EP3437636A1 (en) | 2017-08-02 | 2017-08-02 | Pharmaceutical composition comprising ezetimibe |
PCT/EP2018/070920 WO2019025512A1 (en) | 2017-08-02 | 2018-08-01 | Tablet comprising ezetimibe |
Publications (1)
Publication Number | Publication Date |
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EP3661488A1 true EP3661488A1 (en) | 2020-06-10 |
Family
ID=59520847
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17461579.9A Withdrawn EP3437636A1 (en) | 2017-08-02 | 2017-08-02 | Pharmaceutical composition comprising ezetimibe |
EP18752437.6A Withdrawn EP3661488A1 (en) | 2017-08-02 | 2018-08-01 | Tablet comprising ezetimibe |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17461579.9A Withdrawn EP3437636A1 (en) | 2017-08-02 | 2017-08-02 | Pharmaceutical composition comprising ezetimibe |
Country Status (2)
Country | Link |
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EP (2) | EP3437636A1 (en) |
WO (1) | WO2019025512A1 (en) |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5631365A (en) | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
DE60216890T2 (en) | 2001-01-26 | 2007-08-30 | Schering Corp. | COMBINATIONS OF A STARTER ABSORPTION HEMMER AND A PPAR ACTIVATOR FOR THE TREATMENT OF CARDIOVASCULAR INDICATIONS |
RU2008136765A (en) | 2006-03-06 | 2010-04-20 | Тева Фармасьютикл Индастриес Лтд. (Il) | EZETIMIBE COMPOSITIONS |
US20070275052A1 (en) | 2006-05-24 | 2007-11-29 | Glenmark Pharmaceuticals Limited | Pharmaceutical compositions containing sterol inhibitors |
ES2639995T3 (en) | 2007-12-10 | 2017-10-31 | Ratiopharm Gmbh | Pharmaceutical formulation comprising ezetimibe |
EP2168573A1 (en) * | 2008-09-30 | 2010-03-31 | LEK Pharmaceuticals D.D. | Formulations comprising ezetimibe |
ES2382773T3 (en) | 2009-03-13 | 2012-06-13 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Ezetimibe compositions |
KR101977785B1 (en) * | 2014-06-25 | 2019-05-14 | 한미약품 주식회사 | Composite formulation for oral administration comprising ezetimibe and rosuvastatin and a process for the preparation thereof |
-
2017
- 2017-08-02 EP EP17461579.9A patent/EP3437636A1/en not_active Withdrawn
-
2018
- 2018-08-01 WO PCT/EP2018/070920 patent/WO2019025512A1/en unknown
- 2018-08-01 EP EP18752437.6A patent/EP3661488A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
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EP3437636A1 (en) | 2019-02-06 |
WO2019025512A1 (en) | 2019-02-07 |
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