WO2023211412A1 - A tablet comprising sacubitril and valsartan processed with dry granulation - Google Patents
A tablet comprising sacubitril and valsartan processed with dry granulation Download PDFInfo
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- WO2023211412A1 WO2023211412A1 PCT/TR2023/050359 TR2023050359W WO2023211412A1 WO 2023211412 A1 WO2023211412 A1 WO 2023211412A1 TR 2023050359 W TR2023050359 W TR 2023050359W WO 2023211412 A1 WO2023211412 A1 WO 2023211412A1
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- WO
- WIPO (PCT)
- Prior art keywords
- film coated
- sodium
- coated tablet
- mixing
- composition
- Prior art date
Links
- 239000004072 C09CA03 - Valsartan Substances 0.000 title claims abstract description 35
- 229960004699 valsartan Drugs 0.000 title claims abstract description 35
- 238000007908 dry granulation Methods 0.000 title claims abstract description 13
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 title claims abstract 6
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 title description 9
- 229960003953 sacubitril Drugs 0.000 title description 8
- 239000000203 mixture Substances 0.000 claims abstract description 64
- 239000003826 tablet Substances 0.000 claims abstract description 31
- 239000007941 film coated tablet Substances 0.000 claims abstract description 28
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims abstract description 26
- RRTBVEJIZWGATF-JKSHRDEXSA-M sodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate Chemical compound [Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1 RRTBVEJIZWGATF-JKSHRDEXSA-M 0.000 claims abstract description 23
- 238000007873 sieving Methods 0.000 claims description 28
- 239000007884 disintegrant Substances 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000314 lubricant Substances 0.000 claims description 15
- 239000011230 binding agent Substances 0.000 claims description 13
- 229960000913 crospovidone Drugs 0.000 claims description 13
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 13
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 239000000454 talc Substances 0.000 claims description 11
- 229910052623 talc Inorganic materials 0.000 claims description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 239000000377 silicon dioxide Substances 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 239000011248 coating agent Substances 0.000 claims description 7
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 239000007888 film coating Substances 0.000 claims description 6
- 238000009501 film coating Methods 0.000 claims description 6
- 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 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- 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 4
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 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 4
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 4
- 229960001714 calcium phosphate Drugs 0.000 claims description 4
- 235000011010 calcium phosphates Nutrition 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229920000193 polymethacrylate Polymers 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 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 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 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 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920001100 Polydextrose Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004373 Pullulan Substances 0.000 claims description 2
- 229920001218 Pullulan Polymers 0.000 claims description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004977 anhydrous lactose Drugs 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 229960003563 calcium carbonate Drugs 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 2
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 2
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 2
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- 239000001341 hydroxy propyl starch Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229960001021 lactose monohydrate Drugs 0.000 claims description 2
- 229940037627 magnesium lauryl sulfate Drugs 0.000 claims description 2
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 239000001259 polydextrose Substances 0.000 claims description 2
- 235000013856 polydextrose Nutrition 0.000 claims description 2
- 229940035035 polydextrose Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000019423 pullulan Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 10
- 238000009472 formulation Methods 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 239000013543 active substance Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229940100321 entresto Drugs 0.000 description 2
- ZASXKEGREHRXDL-CAWNUZPDSA-H hexasodium;4-[[(2s,4r)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate;(2s)-3-methyl-2-[pentanoyl-[[4-[2-(1,2,3-triaza-4-azanidacyclopenta-2,5-dien-5-yl)phenyl]phenyl]methyl]amino]butanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC([O-])=O)=CC=C1C1=CC=CC=C1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1.C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C([O-])=O)=CC=C1C1=CC=CC=C1C1=NN=N[N-]1 ZASXKEGREHRXDL-CAWNUZPDSA-H 0.000 description 2
- 239000004407 iron oxides and hydroxides Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 229940051537 valsartan and sacubitril Drugs 0.000 description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- 108090000812 Neurolysin Proteins 0.000 description 1
- 102100023072 Neurolysin, mitochondrial Human genes 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000009700 powder processing Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000005550 wet granulation Methods 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Definitions
- the present invention relates to a film coated tablet comprising intragranular composition comprising sacubitril sodium, valsartan disodium and an extragranular composition, wherein the tablet is obtained by dry granulation.
- Sacubitril is an antihypertensive drug used in combination with valsartan. Its chemical designation is 4-(((2S,4R)-1-([1 ,1 '-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- yl)amino)-4-oxobutanoic acid with the following chemical structure of Formula I.
- Valsartan is a specific angiotensin II receptor antagonist, which selectively and competitively blocks AT1 -receptors and mediates the vasopressor and aldosterone effects of angiotensin II. Its chemical designation is N-(1 -oxopentyl)-N-[[2'-(1 H-tetrazol-5-yl)-[1 ,1'-biphenyl]-4- yl]methyl]-L-valine with the following chemical structure of Formula II.
- a complex comprising valsartan, which is an angiotensin receptor antagonist, and Sacubitril, which is a neurolysin inhibitor, has been approved by US Food and Drug Administration (FDA) under the trade name ENTRESTO® by Novartis for the treatment of heart failure with reduced ejection fraction.
- FDA US Food and Drug Administration
- Entresto® is supplied for oral administration as immediate release film-coated tablets in three strengths: 24/26, 49/51 and 97/103 mg, containing respectively 24.3 mg sacubitril/25.7 mg valsartan, 48.6 mg sacubitril/51 .4 mg valsartan and 97.2 mg sacubitril/102.8 mg valsartan.
- US 8101659 and US 8404744 discloses a composition comprising Valsartan and Sacubitril which are administered in combination in 1 :1 ratio.
- US 8796331 discloses a method of treating hypertension and heart failure by administering a combination of Valsartan and Sacubitril administered in one unit dose form or in two separate unit dose forms.
- WO 2017/012600 discloses a tablet containing a physical mixture of sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof that can be prepared by direct compression, dry-granulation or wet-granulation.
- Valsartan disodium and sacubitril sodium cannot be easily processed due to their poor flowability. Moreover, the amorphous forms of valsartan disodium and sacubitril sodium are very hygroscopic solids. These substances become deliquescent and sticky when exposed to air humidity. Therefore, formulation with these agents and their processing steps are crucial for tablet stability and dissolution.
- the main object of the present invention is to provide a film coated tablet comprising sacubitril sodium and valsartan disodium with having desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
- Another object of the present invention is to provide a film coated tablet comprising sacubitril sodium and valsartan disodium with high stability.
- Another object of the present invention is to provide a process for preparing a film coated tablet composition comprising sacubitril sodium and valsartan disodium with high stability. The process is a simple, rapid, cost effective, time-saving, and industrially convenient method. The process is dry granulation.
- a film coated tablet comprises;
- an intragranular composition comprising sacubitril sodium, valsartan disodium and at least one disintegrant
- the amount of the disintegrants is 4.0% to 15.0% by weight of the total core tablet and the tablet is obtained by dry granulation.
- the ratio of active substances in the total tablet is quite high. Due to this reason as well as the characteristic features of the active ingredients, fluidity and homogeneity problems arise to. These problems were overcome with this preferred disintegrant ratio and dry granulation.
- the tablet is prepared with dry granulation.
- the dry granulation is simple and low-cost method. Since valsartan disodium and sacubitril sodium are very hygroscopic solids, this method and the formulation prepared with the excipients mentioned below provided stability.
- the amount of sacubitril sodium is 20.0% to 30.0% by weight of the total core tablet.
- the amount of valsartan disodium is 22.0% to 35.0% by weight of the total core tablet.
- Suitable disintegrants are selected from the group comprising crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose, sodium alginate, corn starch, sodium glycine carbonate or mixtures thereof.
- the disintegrant is crospovidone.
- crospovidone is used both an intragranular composition and an extragranular composition. This provides the desired dissolution profile. Furthermore, this helps to achieve an effective and an easy process.
- the amount of disintegrant is 5.0% to 10.0% by weight of the total core tablet.
- the dry granulation comprises the following steps;
- composition comprising sacubitril sodium, valsartan disodium and at least one pharmaceutically acceptable excipient
- excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed.
- the formulations should have no physicochemical incompatibility between the active agents and the excipients.
- each composition further comprises the pharmaceutically acceptable excipients which are selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
- Suitable fillers are selected from the group comprising microcrystalline cellulose, pregelatinized starch, mannitol, dicalcium phosphate, lactose monohydrate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, cellulose acetate, ethylcellulose, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sugar sphericals or mixtures thereof.
- the filler is microcrystalline cellulose.
- the filler helps to provide the desired dissolution profile. Also, it helps to provide the desired stability.
- the amount of filler is 15.0% to 25.0% by weight of the total core tablet.
- binder addition is especially valuable for a poorly soluble formulation. Binder can lead to processing problems such as rapid over granulation, tablet hardness increases and dissolution concert diminish.
- Suitable binders are selected from the group comprising low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, ethyl cellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
- the binder is low-substituted hydroxypropyl cellulose. Especially, using low-substituted hydroxypropyl cellulose provides the desired dissolution profile and the desired stability.
- the amount of binders is 8.0% to 15.0% by weight of the total core tablet.
- Suitable lubricants are selected from the group comprising talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, magnesium lauryl sulfate, sodium oleate, polyethylene glycol, sodium lauryl sulphate or mixtures thereof.
- the lubricant is magnesium stearate or talc or mixtures thereof. It improves the powder processing properties. Also, it enhances powder flow by reducing the inter-particle friction.
- the amount of lubricant is 0.8% to 11 .5% by weight of the total composition.
- Suitable glidants are selected from the group comprising silica colloidal anhydrous, silicon dioxide, aluminum silicate or mixtures thereof.
- the glidant is silica colloidal anhydrous.
- the amount of glidant is 0.2% to 5.0% by weight of the total composition.
- the film coated tablet comprises;
- the film coated tablet comprises;
- a process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
- the present invention relates to a process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
- the formulation solves the sticking problem of the tablet in the preparation process.
- the preparation process also solves problems of degradation of the preparation due to hygroscopicity and improves stability of the tablet.
- Example 1 Example 2: Example 3: Coating agents
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Abstract
The present invention relates to a film coated tablet comprising intragranular composition comprising sacubitril sodium, valsartan disodium and an extragranular composition, wherein the tablet is obtained by dry granulation.
Description
A TABLET COMPRISING SACUBITRIL AND VALSARTAN PROCESSED WITH DRY GRANULATION
Field of the Invention
The present invention relates to a film coated tablet comprising intragranular composition comprising sacubitril sodium, valsartan disodium and an extragranular composition, wherein the tablet is obtained by dry granulation.
Background of the Invention
Sacubitril is an antihypertensive drug used in combination with valsartan. Its chemical designation is 4-(((2S,4R)-1-([1 ,1 '-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2- yl)amino)-4-oxobutanoic acid with the following chemical structure of Formula I.
Formula I
Valsartan is a specific angiotensin II receptor antagonist, which selectively and competitively blocks AT1 -receptors and mediates the vasopressor and aldosterone effects of angiotensin II. Its chemical designation is N-(1 -oxopentyl)-N-[[2'-(1 H-tetrazol-5-yl)-[1 ,1'-biphenyl]-4- yl]methyl]-L-valine with the following chemical structure of Formula II.
Formula II
A complex comprising valsartan, which is an angiotensin receptor antagonist, and Sacubitril, which is a neurolysin inhibitor, has been approved by US Food and Drug Administration (FDA) under the trade name ENTRESTO® by Novartis for the treatment of heart failure with reduced ejection fraction. Entresto® is supplied for oral administration as immediate release film-coated tablets in three strengths: 24/26, 49/51 and 97/103 mg, containing respectively
24.3 mg sacubitril/25.7 mg valsartan, 48.6 mg sacubitril/51 .4 mg valsartan and 97.2 mg sacubitril/102.8 mg valsartan.
US 8101659 and US 8404744 discloses a composition comprising Valsartan and Sacubitril which are administered in combination in 1 :1 ratio.
US 8796331 discloses a method of treating hypertension and heart failure by administering a combination of Valsartan and Sacubitril administered in one unit dose form or in two separate unit dose forms.
WO 2017/012600 discloses a tablet containing a physical mixture of sacubitril or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof that can be prepared by direct compression, dry-granulation or wet-granulation.
Valsartan disodium and sacubitril sodium cannot be easily processed due to their poor flowability. Moreover, the amorphous forms of valsartan disodium and sacubitril sodium are very hygroscopic solids. These substances become deliquescent and sticky when exposed to air humidity. Therefore, formulation with these agents and their processing steps are crucial for tablet stability and dissolution.
In prior art, there are also several patents which disclose sacubitril sodium and valsartan disodium in oral pharmaceutical dosage forms. However, despite problems of the poor flowability and stability of sacubitril sodium and valsartan disodium an effective formulation and method has not been disclosed.
There still remains a need in the art to provide an improved a film coated tablet comprising sacubitril sodium and valsartan disodium having high solubility, excellent physicochemical properties and accordingly a high bioavailability and a long-term stability.
Detailed Description of the Invention
The main object of the present invention is to provide a film coated tablet comprising sacubitril sodium and valsartan disodium with having desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
Another object of the present invention is to provide a film coated tablet comprising sacubitril sodium and valsartan disodium with high stability.
Another object of the present invention is to provide a process for preparing a film coated tablet composition comprising sacubitril sodium and valsartan disodium with high stability. The process is a simple, rapid, cost effective, time-saving, and industrially convenient method. The process is dry granulation.
According to this embodiment of the present invention, a film coated tablet comprises;
- an intragranular composition comprising sacubitril sodium, valsartan disodium and at least one disintegrant,
- an extragranular composition comprising at least one disintegrant,
Wherein the amount of the disintegrants is 4.0% to 15.0% by weight of the total core tablet and the tablet is obtained by dry granulation.
The ratio of active substances in the total tablet is quite high. Due to this reason as well as the characteristic features of the active ingredients, fluidity and homogeneity problems arise to. These problems were overcome with this preferred disintegrant ratio and dry granulation.
The tablet is prepared with dry granulation. The dry granulation is simple and low-cost method. Since valsartan disodium and sacubitril sodium are very hygroscopic solids, this method and the formulation prepared with the excipients mentioned below provided stability.
According to this embodiment of the present invention, the amount of sacubitril sodium is 20.0% to 30.0% by weight of the total core tablet.
According to this embodiment of the present invention, the amount of valsartan disodium is 22.0% to 35.0% by weight of the total core tablet.
Suitable disintegrants are selected from the group comprising crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose, sodium alginate, corn starch, sodium glycine carbonate or mixtures thereof.
According to this embodiment of the present invention, the disintegrant is crospovidone.
According to this embodiment of the present invention, crospovidone is used both an intragranular composition and an extragranular composition. This provides the desired dissolution profile. Furthermore, this helps to achieve an effective and an easy process.
According to this embodiment of the present invention, the amount of disintegrant is 5.0% to 10.0% by weight of the total core tablet.
According to this embodiment of the present invention, the dry granulation comprises the following steps;
Preparing intragranular composition comprising sacubitril sodium, valsartan disodium and at least one pharmaceutically acceptable excipient,
Preparing extragranular composition comprising at least one pharmaceutically acceptable excipient,
- Compressing the total mixture, and obtained core tablets,
- Coating the core tablet with a film coating, wherein same excipients have been used for each composition. So, this helps to achieve an effective and an easy process.
In general terms, excipients provided in a formulation may positively or negatively influence the physicochemical and pharmacokinetic properties, e.g. the solubility, absorption, bioavailability of an active agent. For this reason, the excipients which accompany an active agent have to be selected in a careful and conscious manner while a formulation is developed. The formulations should have no physicochemical incompatibility between the active agents and the excipients.
According to this embodiment of the present invention, each composition further comprises the pharmaceutically acceptable excipients which are selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
Suitable fillers are selected from the group comprising microcrystalline cellulose, pregelatinized starch, mannitol, dicalcium phosphate, lactose monohydrate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium phosphate dehydrate, neutral pellets, cellulose acetate, ethylcellulose, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sugar sphericals or mixtures thereof.
According to this embodiment of the present invention, the filler is microcrystalline cellulose. The filler helps to provide the desired dissolution profile. Also, it helps to provide the desired stability.
According to this embodiment of the present invention, the amount of filler is 15.0% to 25.0% by weight of the total core tablet.
The identification of critical binder attributes in the invention enables rational and efficient binder selection of well soluble and poorly soluble formulations. Binder addition is especially valuable for a poorly soluble formulation. Binder can lead to processing problems such as rapid over granulation, tablet hardness increases and dissolution concert diminish.
Suitable binders are selected from the group comprising low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, ethyl cellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
According to this embodiment of the present invention, the binder is low-substituted hydroxypropyl cellulose. Especially, using low-substituted hydroxypropyl cellulose provides the desired dissolution profile and the desired stability.
According to this embodiment of the present invention, the amount of binders is 8.0% to 15.0% by weight of the total core tablet.
Suitable lubricants are selected from the group comprising talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, magnesium lauryl sulfate, sodium oleate, polyethylene glycol, sodium lauryl sulphate or mixtures thereof.
According to this embodiment of the present invention, the lubricant is magnesium stearate or talc or mixtures thereof. It improves the powder processing properties. Also, it enhances powder flow by reducing the inter-particle friction.
According to this embodiment of the present invention, the amount of lubricant is 0.8% to 11 .5% by weight of the total composition.
Suitable glidants are selected from the group comprising silica colloidal anhydrous, silicon dioxide, aluminum silicate or mixtures thereof.
According to this embodiment of the present invention, the glidant is silica colloidal anhydrous.
According to this embodiment of the present invention, the amount of glidant is 0.2% to 5.0% by weight of the total composition.
According to this embodiment of the present invention, the film coated tablet comprises;
- Sacubitril sodium
- Valsartan disodium
Low-substituted hydroxypropylcellulose
Microcrystalline cellulose
- Crospovidone
Silica colloidal anhydrous
According to this embodiment of the present invention, the film coated tablet comprises;
- Sacubitril Sodium
- Valsartan Disodium
Low-substituted hydroxypropylcellulose
Microcrystalline cellulose
- Crospovidone
- Silica colloidal anhydrous
- Magnesium stearate
- Talc
According to this embodiment of the present invention, a process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
- Sieving sacubitril sodium and at least one lubricant and then mixing,
- Sieving at least one filler, at least one binder and at least one disintegrant and then mixing,
Adding valsartan disodium and mixing,
- Sieving at least one glidant and then adding and mixing,
- Sieving at least one lubricant and then adding and mixing, and obtained intragranular composition,
- Compacting the intragranular composition,
- Sieving at least one disintegrant and adding into the intragranular composition and then mixing,
- Sieving at least one glidant and then adding and mixing,
- Sieving at least one lubricant and then adding and mixing,
- Adding at least one lubricant and mixing,
- Compressing the total mixture, and obtained core tablets,
- Coating the core tablet with a film coating.
The present invention relates to a process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
Sieving sacubitril sodium and talc and then mixing,
- Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone and then mixing,
Adding valsartan disodium and mixing,
- Sieving silica colloidal anhydrous and then adding and mixing,
- Sieving magnesium stearate and then adding and mixing, and obtained intragranular composition,
- Compacting the intragranular composition,
- Sieving crospovidone and adding into the intragranular composition and then mixing,
- Sieving silica colloidal anhydrous and then adding and mixing,
- Sieving talc and then adding and mixing,
- Adding magnesium stearate and mixing,
- Compressing the total mixture, and obtained core tablets,
- Coating the core tablet with a film coating.
The formulation solves the sticking problem of the tablet in the preparation process. The preparation process also solves problems of degradation of the preparation due to hygroscopicity and improves stability of the tablet.
Example 1 :
Example 2:
Example 3:
Coating agents
• Hypromellose, substitution type 2910 (3 mPa s)
• Titanium dioxide (E171 )
• Macrogol (4000)
• Talc
• Iron oxide red (E172)
• Iron oxide black (E172)
A process for example 1 or 2 or 3;
Sieving sacubitril sodium and talc through 0.85 mm and then mixing,
- Sieving microcrystalline cellulose, low-substituted hydroxypropylcellulose and crospovidone through 0.85 mm and then mixing,
Adding valsartan disodium and mixing,
- Sieving silica colloidal anhydrous and then adding and mixing,
- Sieving magnesium stearate and then adding and mixing, and obtained intragranular composition,
- Compacting the intragranular composition,
- Sieving crospovidone and adding into the intragranular composition and then mixing,
- Sieving silica colloidal anhydrous and then adding and mixing,
- Sieving talc and then adding and mixing,
- Adding magnesium stearate and mixing,
- Compressing the total mixture, and obtained core tablets,
- Coating the core tablet with a film coating.
Claims
1 ) A film coated tablet comprising;
- an intragranular composition comprising sacubitril sodium, valsartan disodium and at least one disintegrant,
- an extragranular composition comprising at least one disintegrant, wherein the amount of the disintegrants is 4.0% to 15.0% by weight of the total core tablet and the tablet is obtained by dry granulation.
2) The film coated tablet according to claim 1 , wherein disintegrants are selected from the group comprising crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose, sodium alginate, corn starch, sodium glycine carbonate or mixtures thereof.
3) The film coated tablet according to claim 2, wherein the disintegrant is crospovidone.
4) The film coated tablet according to claim 1 , wherein crospovidone is used both an intragranular composition and an extragranular composition.
5) The film coated tablet according to claim 1 , wherein the amount of disintegrant is 5.0% to 10.0% by weight of the total core tablet.
6) The film coated tablet according to claim 1 , wherein the dry granulation comprising the following steps;
Preparing intragranular composition comprising sacubitril sodium, valsartan disodium and at least one pharmaceutically acceptable excipient,
Preparing extragranular composition comprising at least one pharmaceutically acceptable excipient,
- Compressing the total mixture, and obtained core tablets,
- Coating the core tablet with a film coating, wherein same excipients have been used for each composition.
7) The film coated tablet according to claim 1 , wherein each composition further comprising the pharmaceutically acceptable excipients which are selected from the group comprising fillers, binders, disintegrants, lubricants, glidants or mixtures thereof.
8) The film coated tablet according to claim 7, wherein fillers are selected from the group comprising microcrystalline cellulose, pregelatinized starch, mannitol, dicalcium phosphate, lactose monohydrate, calcium carbonate, anhydrous lactose, calcium phosphate, calcium
phosphate dehydrate, neutral pellets, cellulose acetate, ethylcellulose, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sugar sphericals or mixtures thereof.
9) The film coated tablet according to claim 8, wherein the filler is microcrystalline cellulose.
10) The film coated tablet according to claim 7, wherein binders are selected from the group comprising low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose sodium, cellulose acetate phthalate, ethyl cellulose, glyceryl behenate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl starch, hypromellose, magnesium aluminum silicate, methylcellulose, polyethylene oxide, polymethacrylates, aluminum hydroxide, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
11) The film coated tablet according to claim 10, wherein the binder is low-substituted hydroxypropyl cellulose.
12) The film coated tablet according to claim 7, wherein lubricants are selected from the group comprising talc, magnesium stearate, sodium stearyl fumarate, calcium stearate, zinc stearate, magnesium lauryl sulfate, sodium oleate, polyethylene glycol, sodium lauryl sulphate or mixtures thereof.
13) The film coated tablet according to claim 12, wherein the lubricant is magnesium stearate or talc or mixtures thereof.
14) The film coated tablet according to claim 1 , wherein the film coated tablet comprises;
- Sacubitril Sodium
- Valsartan Disodium
Low-substituted hydroxypropylcellulose Microcrystalline cellulose
- Crospovidone
- Silica colloidal anhydrous
- Magnesium stearate
- Talc
15) A process for preparing a film coated tablet comprising sacubitril sodium and valsartan disodium comprises the following steps;
- Sieving sacubitril sodium and at least one lubricant and then mixing,
- Sieving at least one filler, at least one binder and at least one disintegrant and then mixing,
Adding valsartan disodium and mixing,
- Sieving at least one glidant and then adding and mixing,
- Sieving at least one lubricant and then adding and mixing, and obtained intragranular composition,
- Compacting the intragranular composition,
- Sieving at least one disintegrant and adding into the intragranular composition and then mixing,
- Sieving at least one glidant and then adding and mixing,
- Sieving at least one lubricant and then adding and mixing,
- Adding at least one lubricant and mixing,
- Compressing the total mixture, and obtained core tablets,
- Coating the core tablet with a film coating.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2022/006846 TR2022006846A1 (en) | 2022-04-26 | A TABLET CONTAINING SACUBITRILE AND VALSARTAN PREPARED BY DRY GRANULATION METHOD | |
| TR2022006846 | 2022-04-26 |
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| Publication Number | Publication Date |
|---|---|
| WO2023211412A1 true WO2023211412A1 (en) | 2023-11-02 |
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| PCT/TR2023/050359 WO2023211412A1 (en) | 2022-04-26 | 2023-04-17 | A tablet comprising sacubitril and valsartan processed with dry granulation |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018069937A1 (en) * | 2016-10-13 | 2018-04-19 | Mylan Laboratories Limited | Solid dispersions of trisodium sacubitril valsartan and process for the preparation thereof |
| WO2018211479A1 (en) * | 2017-05-19 | 2018-11-22 | Lupin Limited | Stabilized compositions of angiotensin ii inhibitors and neutral endopeptidase inhibitors and process for preparation thereof |
| WO2019020706A1 (en) * | 2017-07-28 | 2019-01-31 | Synthon B.V. | Pharmaceutical composition comprising sacubitril and valsartan |
-
2023
- 2023-04-17 WO PCT/TR2023/050359 patent/WO2023211412A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018069937A1 (en) * | 2016-10-13 | 2018-04-19 | Mylan Laboratories Limited | Solid dispersions of trisodium sacubitril valsartan and process for the preparation thereof |
| WO2018211479A1 (en) * | 2017-05-19 | 2018-11-22 | Lupin Limited | Stabilized compositions of angiotensin ii inhibitors and neutral endopeptidase inhibitors and process for preparation thereof |
| WO2019020706A1 (en) * | 2017-07-28 | 2019-01-31 | Synthon B.V. | Pharmaceutical composition comprising sacubitril and valsartan |
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