MXPA96000024A - Form of oral dosing of metoprolol one time - Google Patents
Form of oral dosing of metoprolol one timeInfo
- Publication number
- MXPA96000024A MXPA96000024A MXPA/A/1996/000024A MX9600024A MXPA96000024A MX PA96000024 A MXPA96000024 A MX PA96000024A MX 9600024 A MX9600024 A MX 9600024A MX PA96000024 A MXPA96000024 A MX PA96000024A
- Authority
- MX
- Mexico
- Prior art keywords
- metoprolol
- dosage form
- sustained release
- gum
- oral solid
- Prior art date
Links
- IUBSYMUCCVWXPE-UHFFFAOYSA-N Metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960002237 Metoprolol Drugs 0.000 title claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 64
- 230000002459 sustained Effects 0.000 claims abstract description 55
- 229920000591 gum Polymers 0.000 claims abstract description 43
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- 239000012530 fluid Substances 0.000 claims abstract description 21
- 238000009472 formulation Methods 0.000 claims abstract description 21
- 239000011780 sodium chloride Substances 0.000 claims abstract description 21
- 125000002091 cationic group Chemical group 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000002552 dosage form Substances 0.000 claims abstract description 12
- 239000003701 inert diluent Substances 0.000 claims abstract description 8
- 230000001225 therapeutic Effects 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000002016 disaccharides Chemical class 0.000 claims abstract description 6
- 150000002772 monosaccharides Chemical class 0.000 claims abstract description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 5
- 150000001342 alkaline earth metals Chemical class 0.000 claims abstract description 4
- 239000003814 drug Substances 0.000 claims description 38
- 229940079593 drugs Drugs 0.000 claims description 29
- 239000011159 matrix material Substances 0.000 claims description 24
- 239000008184 oral solid dosage form Substances 0.000 claims description 22
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 15
- 230000002209 hydrophobic Effects 0.000 claims description 12
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 10
- 238000007907 direct compression Methods 0.000 claims description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 9
- 229920002472 Starch Polymers 0.000 claims description 8
- 229940032147 Starch Drugs 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 7
- 150000004676 glycans Polymers 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 229920001282 polysaccharide Polymers 0.000 claims description 7
- 239000005017 polysaccharide Substances 0.000 claims description 7
- 150000004804 polysaccharides Polymers 0.000 claims description 7
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000008121 dextrose Substances 0.000 claims description 6
- 230000036571 hydration Effects 0.000 claims description 6
- 238000006703 hydration reaction Methods 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 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 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 5
- 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 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 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
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 238000010348 incorporation Methods 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 229960000913 Crospovidone Drugs 0.000 claims description 2
- 229940096516 Dextrates Drugs 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229960002675 Xylitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 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
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229920001600 hydrophobic polymer Polymers 0.000 claims 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 2
- 150000001340 alkali metals Chemical class 0.000 claims 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 2
- 125000005395 methacrylic acid group Chemical group 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 2
- 229920000881 Modified starch Polymers 0.000 claims 1
- 150000001242 acetic acid derivatives Chemical class 0.000 abstract description 2
- 150000001642 boronic acid derivatives Chemical class 0.000 abstract description 2
- 150000003842 bromide salts Chemical class 0.000 abstract description 2
- 150000003841 chloride salts Chemical class 0.000 abstract description 2
- 150000001860 citric acid derivatives Chemical class 0.000 abstract description 2
- 150000003893 lactate salts Chemical class 0.000 abstract description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 abstract description 2
- 230000003179 granulation Effects 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical group [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000000230 xanthan gum Substances 0.000 description 5
- 235000010493 xanthan gum Nutrition 0.000 description 5
- 229920001285 xanthan gum Polymers 0.000 description 5
- 229940082509 xanthan gum Drugs 0.000 description 5
- 229960001375 Lactose Drugs 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000003892 tartrate salts Chemical class 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003431 cross linking reagent Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 230000002496 gastric Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000000416 hydrocolloid Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 description 2
- 230000035639 Blood Levels Effects 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 229940089504 Lopressor Drugs 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M Potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M Potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 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 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- 229960005069 Calcium Drugs 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L Calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 210000001736 Capillaries Anatomy 0.000 description 1
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- MZYRDLHIWXQJCQ-YZOKENDUSA-L Potassium alginate Chemical compound [K+].[K+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O MZYRDLHIWXQJCQ-YZOKENDUSA-L 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L Potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
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- 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 1
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- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
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- 238000000338 in vitro Methods 0.000 description 1
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960000939 metoprolol succinate Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 239000008019 pharmaceutical lubricant Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
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- 239000011148 porous material Substances 0.000 description 1
- 235000010408 potassium alginate Nutrition 0.000 description 1
- 239000000737 potassium alginate Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- VILMUCRZVVVJCA-UHFFFAOYSA-M sodium;2-hydroxyacetate Chemical compound [Na+].OCC([O-])=O VILMUCRZVVVJCA-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
Abstract
The present invention relates to a tablet for the sustained release of metoprolol or its salt, characterized in that it comprises: metoprolol or a pharmaceutically acceptable salt thereof, in an amount necessary to produce a therapeutic effect in a human patient, from about 8% to about 35% heteropolysaccharide gum from about 0.5% to about 20% of a cationic entanglement agent selected from the group consisting of sulfates, chlorides, borates, bromides, citrates, acetates or lactates of metacalcali and alkaline earth metal and mixtures thereof which are capable of interlacing with the heteropolysaccharide gum to increase the gel strength when said formulation is exposed to an ambient fluid; a pharmaceutically inert diluent selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol and mixtures thereof; the proportion of metoprolol to heteropolysaccharide gum is from about 1: 1 to about 1: 5, whose dosage form provides a sustained release of metoprolol for at least about 24 hours when exposed to an ambient fluid
Description
METQPRQLQL ONE-TO-DAY ORAL DOSAGE FORM BACKGROUND OF THE INVENTION The advantages of controlled release products are well known in the pharmaceutical field and include a capacity to maintain a desired blood level of a drug over a comparatively longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve it. These advantages have been achieved by a wide variety of methods. For example, different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi-synthetic or naturally occurring. A few contain both synthetic and non-synthetic material. However, some of the systems require special processes and production equipment, and some of these systems are also susceptible to variable drug release. Systems for oral controlled release delivery ideally should be adaptable in such a way that profiles and release rates can be adjusted to physiological and chronotherapeutic requirements. While many sustained and controlled release formulations are already known, it is often not possible to easily predict whether a particular sustained release formulation will provide the desired sustained release for a particular drug and it has generally been found that experimentation is necessary. considerable to obtain sustained release formulations of these drugs that have the desired release rate when ingested. There have been a number of patents in the prior art, which relate to controlled release metoprolol formulations. For example, the US patent. No. 5,169,638 describes a pharmaceutical formulation of floating controlled release, in the form of a capsule filled with powder wherein an active ingredient of a basic character exhibits an independent controlled release of pH. The powder comprises the active agent, which may be metoprolol, a water-soluble salt of polyuronic acid, a pH-independent hydrocolloid gelation agent. { for example hydroxypropylcellulose, methylcellulose or hydroxypropylcellulose) and a binder (HPMC). The formulation is free of calcium ion and a carbon dioxide producing material, and is said to float in gastric juices, so that it will have a residence time in the stomach. The patent of the U.S.A. No. 4,792,452 discloses controlled release pharmaceutical compositions which are said to provide independent pH release for a basic drug such as metoprolol. The formulations include a pH-dependent polymer which is a salt of alginic acid, a pH-independent hydrocolloid gelling agent and a binder. The salt of the alginic acid is preferably sodium alginate or potassium alginate. The weight ratio of the alginic acid salt to the hydrocolloid gelling agent is all within the range 0.1: 1 to 10: 1 and the formulation is free of calcium ion and carbon dioxide producing material. The patent of the U.S.A. No. 4,957,745 also describes a controlled release metoprolol. The preparation includes a plurality of beads containing metoprolol coated with a polymeric membrane comprising ethyl cellulose with or without hydroxypropylmethylcellulose. The patent of the U.S.A. No. 4,871,549 describes a time-controlled explosion system comprising metoprolol, a swelling agent, such as substituted low hydroxypropyl cellulose, sodium starch glycolate or sodium carboxymethylcellulose, coated with a water-insoluble coating material, such that Drug release is made by the explosion of the membrane after a defined period of time. The patent of the U.S.A. No. 5,081,154 is directed to metoprolol succinate in an oral composition coated with a soluble anionic polymer at pH above 5.5 and an acrylic polymer substituted with water-insoluble quaternary ammonium.
Previously, a heterodisperse polysaccharide excipient system and controlled release oral solid dosage forms were described in our U.S. Patents. Nos. 4,994,276; 5,128,143 and 5,135,757, all of which are incorporated herein by reference. These systems are commercially available under the trademark TlMERxMH from Ed ard Mendell Co., Inc., N.Y., which is the assignee of the present invention. These patents are hereby incorporated by reference. OBJECTIVES AND COMPENDIUM OF THE INVENTION It is an objective of the present invention to provide oral solid sustained release formulations that release metoprolol for a period of time of at least about 24 hours, when the formulations are exposed to an environment of use (eg, gastrointestinal tract). A further objective of the present invention is to provide methods for preparing sustained release metoprolol formulations, which can be administered to patients on a once-a-day basis, or a longer desired time interval. The aforementioned and other objects are achieved by virtue of the present invention, which relates in part to a controlled release formulation, which comprises a therapeutically effective amount of metoprolol, and a sustained release matrix comprising a heteropolysaccharide gum; an inert diluent selected from for example monosaccharide, a disaccharide, a polyhydric alcohol, or mixtures thereof; and an effective amount of a pharmaceutically acceptable water-soluble cationic entanglement agent, to provide a sustained release of the medicament for at least about 24 hours, when the dosage form is exposed to an ambient fluid. In certain preferred embodiments of the invention, the gum is included in an amount of about 8% to about 35%, by weight of the final product. The ratio of drug to gum can be, for example, from about 1: 1 to about 1: 5. More preferably, the ratio of drug to gum is from about 1: 1.5 to about 1: 4. The present invention also relates to a sustained release oral solid dosage form for metoprolol or its salt, comprising metoprolol or a pharmaceutically acceptable salt in an amount necessary to produce a therapeutic effect in a human patient; from about 25% to about 35% hetero-polysaccharide gum; and a pharmaceutically inert diluent selected from the group consisting of monosaccharide, a disaccharide, a polyhydric alcohol, and mixtures thereof. The ratio of metoprolol to heteropolysaccharide gum is from about 1: 1 to about 1: 5. The dosage form provides a sustained release of metoprolol for at least about 24 hours when exposed to an ambient fluid.
The formulations of the present invention are prepared as a pharmaceutically acceptable oral solid dosage form, such as tablets. The present invention also relates to a method for providing a sustained release formulation of metoprolol, which comprises preparing a sustained release matrix comprising from about 8 to about 35% of a heteropolysaccharide gum and from about 1 to about 20% of a cationic interlacing agent capable of interlacing are the heteropolysaccharide gum agent, to increase the gel strength when the gum is exposed to an environmental fluid and an inert pharmaceutical diluent. The sustained release matrix is combined with metoprolol or a pharmaceutically acceptable salt, to deliver a drug: gum ratio of from about 1: 1 to about 1: 5; and manufactured in a final product. For example, the resulting mixture can be tabletted such that each tablet includes a dose of metoprolol, sufficient to provide a therapeutic effect for at least about 24 hours. The present invention further relates to a method of treating a patient comprising administering orally the sustained release metoprolol tablets to a patient, thereby providing therapeutically effective blood levels of the drug, at least for about 24 hours.
By "sustained release" it is intended for the purposes of the present invention, that the therapeutically active drug is released from the formulation at a controlled rate such that the therapeutically beneficial blood levels (but below toxic levels) of the medicament, They are maintained for a prolonged period of time, for example by providing a dosage form for 24 hours. The term "environmental fluid" is intended for purposes of the present invention encompassing, for example, an aqueous solution, such as that employed for in-vitro dissolution tests or gastrointestinal fluid. PESCRIPTION MTTAT.TJ PA Metoprolol is a beta-selective adrenergic blocking agent (cardioselective). Reduces the oxygen demand to the heart, slowing the heart rate, and reducing the cardiac output at rest and before exercise; reduces systolic blood pressure among other things. The drug is available in the
E.U.A. such as tartrate salt (Lopressor "*, Geigy Pharmaceuticals), as 50 mg and 100 mg tablets The effective daily dose is 100 mg to 450 mg and Lopressor is usually dosed as 100 mg given in two daily doses Metoprolol is also available as prolonged-release tablets of 50 mg, 100 mg and 200 mg in the USA, such as the succinate salt (Toprol XLHR, Astra Pharmaceutical Products, Inc.), which can be dosed once daily, as reported in our US patents Nos. 4,994,276, 5,128,143 and 5,135,757, the hetero-dispersed excipient of the present invention comprises both hetero- and ho or-polysaccharides exhibiting synergism, for example the combination of two or more polysaccharide gums produces a higher viscosity and faster hydration than which would be expected by either of the gums alone, the resulting gel is of faster formation and more rigid.In the present invention, it has been found that a release excipient A sustained release comprising only the heteropolysaccharide, for example xanthan gum, is sufficient to provide a convenient sustained release of an insoluble drug, to provide a 24-hour formulation not to avoid an initial "burst" of drug release from the formulation , when the formulation is exposed to a fluid in an environment of use, for example an aqueous solution or gastrointestinal fluid. The term "heteropolysaccharide" as used in the present invention is defined as a water soluble polysaccharide containing two or more types of sugar units, the heteropolysaccharide has a branched or helical configuration and has excellent properties of water absorption by capillary action and immense thickening properties.
An especially preferred heteropolysaccharide is xanthan gum, which is a high molecular weight heteropolysaccharide
(> 106). Other preferred heteropolysaccharides include xanthan gum derivatives, such as deacylated xatano gum, carboxymethyl ether and propylene glycol ether. The sustained release formulations of the present invention are substantially insensitive to the solubility of the medicament and equally insensitive to changes in pH throughout the gastrointestinal tract. In this way, the formulations of the present invention are pH independent. In certain preferred embodiments, wherein substantially sustained release of the drug is provided only by the heteropolysaccharide, the sustained release metoprolol formulation comprises from about 25% to about 35% heteropolysaccharide gum. In other preferred embodiments, the sustained release matrix further includes a cationic entanglement agent, for example monovalent or multivalent metal cations. Preferred salts are the inorganic salts, including various sulfates of alkali and / or alkaline earth metals, chlorides, borates, bromides, citrates, acetates, lactates, etc. Specific examples of suitable cationic crosslinking agents include calcium sulfate., sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium sodium, calcium lactate, magnesium sulfate and sodium fluoride. Cations of ultivalent metals can also be used. However, the preferred cationic crosslinking agents are divalent. Particularly preferred salts are calcium sulfate and sodium chloride. In these embodiments, the heteropolysaccharide gum is preferably included in an amount of about 8% to about 35% of the formulation, and the cationic entanglement agent is included in the sustained release excipient of the present invention, in an amount of about 1% to about 20% by weight of the sustained release excipient and an amount of about 1% to about 20% by weight of the final dosage form. In preferred embodiments of the present invention, the heteropolysaccharide comprises from about 15% to about 30% of the sustained release matrix and the cationic crosslinking agent comprises about 10% by weight of the sustained release matrix. The inert filler of the sustained release matrix preferably comprises a pharmaceutically acceptable saccharide, including a monosaccharide, a disaccharide, or a polyhydric alcohol, a pre-manufactured direct compression diluent, and / or a mixture of any of the foregoing.
Examples of suitable pharmaceutically inert fillers include sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, a starch, mixtures thereof and the like. If the mixture is to be manufactured without a wet granulation step, and the final mixture is to be tableted, it is preferred that all or part of the inert diluent comprises a pre-manufactured direct compression diluent. These direct compression diluents are widely employed in pharmaceutical techniques and can be obtained from a wide variety of commercial sources. Examples of these pre-manufactured direct compression excipients include EmcocelMB (microcrystalline cellulose, NF), Emdex * 01 (dextrates, NF) and Tab-Fine "* (a quantity of direct compression sugars including sucrose, fructose and dextrose) , all of which are commercially available from Edward Mendell Co., Inc., Patterson, New York Other direct compression diluents include Anhydrous lactose (Lactose NF, anhydrous direct tableting) from Sheffield Chemical, Union, NJ 07083; Elcems ™ G-250 (Powdered cellulose, NF) from Degussa, D-600 Frankfurt (Main) Germany, MaltrinMR (Agglomerated maltodextrin) from Grain Processing Corp., Muscatine, IA 52761; Neosorb 60"* (Sorbitol, NF direct compression) from Roquette Corp., 6455th Ave., New York, NY 10022; Nu-Tab "* (Compressed Sugar, NF) from Ingredient Technology, Inc., Pennsauken, NJ 08110; Polyplasdone XL ™ (Crospovidone, NF, Interlaced Polyvinylpyrrolidone) from GAF Corp., New York, NY 10020; Primojel1" 4 (Glycolate) sodium starch, NF, carboxymethyl starch) from Generichem Corp., Little Falls, NJ 07424; Solka Ploc "® (cellulose flocs) from Edward Mendell Co., Carmel, NY 10512; Fast-Flo Lactose" * (Lactose NF, spray-dried) from Foremost Whey Products, Baraboo, Wl 53913 and DMV Corp., Vehgel, Holland; and Sta-Rx 1500HR (Starch 1500) (Pregelatinized, NF, Compressible Starch) from Colorcon, Inc., West Point, PA 19486. However, it is preferred that a pharmaceutically soluble filler such as lactose, dextrose, sucrose or mixtures The sustained-release matrices of the invention have uniform packing characteristics, in a wide range of different particle size distributions and are capable of processing into tablets using direct compression, following the addition of drug and lubricating powder or conventional wet granulation. In wet granulation techniques, the desired amounts of heteropolysaccharide gum, with or without the cationic entanglement agent, and the inert diluent are mixed and subsequently a wetting agent such as water, propylene glycol, glycerol, alcohol or the like, are added to prepare a moisturized mass. Next, the moist mass is dried. The dry mass is then ground with conventional equipment to obtain the desired particle size.
Once the sustained release excipient of the present invention has been prepared, it is then possible to mix the same with metoprolol, for example in a V-blender, or by wet granulation. An effective amount of any generally accepted pharmaceutical lubricant, including calcium or magnesium soaps can be added to the aforementioned ingredients of the excipient while adding the medicament, or in any case prior to compression in a solid dosage form. An example of a suitable lubricant is magnesium stearate in an amount of about 0.5% to about 3% by weight of the solid dosage form. An especially preferred lubricant is sodium stearyl fumarate, NF, commercially available under the trademark Pruv ™ from Edward Mendell Co., Inc. In certain preferred embodiments of the invention, the sustained release matrix further comprises a hydrophobic material in an effective amount to slow down the hydration of the gum without interrupting or breaking the hydrophilic matrix formed by the heteropolysaccharide, when the formulation is exposed to fluids in an environment of use. This can be achieved by granulating the sustained release matrix with a solution or dispersion of hydrophobic material before the drug is incorporated. The hydrophobic material may be selected from ethylcellulose, polymers or copolymers of acrylic and / or methacrylic acid, hydrogenated vegetable oils, zein, as well as other hydrophobic pharmaceutically acceptable materials known to those skilled in the art. Other hydrophobic cellulosic materials such as other alkyl celluloses can also be employed. The amount of hydrophobic material incorporated in the sustained release matrix is that which is effective to stop the hydration of the gums without interrupting the hydrophilic matrix formed upon exposure to an environmental fluid. In certain preferred embodiments of the present invention, the hydrophobic material can be included in the sustained release matrix, in an amount of about 1% to about 20% by weight. More preferably, the hydrophobic material can be included in the sustained release matrix, in an amount from about 3% to about 12% and more preferably from about 5% to about 10%, by weight of the final formulation. The hydrophobic material can be dissolved in an organic solvent or dispersed in an aqueous solution for incorporation of the formulation. The dosage forms of the present invention are preferably tablets, however the ingredients can also be formulated in a capsule, extruded and spheronized with an active medicament to form nodules, etc. In certain embodiments, the complete mixture in an amount sufficient to produce a uniform batch of tablets, is then subjected to tabletting in a conventional tablet-scale tableting machine at normal compression pressure, i.e. about 140.6 to 112.48 kg / cm2 ( 2000-1600 lbs / sq in.). However, the mixture should not be compressed to such a degree that there is subsequent difficulty in achieving hydration when exposed to gastric fluid. The average tablet weight can be from about 300 mg to 950 mg. For metoprolol tablets which will contain approximately 100 mg of drug, the tablet weight is preferably from about 450 mg to 950 mg. The average particle size of the granulated excipient of the present invention is in the range of about 50 microns to about 400 microns and preferably from about 35 microns to about 265 microns. The particle size of the granulation is not markedly critical, the important parameter is that the average particle size of the granules should allow the formation of a directly compressible excipient which forms pharmaceutically acceptable tablets. The bulk densities and powder density desired of the granulation of the present invention are typically between about 0.3 to about 0.8 g / ml, with an average density of about 0.5 to about 0.7 g / ml. For best results, the tablets formed from the granulations of the present invention are from about 6 to about 8 kg of hardness. The average flow of the granulations prepared according to the present invention is from about 25 to about 40 g / sec. Tablets compacted using an instrumented rotary tableting machine have been found to possess strength profiles that are substantially independent of the inert saccharide component. Scanning electron micrographs of large tablet surfaces have provided qualitative evidence of extensive plastic deformation upon compaction, both on the surface of the tablet and across the surface of the fracture, and also show evidence of surface pores across the surface. which can occur solvent entry and initial solvent discharge and solution discharge. The amount of metoprolol or salt incorporated into the unit dosage formulations (e.g., tablets) of the present invention may be 50 mg, 100 mg or 200 mg, based on the tartrate salt. Of course, if other metoprolol salts are to be used, the weight of the particular metoprolol salt to be included can be calculated based on a weight equivalent to the tartrate salt. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The following examples illustrate various aspects of the present invention. It should not be considered as limiting claims in any way. EXAMPLES 1-3 The sustained-release excipient is prepared by dry mixing the required amounts of xanthan gum, dextrose and calcium sulfate in a high-speed mixer / granulator for 2 minutes. While processors / - impellers operate, the water is added and the mixture is granulated for another 2 minutes. The granulation is then dried in a fluid bed dryer at a drying weight loss (LOD) of between 4 and 7%. The granulation is then ground using mesh 20 sieves. The ingredients of the sustained release excipient of Example 1 are set forth in Table 1 below.
EXCIPIENT PREPARATION Dfi SUSTAINED RELEASE Component% -Ej. 1% -Ej,% -Ej. 3 1. Xanthan gum 30 15 30 2. Dextrose 60 75 70 3. Calcium sulfate 10 10 0 4. Water 10 * 10 * 10 * * removed during processing Next, the sustained-release excipient prepared as detailed above is dry mix with a desired amount of medicament (in the following examples metoprolol is provided as the tartrate salt) in a V-blender for 10 minutes. A convenient amount of Pruv ™ tableting lubricant (sodium stearyl fumarate, NF, commercially available from Edward Mendell Co., Inc.) for the following examples is added and the mixture is formulated for another 5 minutes. This final mixture is compressed into tablets, each tablet contains 100 mg of metoprolol. The tablets of Example 1 weighed 618.5 mg. The tablets of Example 2 weighed 618.5 mg. The tablets of Example 3 weighed 618.5 mg. The drug: gum ratio of the tablet of Example 1 was 1: 1.5. The drug: gum ratio of the tablet of Example 2 was 1: .75. The drug: gum ratio of the tablet of Example 3 was 1: 1.5. The ingredients of the tablets of Examples 1-3 are set forth in Table 2 below: TABLE 2 Component _ 1. Sustained Release Excipient 80.8% 2. Metoprolol 16.2% 3. Pruv "* 3.0% Dissolution tests then taken away performed in the tablets of Examples 1-3 The dissolution tests are conducted in an automated USP dissolution apparatus (Type of
Palette II, buffer 6.8, 100 rpm). The results are set forth in Table 3 below:
SINGLE RUBBER COMPOSITION EFFECT Time (ho?) Ej fi l. 3 fixed 3 o oo oo o oo 2 25.3 29.0 20.7 TABLE 3 (Continued) EFFECT OF COMPOSITION OF RUBBER SKNCTTJA Time fhoras Efijj .. i1 Ex. 2 fixed, 3 4 37. 9 42.7 32. 3 8 56. 3 63 - 6 50. 2 12 70 .6 77.9 64. 1 16 81. 3 88. 2 74. 3 20 89. 0 94.9 81. 3 24 97 .6 98.8 _ From the results provided in Table 3, it can be seen that formulations made with a higher concentration of gum produced slower rates of drug release. It is also evident that the incorporation of calcium sulfate in simple rubber systems results in faster drug release rates compared to formulations without calcium sulfate. Accordingly, the results provide that the tablets in Example 1 are convenient for delivering drugs as an oral solid dosage form during an oral 24 hour time period. The examples provided above are not intended to be exclusive. Many other variations of the present invention will be apparent to those skilled in the art and contemplated within the scope of the appended claims.
Claims (29)
- CLAIMS 1. A sustained release oral solid dosage form for metoprolol or its salt, comprising: metoprolol or a pharmaceutically acceptable salt thereof, in an amount necessary to produce a therapeutic effect in a human patient; and a sustained release matrix comprising from about 8% to about 35% heteropolysaccharide gum; from about 0.5% to about 20% of cationic entanglement agent capable of interlacing with the heteropolysaccharide gum, to increase the gel strength when the formulation is exposed to an ambient fluid; and an inert pharmaceutical diluent; the ratio of metoprolol to the heteropolysaccharide gum is from about 1: 1 to about 1: 5, the dosage form provides sustained release of metoprolol at least for about 24 hours, when exposed to an ambient fluid.
- 2. The oral solid dosage form of claim 1, wherein the ratio of drug to gum is from about 1: 1.5 to about 1: 4.
- 3. The oral solid dosage form of claims 1 to 2, wherein the cationic entanglement agent comprises a sulfate, chloride, borate, bromide, citrate, acetate or lactate of alkali metal or alkaline earth metal.
- 4. The oral solid dosage form of claims 1 to 3, wherein the cationic entanglement agent comprises calcium sulfate.
- The oral solid dosage form of claim 1, wherein the inert pharmaceutical diluent is selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, microcrystalline cellulose, a starch, and mixtures thereof, 6.
- The oral solid dosage form of claim 1, wherein the inert diluent is directly compressible prior to incorporation into the dosage form.
- The oral solid dosage form of claim 5, wherein the inert diluent is selected from the group consisting of sucrose, dextrose, lactose, icro-crystalline cellulose, fructose, xylitol, sorbitol, a starch and mixtures thereof.
- 8. The oral solid dosage form of claim 6, wherein the inert diluent is selected from the group consisting of a compressible microcrystalline cellulose, dextrates, a directly compressible sugar, anhydrous direct tableted lactose, powdery cellulose, dried lactose by roclo, agglomerated maltodextrin, direct compression sorbitol, crospovidone, sodium starch glycolate, carboxymethyl starch, cellulose floc, pregelatinized starch and their combinations.
- 9. The oral solid dosage form of claims 1 to 8, wherein the cationic entanglement agent comprises about 10 percent of the formulation by weight.
- 10. The oral solid dosage form of claims 1 to 8 »further comprises a hydrophobic polymer selected from the group consisting of an alkylcellulose, a copolymer of acrylic and methacrylic esters and a mixture of the above, prior to incorporation into the medicament. , the hydrophobic polymer is included in the dosage form, in an amount effective to slow the hydration of the gums when exposed to an ambient fluid.
- 11. The oral solid dosage form of claim 10, wherein the hydrophobic polymer comprises ethyl cellulose.
- 12. The oral solid dosage form of claims 10 to 11, wherein the hydrophobic material comprises about 1 to 20 percent of the dosage form by weight.
- The oral solid dosage form of claims 10 to 12, wherein the hydrophobic polymer comprises about 5 to about 10 percent of the dosage form by weight.
- 14. The oral solid dosage form of claims 1 to 13, which is a tablet.
- 15. The oral solid dosage form of claims 1 to 14, wherein it comprises 50 mg, 100 mg or 200 mg of metoprolol.
- 16. The oral solid dosage form of claims 1 to 15, wherein the sustained release matrix comprises agglomerated particles.
- 17. Method for preparing a 24-hour formulation of raetoprolol, comprising: preparing a sustained release matrix comprising from about 8 to about 35% of a heteropolysaccharide gum and from about 1 to about 20% of a cationic interlacing agent capable of entanglement with the agent heteropolysaccharide gum to increase the gel strength, when the gum is exposed to an environmental fluid and an inert pharmaceutical diluent; combining the sustained release matrix with metoprolol or a pharmaceutically acceptable salt, to deliver a drug: gum ratio of from about 1: 1 to about 1: 5; and tabletting the resulting mixture, such that each tablet includes a dose of metoprolol, sufficient to provide a therapeutic effect, at least for about 24 hours.
- 18. Method for preparing a 24-hour formulation of metoprolol, comprising: preparing a granulated sustained release matrix, by wet granulation, comprising about 8 to about 35% of a hetero-polysaccharide gum and from about 1 to about 20 % a cationic entanglement agent, capable of entanglement with the heteropolysaccharide gum agent to increase gel strength or resistance when the gum is exposed to an environmental fluid and an inert pharmaceutical diluent; combining the sustained release matrix with metoprolol or a pharmaceutically acceptable salt to deliver a drug: gum ratio of from about 1: 1 to about 1: 5; and tabletting the resulting mixture such that each tablet includes a sufficient dose of metoprolol to provide a therapeutic effect, at least for about 24 hours.
- 19 * Method for treating a patient with metoprolol, comprising: preparing a sustained release matrix comprising from about 8 to about 35% of a heteropolysaccharide gum and from about 1 to about 20% of a cationic entanglement agent capable of interlacing with the heteropolysaccharide gum agent, to increase the gel strength when the gum is exposed to an ambient fluid and an inert pharmaceutical diluent; combining the sustained release excipient with metoprolol or a pharmaceutically acceptable salt, to deliver a drug: oma ratio of about 1: 1 to about 1: 5; and tabletting the resulting mixture such that each tablet includes a dose of metoprolol, sufficient to provide a therapeutic effect for at least about 24 hours, and administering the tablets to a patient at an appropriate dosage range.
- 20. Method according to claims 17 to 19, further comprising adding a hydrophobic material to the mixture of the sustained release matrix and metoprolol, in an amount effective to slow the hydration of the gum when exposed to an environmental fluid before rattle.
- 21. Method according to claims 17 to 19, further comprising providing the tableted formulation with a drug to gum ratio of from about 1: 1.5 to about 1: 4.
- 22. Method according to claims 17 to 19, wherein the cationic entanglement agent comprises a sulfate, chloride, borate, bromide, citrate, acetate or lactate of alkali metal or alkaline earth metal and the hydrophobic polymer is selected from the group which consists of an alkyl cellulose, a copolymer of acrylic and methacrylic esters and a mixture of the foregoing.
- 23. Method according to claim 20, wherein the hydrophobic polymer comprises ethylcellulose and the cationic entanglement agent comprises calcium sulfate.
- 24. Method according to claim 23, wherein the hydrophobic material comprises from about 1 to 10 percent of the formulation by weight.
- 25. Method according to claims 17 to 19, further comprising the step of wet granulating the granulated sustained release matrix with the metoprolol.
- 26. Method according to claims 17 to 19, wherein the heteropolysaccharide gum and the cationic entanglement agent are wet granulated to form an agglomerate and add the inert pharmaceutical diluent.
- 27. Method according to claims 17 to 19, wherein the heteropolysaccharide gum, the cationic entanglement agent and the inert pharmaceutical diluent are wet granulated to form the granulated sustained release matrix.
- 28. Oral solid dosage form of ssotenida release for metoprolol or its salt, comprising: metoprolol or its pharmaceutically acceptable salt, in an amount necessary to produce a therapeutic effect in a human patient; from about 25% to about 35% hetero-polysaccharide gum; and an inert pharmaceutical diluent; the ratio of metoprolol to the heteropolysaccharide gum is from about 1: 1 to about 1: 5, the dosage form provides a sustained release of metoprolol, at least for about 24 hours when exposed to an ambient fluid.
- 29. The sustained release oral solid dosage form according to claim 28, wherein the inert pharmaceutical diluent is selected from the group consisting of a monosaccharide, a disaccharide, a polyhydric alcohol, a starch, microcrystalline cellulose and mixtures thereof. .
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08232719 | 1994-04-25 | ||
US08/232,719 US5399362A (en) | 1994-04-25 | 1994-04-25 | Once-a-day metoprolol oral dosage form |
Publications (2)
Publication Number | Publication Date |
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MX9600024A MX9600024A (en) | 1998-11-30 |
MXPA96000024A true MXPA96000024A (en) | 1999-01-15 |
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