CN101400342A - Controlled release formulation of divalproic acid and its derivatives - Google Patents
Controlled release formulation of divalproic acid and its derivatives Download PDFInfo
- Publication number
- CN101400342A CN101400342A CNA2006800538183A CN200680053818A CN101400342A CN 101400342 A CN101400342 A CN 101400342A CN A2006800538183 A CNA2006800538183 A CN A2006800538183A CN 200680053818 A CN200680053818 A CN 200680053818A CN 101400342 A CN101400342 A CN 101400342A
- Authority
- CN
- China
- Prior art keywords
- controlled release
- preparation
- polymer
- hypromellose
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000013270 controlled release Methods 0.000 title claims abstract description 53
- 239000000203 mixture Substances 0.000 title claims abstract description 50
- 238000009472 formulation Methods 0.000 title claims abstract description 13
- 239000002253 acid Substances 0.000 title description 8
- -1 valproic acid compound Chemical class 0.000 claims abstract description 67
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 claims abstract description 60
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 claims abstract description 53
- 229920000642 polymer Polymers 0.000 claims abstract description 50
- 229940028937 divalproex sodium Drugs 0.000 claims abstract description 33
- 229960000604 valproic acid Drugs 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims description 83
- 229940102566 valproate Drugs 0.000 claims description 73
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 43
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 43
- 239000003405 delayed action preparation Substances 0.000 claims description 40
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 35
- 229960003943 hypromellose Drugs 0.000 claims description 35
- 229920001477 hydrophilic polymer Polymers 0.000 claims description 32
- 238000000576 coating method Methods 0.000 claims description 28
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 24
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 23
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 23
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 23
- 239000008187 granular material Substances 0.000 claims description 20
- 239000002775 capsule Substances 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000011248 coating agent Substances 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 229920003091 Methocel™ Polymers 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 239000007931 coated granule Substances 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 10
- 239000011159 matrix material Substances 0.000 claims description 10
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- 235000012239 silicon dioxide Nutrition 0.000 claims description 9
- 239000001856 Ethyl cellulose Substances 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 235000021355 Stearic acid Nutrition 0.000 claims description 8
- 229920001249 ethyl cellulose Polymers 0.000 claims description 8
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 8
- 239000008117 stearic acid Substances 0.000 claims description 8
- 229920000881 Modified starch Polymers 0.000 claims description 7
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229920001600 hydrophobic polymer Polymers 0.000 claims description 6
- 235000020925 non fasting Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 241001597008 Nomeidae Species 0.000 claims description 5
- 239000006185 dispersion Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 229950005770 hyprolose Drugs 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 239000005002 finish coating Substances 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 4
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 4
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 4
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 239000005017 polysaccharide Substances 0.000 claims description 4
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 4
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 4
- 238000012216 screening Methods 0.000 claims description 3
- 230000003139 buffering effect Effects 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims 8
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 30
- 239000003814 drug Substances 0.000 description 23
- 239000002552 dosage form Substances 0.000 description 15
- 229940084026 sodium valproate Drugs 0.000 description 12
- 239000002671 adjuvant Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 6
- 206010015037 epilepsy Diseases 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000009492 tablet coating Methods 0.000 description 4
- 239000002700 tablet coating Substances 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 230000037058 blood plasma level Effects 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000975 dye Substances 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- OMOMUFTZPTXCHP-UHFFFAOYSA-N valpromide Chemical compound CCCC(C(N)=O)CCC OMOMUFTZPTXCHP-UHFFFAOYSA-N 0.000 description 3
- 229960001930 valpromide Drugs 0.000 description 3
- 229920003084 Avicel® PH-102 Polymers 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 208000019695 Migraine disease Diseases 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 229940089052 depakene Drugs 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 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
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
Abstract
The present invention provides a controlled release dosage formulation comprising a) about 40% to about 80% of a valproic acid compound such as Divalproex Sodium and b) at least two, preferably hydrophilic, polymers each in an amount of less than about 20% of the dosage weight.
Description
Invention field
The present invention relates to pharmaceutical preparation.More specifically, the present invention relates to contain the controlled-release tablet preparation of two valproic acids, the acceptable salt of its pharmacy, ester or amide or divalproex sodium.
Background of invention
The 2-Propylpentanoic, the more normal valproic acid (VAP) that is known as, its amide form valpromide (VPO) and some salt that should acid and ester can effectively be treated epilepsy or as antipsychotic drug.Meade has described sodium valproate in United States Patent (USP) 4988731 and the valproic acid mol ratio is 4 the unitary oligomer that contain of 1:1, Meade has described a kind of stable, nonhygroscopic solid form of valproic acid in United States Patent (USP) 5212326, it contains sodium valproate and valproic acid mol ratio is 1:1's and contain 4 to 6 unitary oligomer.Sodium valproate (valproic acid hydrogen sodium) can be used for prevention adult migraine, also can be used for treatment or prevention epilepsy.
Although yet it can effectively treat epilepsy, the elimination half-life of valproic acid is significantly shorter than other antuepileptic commonly used.Reported this medicine half-life of 4 to 14 hours in 6 to 17 hours and the child's body in becoming human body.This can cause the fluctuation of drug plasma concentration, especially in long term administration.In order to keep reasonably stablizing plasma concentration, have necessity by means of frequent drug administration, but its inconvenience that brings to patient usually causes the low compliance of prescription dosage regimen.In addition, the fluctuating widely of plasma concentration can cause for some patient the dosage in the conservative dosage regimen less than therapeutic dose, or actively in the dosage regimen dosage too big.
In order to overcome this shortcoming, researched and developed the Depakene that after administration, to keep more constant blood plasma level.Final purpose is that research and development can provide the preparation of stablizing blood plasma level in dosage regimen once a day.Roughly be divided into two classes for reaching the effort that this target carries out: (a) seek this active component a kind of can be in vivo the form that discharges of metabolic more lentamente; (b) seek a kind of preparation by timing release or the administration of controlled release mechanism.
For example, United States Patent (USP) 4369172 (Schor etc.) has been described a kind of extended release therapeutic combination based on hydroxypropyl emthylcellulose, ethyl cellulose and/or sodium carboxymethyl cellulose mixture.Schor etc. provide a lot of they think and can mix the therapeutic agent that contains in the Depakene, comprise sodium valproate.
United States Patent (USP) 4931906 (Friedman etc.) has been described valproic acid, its amide or one of its salt or ester and has been pressed into a kind of control dosage form of tablet with natural or synthetic polymer under strong pressure.
United States Patent (USP) 5009897 (Blinker etc.) has been described and has been applicable to that the granule that is pressed into tablet, this granule contain the coating of the mixture of sodium valproate label and polymer and microcrystalline Cellulose.
United States Patent (USP) 5019398 (Daste) has been described a kind of sodium valproate slow releasing tablet in hydroxypropyl emthylcellulose and hydrated SiO 2 substrate.
United States Patent (USP) 5055306 (Barry etc.) has been described suitable effervescent or the water dispersible granular slow releasing preparation that uses with various therapeutic agents.This granule comprises the label that contains active component and at least a adjuvant, and the water solublity, hydroexpansivity coating and the water soluble hydroxy cellulose derivative that contain ethyl acrylate and methylmethacrylate copolymer.The patentee has proposed can be used for a lot of therapeutic agents of preparation of the present invention, comprises sodium valproate.
United States Patent (USP) 5169642 (Brinkler etc.) has been described a kind of slow release formulation that contains the amide of divalproex sodium (divalproex sodium) or valproic acid or the granule of ester (with the slow releasing composition coating that comprises ethyl cellulose or methacrylic methyl ester), a kind of plasticizer, a kind of antitack agent and a kind of slow release macromolecule viscous agent.
United States Patent (USP) 5185159 (Aubert etc.) has been described the preparation of a kind of valproic acid and sodium valproate, does not use binding agent or system granule solvent in its preparation.Said preparation can be chosen wantonly and contain precipitated silica as anti-adhesive or antitack agent.
United States Patent (USP) 5589191 (Exigua etc.) has been described a kind of slow release valproic acid tablet preparation, wherein with containing the ethyl cellulose of silicic acid anhydride with the tablet coating.
Openly PCT application WO 94/27587 (Ayer etc.) has described a kind of by giving valproic acid or derivatives thereof and a kind of method of gathering the therapeutic combination Taking Control of Epilepsy of (alkylene oxide).
Bialer etc., " metabolism of antiepileptic " (＂ Metabolism of AntiepilepticDrugs ＂) 143-151 page or leaf, R.H.Levy, Ed, Raven publishing house, New York, 1984; Int.J.Pharmaceutics, 20:53-63 (1984); Biopharmaceutics and drug distribution (Biopharmaceutics and Drug Disposition, 6:401-411 (1985); And IsraelJ.Med.ScL, 20:46-49 (1995) has reported the pharmacokinetics evaluation of several valproic acid slow releasing preparation.
United States Patent (USP) 6419953 (Qiu etc.) has been described and has been applicable to that for example hydrophilic substrate tablet of sodium valproate administration once a day of valproate compound, hydroxypropyl emthylcellulose amount are about 20 to about 40 percentage by weights.
It is said that United States Patent (USP) 6528090 (Qiu etc.) described the controlled release formulations for oral administration that is applicable to valproate compound administration once a day, pharmacy can be accepted the hydrophilic polymer amount and be the about 50% dose of weight of about 20%-.
Yet we still need effectively to keep the valproic acid slow releasing preparation of more stable plasma concentration.
Summary of the invention
The invention provides the controlled release tablet that comprises following composition: a) valproate compound of about 40%-about 80% for example sodium valproate and
B) polymer of at least two kinds of preferred hydrophilic, each plant demand less than sheet heavy 20%.Preferred described controlled release form comprises 2-4 kind polymer, more preferably 2 kinds of polymer.Preferred described controlled release preparation comprises the valproate compound of about 45%-about 55%.In addition, described polymer is preferably selected from hypromellose (hypromellose HPMC), hydroxyethyl-cellulose and polyethylene glycol oxide.
The present invention also provides and has comprised valproate compound and at least two kinds of each plant demands weigh the polymer of 20% preferred hydrophilic less than sheet controlled release tablet dosage form on the other hand, and its 37 ℃ of stripping curves in the pH5.5 water-containing buffering liquid are:
A) in described instrument during 3 hours or within the burst size measured less than about 30% overall valproate;
B) in described instrument during 9 hours or within the burst size measured be about 35%-about 70% overall valproate;
C) in described instrument during 12 hours or within the burst size measured be about 50% to-95% overall valproate, reach;
D) in described instrument during 18 hours or within the burst size measured be not less than 75% overall valproate.
The present invention further provides the method that preparation is applicable to filled capsules or is pressed into the particulate composition of controlled release tablet dosage form, it may further comprise the steps:
A) will contain the polymeric blends dry mixed of valproate compound (for example divalproex sodium), at least two kinds of polymer (preferred two to four kinds, more preferably two kinds, preferred hydrophilic, preferred hypromellose) and binding agent (preferably pregelatinized Starch);
B) make wet granular to form uniform homogeneous blend with aqueous alcohol solutions (mixture of alcohol and water);
C) with wet grain drying and screening (sizing);
D) usefulness contains the dispersion of hydrophilic polymer (preferred hypromellose) and Pulvis Talci and pure water with the dried particles surface coatings;
E) drying coated granules;
F) add fluidizer (preferred silicon dioxide) coated granule sieve;
G) incite somebody to action coated granule and filler (preferably microcrystalline cellulose) and lubricant (preferred stearic acid) dry mixed;
H) hybrid particles is pressed into tablet; And
I) use the finish coating with the tablet coating.
Going in the capsular embodiment particles filled, this step can be carried out after step e) and step f), and therefore step g) becomes optional, need not step f) and step I).
On the other hand, the invention provides treatment and suffer from the patient's of the disease that needs the treatment of the controlled release preparation of use valproate compound method, it comprises the valproic acid controlled release tablet preparation for the treatment of effective dose once a day, and its each plant demand that comprises the valproate compound of about 40%-about 80% and at least two kinds of preferred hydrophilic is less than the polymer of about 20% weight.
Detailed Description Of The Invention
As using herein, term " slow release ", " prolong and discharge " and " controlled release " of being used for pharmaceutical preparation have ＂ Remington ' s Pharmaceutical Sciences, ＂ the 18th edition, 1677 pages, MackPub.Co., Easton, given implication among the Pa. (1990).Slow release medicine system comprises any drug-supplying system that can reach slow drug release in the time that prolongs.If this slow-released system can effectively be kept levels of drugs stable basically in blood or the target tissue, just think that it is a controlled-release administrating system.Yet, if a kind of drug-supplying system by the action time of traditional administering mode prolong drug, no matter whether it can reach stable basically blood or organize levels of drugs, does not think that all it is a slow-released system.
Preparation of the present invention provides a kind of controlled release preparation of valproate compound.Term " valproic acid " mean comprise chemical compound 2-Propylpentanoic self and the acceptable salt of pharmacy thereof and in vivo metabolism produce the chemical compound of valproic acid, valproic acid amide (valpromide) for example, and should acceptable amide of other pharmacy of acid and ester.The especially preferred valproic acid form of the present composition is the complex of 2-Propylpentanoic and its sodium salt (2:1), so-called " divalproex sodium ".
Divalproex sodium can be represented that wherein m is the integer between the 2-6 by following structure.
Oberreit, Ber.29,1998 (1896) and Keil, Z.Physiol.Chem.282,137 (1947) have described the method for preparing valproic acid.Doctor's handbook (Physician Desk Reference) on the desk, the 52nd edition, 421 pages (1998) have described its activity as the epilepsy chemical compound.Oral back is in gastrointestinal tract, and this acid moieties dissociates and forms carboxylate part (being the valproate ion).Can be used as the epilepsy medicament in sodium salt of valproic acid known in the art.It also is known as sodium valproate and has a detailed description in Merck index the 12nd edition the 1691st page (1996).Doctor's handbook (Physician Desk Reference) on the desk, has further description in the 417th page (1998) by the 52nd edition.
Divalproex sodium is effective Anti-epileptics, and it also can be used for migraine and bipolar disorder.Can find its preparation method in United States Patent (USP) 4988731 and 5212326, the content of these two patents all and in this paper as a reference.Similar to valproic acid, divalproex sodium also dissociates in gastrointestinal tract and forms the valproate ion.
In addition, as used herein:
All be interpreted as being included in the gastrointestinal tract or the ionic chemical compound of formation valproate that can dissociate in the external dissolution medium as long as a) mention " valproate compound (valproic acid compound) ", this ion includes but not limited to one of valproic acid, valproic acid sodium salt, divalproex sodium, various valproates described above and above-mentioned any valproic acid prodrug.Divalproex sodium is most preferred valproate compound of the present invention (valproate compound).
B) ＂ Cmax ＂ refers to absorb the valproate ion maximal plasma concentration that produces behind the present composition.
C) as using herein, ＂ AUC ＂ refers to area under plasma concentration-time graph, calculates according to complete 24 hours interior at interval trapezoidal rules for all preparations.
D) as using herein, " pharmacy can be accepted " means those in reliable medical science judgement scope, be applicable to contact with the tissue of people and rudimentary animal and do not cause undue toxicity, stimulation, anaphylaxis and analogue, can keep rational interests/risk than, help salt, polymer or the adjuvant of their desired use in treatment and prevention various diseases.
Further, in medicine production, usually use external stripping curve.They can be used as quality control method has identical stripping curve and therefore produces suitable biological respinse to guarantee different batches.
The invention provides and compare novel valproate compound dosage form with the slow releasing preparation of prior art with remarkable advantage.These preparations can provide zero (0) level of valproate to discharge, and reduce to the peak of valproate and the variation of paddy blood plasma level minimum.All preparations of the present invention comprise matrix system, and it comprises the polymer of at least two kinds of preferred hydrophilic, and consumption separately is less than 20% weight, and can further comprise the particle matrix surface coatings.
In matrix system, medicine or active pharmaceutical ingredients are scattered in polymer and the conventional adjuvant equably.This mixture can be pressed into tablet under pressure.Medicine discharges from tablet by diffusion and corrosion.(1) medicine controlled releasing technical manual (Handbook ofpharmaceutical controlled release technology), editor D.L.Wise, MarcelDekker, Inc.New York, N.Y. (2000) and (2) controlled release drug administration paper, rudimentary knowledge, optimize and application (Treatise on controlled drug delivery, fundamentals, optimization, applications) editor Ed.A.Kydonieus, Marcel Dekker, Inc.New York, N.Y. has all described matrix system in (1992), its two all and as a reference in this paper.
Can obtain hereinafter enhanced in greater detail pharmacokinetic curve by the valproate compound matrix formulations that contains at least two kinds of preferred hydrophilic polymer.In one embodiment, described controlled release form according to the present invention comprises:
A) be enough to provide every day required valproate dosage valproate compound and
B) at least two kinds, more preferably 2 kinds of preferred 2-4 kinds, the polymer of preferred hydrophilic, wherein the consumption of each polymer is less than about 20% weight, preferably less than about 16% weight.
The controlled release preparation that comprises following composition is provided in another embodiment:
A) be enough to provide the valproate compound of required valproate dosage every day;
B) contain at least two kinds, more preferably 2 kinds of preferred 2-4 kinds, the polymer of preferred hydrophilic;
C) comprise the particulate particle surface coating of drug matrices of polymer (preferred hydrophilic polymer), wherein the consumption of each independent type polymer is less than about 20% preparation, preferably less than about 16% compositions.
In preferred embodiments with this surface coatings granule of coating be pressed into label, the latter can choose wantonly with finish coating parcel.
The preferred divalproex sodium of described valproate compound.The amount of valproate compound should be enough to valproate dosage every day that provides required, does not wait from about 80% formulation weight of about 40%-.Controlled release form of the present invention more preferably contains the valproate compound of about 60% weight ratio of the 45%-that has an appointment, more preferably from about the valproate compound of 45%-55% weight ratio.
The preferred hydrophilic polymer that is applicable to controlled release form be selected from hypromellose (HPMC, for example Methocel K100, Methocel E15 and Pharmacoat 606), hydroxyethyl-cellulose (HEC, for example
250M), polyethylene glycol oxide, polyvinylpyrrolidine, hyprolose, methylcellulose, vinyl acetate co-polymer (for example Kollicoat SR 30, a kind of polyvinyl acetate ester aqueous dispersion with polyvidon and sodium lauryl sulfate stabilisation), polysaccharide (for example alginate, xanthan gum etc.), methacrylic acid copolymer, maleic anhydride/methyl ethylene ether copolymer and derivant thereof.Described hydrophilic polymer is preferably from hypromellose, hydroxyethyl-cellulose, polyethylene glycol oxide and Kollicoat.Most preferred hydrophilic polymer is hypromellose and hydroxyethyl-cellulose.Preferred hypromellose chemical compound comprises commercially available Methocel K100, Methocel E15 and Pharmacoat 606.A kind of preferred commercially available hydroxyethyl-cellulose is
250M.
The consumption of each polymer is less than about 20% composition weight in the dosage form of the present invention.The consumption of preferred each polymer is less than about 16% composition weight.More preferably the consumption of each polymer is about 16% formulation weight of about 10%-.Most preferably the consumption of each polymer is about 16% formulation weight of about 12%-.
Controlled-release tablet preparation of the present invention can further comprise for example ethyl cellulose of hydrophobic polymer.Preferred commercially available ethyl cellulose comprises Ethocel Premium 7cps and EthocelPremium 100cps.
Compositions of the present invention also comprises pharmacy usually can accept adjuvant.As is known to the person skilled in the art, pharmaceutic adjuvant is contained in the solid dosage forms routinely.Do the performance that to simplify production technology and improve dosage form like this.Common adjuvant comprises diluent or filler, lubricant, binding agent etc.These adjuvants are applied in the dosage form of the present invention routinely.
Add diluent or filler and the quality of single dosage can be increased to the scale that is suitable for tabletting.The suitable dilution agent comprises Icing Sugar, calcium phosphate, calcium sulfate, microcrystalline Cellulose, lactose, mannitol, Kaolin, sodium chloride, dried starch, sorbitol etc.
There are many reasons to need in preparation, to add lubricant.They can reduce the friction between tabletting and At time of eject granule and the mold wall.This can prevent that granule and tablet drift and mould from adhering to, and promotes it from the ejection of tablet drift etc.The example of proper lubrication agent comprises Pulvis Talci, sodium lauryl sulfate, stearic acid, vegetable oil, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate etc.
Also add fluidizer in the preparation usually.Fluidizer can improve particulate flow behavior.Suitably the example of fluidizer comprises Pulvis Talci, silicon dioxide and corn starch.
Also can add binding agent in the preparation.If the production of dosage form is used and is used binding agent when granulating this step usually.Suitably the example of binding agent comprises polyvidone, polyvinylpyrrolidone, xanthan gum, cellulose gum for example carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, hydroxylated cellulose, gelatin, starch and pregelatinized starch.And binding agent also usually is and controls the used polymer phase polymer together of active component release in the preparation.
Can in preparation, add other adjuvant and comprise any other adjuvant commonly used in antiseptic, antioxidant or the pharmaceuticals industry etc.The optional preferred finish of tablet coating (cosmatic) and can be from for example powder preparation of commercially available coating suspension, the latter is based on hypromellose or polyvinyl alcohol and Polyethylene Glycol and coloring agent etc.
A kind of controlled release label dosage form is provided in another embodiment of the invention, and it contains the valproate compound of about 50% percentage by weight of the 47%-that has an appointment; The hypromellose of about 13%-16% percentage by weight; The hydroxyethyl-cellulose of about 13%-15% percentage by weight; The pregelatinized Starch of the percentage by weight of about 8%-9%; The microcrystalline Cellulose of the percentage by weight of about 4%-10%; The stearic acid of the silicon dioxide of about 3%-4% percentage by weight and about 1%-2% percentage by weight; All percentage by weights are all based on the gross weight of tablet dosage form.
Described the especially preferred controlled release preparation of the present invention in following table 1, wherein all percentage by weights are all based on the gross weight of dosage form.
Table 1: the preferred controlled release preparation of the present invention (uncoated tablets core)
| Composition | Preparation (mg) | (%) sheet is heavy |
| Label: | ||
| Divalproex sodium | 538.2 | 47.1-50.6 |
| Starch | 91.8 | 8.0-8.6 |
| Hydroxypropyl emthylcellulose (Methocel-K) | 90.0-150.0 | 8.0-13.1 |
| Hydroxyethyl-cellulose NF | 150.0 | 13.1-14.1 |
| Surface coatings: |
| Hydroxypropyl emthylcellulose (Methocel E-15) | 24.0-84.0 | 2.2-7.4 |
| Meticulous Pulvis Talci | 28.0 | 2.5-2.6 |
| Dry mixed: | ||
| Silicon dioxide (Syloid 244) | 40.0 | 3.5-3.8 |
| Microcrystalline Cellulose (Avicel PH102) | 50.0 | 4.6-8.8 |
| Stearic acid NF | 20.0 | 1.8-1.9 |
| Amount to | 1064.0-1142.0 | 100 |
A kind of controlled-release tablet preparation is provided in another embodiment of the invention, it comprises at least two kinds, preferred two to four kinds more preferably two kinds, the polymer of preferred hydrophilic, the stripping curve of said preparation a) during 3 hours or within burst size no more than about 30% total valproate compound; B) during 9 hours or within burst size be about 35%-about 70% total valproate compound; C) during 12 hours or within burst size be the total valproate compound of about 55%-95%; And d) during 18 hours or within burst size be no less than 75% total valproate compound.The condition determination of controlled release tablet dosage form stripping curve of the present invention is: USP II type instrument, rotating speed 100rpm, 37 ℃ of temperature, stripping is 45 minutes in the acidic phase of 500mL 0.1N HCl, then stripping in the 900mL 0.05M phosphate buffer alkali stage of (containing 75mM sodium lauryl sulfate (SLS) pH5.5).
A kind of controlled release tablet preparation is provided in another embodiment of the present invention, it contains valproate compound and at least two kinds, the polymer of preferred two to four kinds and preferred hydrophilic, described preparation has the intravital relative pharmacokinetics curve of comparing with Depakote ER (a kind of commercially available slow release divalproex sodium preparation) pharmacokinetics curve of mammal: a) average A UC value is in the scope of about 85%-about 120%, wherein the AUC observed value with Depakote ER is set at 100%, b) C
MaxValue is in the scope of about 90%-about 160%, wherein with the C of Depakote ER
MaxObserved value is set at 100%, wherein described controlled-release tablet preparation is given the mammal of non-fasting.In addition, in the intravital AUC value of fasting mammal in the scope of about 90%-about 130%, C
MaxValue is in the scope of about 100%-about 160%.In this pharmacokinetics curve, AUC and C
MaxParametric representation be the observed value of preparation of the present invention and 100 times of Depakote ER observed value ratio.The pharmacokinetics parameter values of preferred dosage form of the present invention satisfies the 0.80-1.25 standard with Depakote ER equivalence.Dosage formulation of the present invention contains the polymer of valproate compound and at least two kinds of preferred hydrophilic, the latter's consumption is less than 20%, preferably less than 16%, therefore compare and have suitable pharmacokinetics and preferably bioequivalent with commercially available Depakote ER preparation.
Usually use standard technique known in the art to prepare controlled release form.Usually in the following manner the preparation: with polymer, filler, valproate compound and other adjuvant dry mixed of preferred hydrophilic use then aqueous alcohol solutions (mixture of alcohol and water) with granulating mixture until obtaining suitable granule.Can adopt methods known in the art to granulate.Wet granular is dry in fluidized bed dryer.Sieve and grind to form suitable size, follow the available dispersion surface coating that contains hydrophilic polymer.Filler and lubricant mixed with dried granules obtain final preparation.
The controlled release tablet preparation that more specifically, can contain valproate compound and at least two kinds of preferred hydrophilic polymer as following examples preparation.The method that preparation is suitable for being pressed into the particulate composition of controlled release tablet dosage form may further comprise the steps:
1) will contain for example dry mixing of polymer of valproate compound, at least two kinds of (preferred two to four kinds) polymer (preferred hydrophilic, preferred hypromellose and hydroxyethyl-cellulose) and the binding agent (preferred pregelatinized Starch) of divalproex sodium;
2) obtain uniform homogeneous blend with aqueous alcohol solutions (a kind of mixture of alcohol and water) system wet granular;
3) with wet grain drying and screening;
4) with the surface coatings of the dispersion that contains diluent, polymer (preferred hydrophilic polymer, more preferably hypromellose) and Pulvis Talci and pure water with dried particles;
5) drying coated granule;
6) add fluidizer, preferred silicon dioxide, coated granule sieves;
7) incite somebody to action coated granule and filler (preferably microcrystalline cellulose) and lubricant (preferred stearic acid) dry mixed;
8) blended granule is suppressed in flakes; And
9) the optional finish coating of using is with the tablet coating.
The present composition can tablet, pill or the loose particle form oral administration that is filled in the capsule.Described tablet can be by technology known in the art preparation, and comprises the valproate compound for the treatment of effective dose and form the requisite adjuvant of described tablet by these technology.Also can use enteric coating and other controlled release coat to prepare tablet and pill and be used for acid protection, easy-to-swallow etc.Can use the acceptable dyestuff of pharmacy that coating is painted.The consumption of dyestuff and other adjuvant can change and can not influence the drug effect of slow releasing tablet in the coating solution.Coating solution contain usually can film forming polymer for example cellulose acetate or ethyl cellulose, acrylate copolymer or polymeric blends of hyprolose, polyvinyl alcohol, hydroxypropyl emthylcellulose, cellulose esters or ether for example.Coating solution is generally aqueous solution or organic solvent, and it further comprises plasticizer for example Polyethylene Glycol, propylene glycol, sorbitol monooleate, sorbic acid, and coloring agent is titanium dioxide for example, and pharmacy can be accepted dyestuff or lacquer.
In another embodiment of the invention, provide treatment to suffer from the patient's of the disease that need use the treatment of valproate compound controlled release preparation method, it comprises the valproate compound controlled release tablet preparation for the treatment of effective dose once a day, it contains about 80% valproate compound of the 40%-that has an appointment and at least two kinds of (preferred two to four kinds more preferably two kinds) polymer (preferred hydrophilic), the consumption of every kind of polymer is less than about 20% weight, preferably less than about 16% weight.Controlled-release tablet preparation of the present invention provides an effective drug-supplying system for the patient to the treatment of this kind of needs gives valproate compound (sodium valproate) once a day.Preparation of the present invention can make the valproic acid plasma concentration that is in a period of time in the Drug therapy scope keep level basically, thereby allows be administered once every day.
Following examples are used to further specify the present invention.Should not explain these embodiment in any restriction mode of the present invention.
Embodiment
Embodiment 1: the divalproex sodium preparation
Preparation contains the tablet of the label of 538g divalproex sodium, starch and various polymer.The tablet composition sees Table 2.
Table 2: divalproex sodium controlled release preparation (mg/ sheet)
Embodiment 2: preparation divalproex sodium controlled release preparation
Present embodiment is to produce 2500 scale explanation production preferred dosage form of the present invention.
Grind divalproex sodium with the Quadro comill that 0.187 inch aperture screen cloth is installed.The medicine that 2.691kg has been ground be loaded directly in the mixed instrument and with 230g starch NF, 225gMethocel K-100M (hypromellose NF) and 375g
250M (hydroxyethyl-cellulose NF) mixed 4 minutes., continue to granulate 30 seconds with 25g pure water and 25g 95% alcoholic acid mixture then with granulating mixture 1 minute with 150g 95% ethanol USP, dry then.Dried particles grinds with 1mm aperture screen cloth.In fluidized bed dryer, use the suspension for preparing by 1350g pure water, 280g Methocel E-15 (hypromellose 15 cps NF) and 140g Pulvis Talci with granule coating then.Coated granule mixed in mixed instrument 10 minutes with 100g silicon dioxide (Syloid 244) and 125g microcrystalline Cellulose (Avicel PH 102).Add the 50g stearic acid and continue and mixed 5 minutes.Mixture is pressed into the label of 1.00g.
Embodiment 3: the dissolution test of divalproex sodium controlled release tablet
Carry out the dissolution test of controlled release divalproex sodium tablet preparation.Use the apparatus II of describing among the prescription XVI of American Pharmacopeia XXI/ country to carry out these external dissolution tests.In release medium, compare dissolution test according to following condition.Divalproex sodium ER sheet is dissolved in the USP II type instrument of 100rpm, 37 ℃ of temperature, stripping is 45 minutes in the acidic phase of 500mL 0.1N HCl, then stripping in the 900mL 0.05M phosphate buffer alkali stage of (containing 75mM sodium lauryl sulfate (SLS) pH5.5).Be the 3rd, 9,12 and 18 hour the sample time of alkali stage.This dissolution test the results are shown in Table 3.
Table 3: in the contrast dissolution test at dissolving labelled amount percentage ratio with the sampling time point that hour calculates
| Time, hour | K-30965 | K-32752 | K-33429 | K-33861 | K-34999 | K-35002 | K-35989 | K-36076 |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 0.75 | 4 | 2 | 1 | 2 | 3 | 2 | 2 | 3 |
| 3.75 | 20 | 13 | 25 | 23 | 22 | 17 | 29 | 19 |
| 9.75 | 59 | 39 | 60 | 52 | 58 | 42 | 59 | 47 |
| 12.75 | 98 | 51 | 80 | 64 | 68 | 58 | 67 | 55 |
| 18.75 | 102 | 87 | 95 | 81 | 85 | 84 | 81 | 71 |
| 24.75 | 96 | 102 |
Based on these dissolution studies, the results are shown in Table 3, we obtain to draw a conclusion: a) in described instrument during 3 hours or within release amount no more than about 30% total valproate of measuring; B) in described instrument during 9 hours or within the release amount measured be about 35%-about 70% total valproate; C) in described instrument during 12 hours or within the release amount measured be about 55%-about 95% total valproate; D) in described instrument during 18 hours or within the release amount measured be no less than about 75% total valproate.
Embodiment 4: the body giving drugs into nose is for dynamics research
Three individual in the biological study, the pharmacokinetics of comparative optimization preparation and a kind of reference medicine.The bioavailability of valproate and plasma concentration-time graph and commercially available slow release divalproex sodium tablet preparation (Depakote ER) compare in health volunteer's (in the non-fasting test 15 experimenters are arranged, in the fasting test 13 experimenters are arranged) under the same conditions in the divalproex sodium of measuring under fasting and non-fasted conditions (K-34999 described in the table 2, K-35002 and K-35689) the oral controlled-release tablet preparation.
In fasting and non-fasting (feed) biological study, obtain to be used for C
MaxAnd AUC
0-24Pharmacokinetic parameter.Also obtain variance analysis (ANOVAs) to these parameters.The pharmacokinetics result of each preparation and reference preparation relatively is summarized in table 5.
Table 5: the contrast pharmacokinetics that preparation is compared with reference preparation
90% confidence interval that gives detected preparation AUC value under fasting and non-fasted conditions is compared with the numerical value of fasting of reference medicine and non-fasting, satisfies the condition of bioequivalence when numerical value is 0.80-1.25 times of reference numerical value.In addition, detected formulation C in fasting and non-fasting dosage regimen
MaxIdentical bioequivalence condition is also satisfied in 90% confidence interval of the described ratio of central value.
The controlled release tablet preparation has good performance.With regard to the degree of absorption that characterizes with AUC, controlled release drug administration scheme or bioequivalence similar to the reference dosage regimen.C with regard to the controlled release drug administration scheme
MaxValue and reference dosage regimen comparatively speaking, there are not remarkable significant difference in two kinds of tested dosage regimens and reference dosage regimen, this show controlled-release tablet preparation can be in body under fasting and non-fasted conditions the controlled release valproic acid.
When in addition, these results have shown the controlled release characteristics of tested preparation and have compared with reference preparation based on the similarity of the bioavailability of AUC.
Claims (53)
1. controlled release preparation, it comprises:
A) consumption for the valproate compound of about 80% formulation weight of about 40%-and
B) at least two kinds of polymer, consumption separately is less than about 20% weight.
2. according to the controlled release preparation of claim 1, wherein said valproate compound is selected from valproic acid, the acceptable salt of its pharmacy, ester or amide, and divalproex sodium.
3. according to the controlled release preparation of claim 1, wherein said preparation is a tablet.
4. according to the controlled release preparation of claim 1, wherein at least a polymer is a hydrophilic polymer.
5. according to the controlled release preparation of claim 1, the consumption of wherein said valproate compound is about 45%-about 60%.
6. according to the controlled release preparation of claim 5, the consumption of wherein said valproate compound is about 45%-about 55%.
7. according to the controlled release preparation of claim 1, wherein said valproate compound is a divalproex sodium.
8. according to the controlled release preparation of claim 1, wherein the consumption of each polymer is less than about 16% weight.
9. according to the controlled release preparation of claim 1, wherein the consumption of each polymer is about 16% weight of about 10%-.
10. according to the controlled release preparation of claim 1, wherein the consumption of each polymer is about 16% weight of about 12%-.
11. according to the controlled release preparation of claim 1, wherein said polymer is selected from hypromellose (HPMC), hydroxyethyl-cellulose (HEC), polyethylene glycol oxide (Polyox), polyvinylpyrrolidine, hyprolose, methylcellulose, vinyl acetate co-polymer, polysaccharide, methacrylic acid copolymer, maleic anhydride/methyl ethylene ether copolymer and derivant thereof.
12. according to the controlled release preparation of claim 1, wherein said polymer be selected from hypromellose (hypromellose, HPMC), hydroxyethyl-cellulose, polyethylene glycol oxide and Kollicoat30SR.
13. according to the controlled release preparation of claim 1, wherein said polymer is selected from hypromellose K100 (Methocel K100), hypromellose E15 (Methocel E15) and hydroxyethyl-cellulose 250
250M).
14. according to the controlled release preparation of claim 4, it further contains at least a additional hydrophobic polymer.
15. according to the controlled release preparation of claim 14, wherein at least a hydrophobic polymer is an ethyl cellulose.
16. according to the controlled release preparation of claim 1, wherein said polymer is hydrophilic and further contains at least a hydrophobic polymer.
17. according to the controlled release preparation of claim 16, wherein at least a hydrophobic polymer is an ethyl cellulose.
18. according to the controlled release preparation of claim 1, wherein said preparation is the Dragees form, comprises:
A) matrix granule of repressed surface coatings and
B) suppressed coating on the core.
19., wherein contained valproate compound and at least two kinds of hydrophilic polymers by the matrix granule of surface coatings according to the Dragees of claim 18.
20. according to the Dragees of claim 19, wherein said hydrophilic polymer is selected from hypromellose (HPMC), hydroxyethyl-cellulose (HEC), polyethylene glycol oxide, polyvinylpyrrolidine, hyprolose, methylcellulose, vinyl acetate co-polymer, polysaccharide, polyethylene glycol oxide, methacrylic acid copolymer, maleic anhydride/methyl ethylene ether copolymer and derivant thereof.
21. according to the Dragees of claim 19, wherein said hydrophilic polymer be selected from hypromellose (hypromellose, HPMC), hydroxyethyl-cellulose, polyethylene glycol oxide and Kollicoat 30SR.
22. according to the Dragees of claim 19, wherein said hydrophilic polymer is selected from hypromellose K100 (Methocel K100), hypromellose E15 (Methocel E15) and hydroxyethyl-cellulose 250
250M).
23. according to the Dragees of claim 19, wherein said surface coatings by the matrix granule of surface coatings contains hydrophilic polymer.
24. according to the Dragees of claim 23, wherein said hydrophilic polymer is selected from hypromellose (Pharmacoat 606), hypromellose E15 (Methocel E15) and Kollicoat 30 SR.
25. according to the Dragees of claim 21, wherein said hydrophilic polymer is hypromellose E15 (Methocel E15).
26. according to the controlled release preparation of claim 1, wherein said preparation comprises:
A) valproate compound of about 47-50 percentage by weight;
B) hypromellose of about 13-16 percentage by weight;
C) hydroxyethyl-cellulose of about 13-15 percentage by weight;
D) pregelatinized starch of about 8-9 percentage by weight;
E) microcrystalline Cellulose of about 4-10 percentage by weight;
F) silicon dioxide of about 3-4 percentage by weight; And
G) stearic acid of about 1-2 percentage by weight.
27. according to the controlled release preparation of claim 26, wherein said valproate compound is a divalproex sodium.
28. according to the controlled release preparation of claim 1, it is in 37 ℃ of stripping curves in the water-containing buffering liquid of pH 5.5:
A) during 3 hours or within burst size be not more than about 30% overall valproate compound;
B) during 9 hours or within burst size be about 40% to about 70% overall valproate compound;
C) during 12 hours or within burst size be about 50% to about 95% overall valproate compound; And
D) during 18 hours or within burst size be not less than 75% overall valproate compound.
29. according to the controlled release preparation of claim 1, it is when giving mammal and the pharmacokinetic curve of commercially available divalproex sodium ER500mg sheet (Depakote ER) contrast pharmacokinetic curve relatively:
A) average A UC value is in the scope of about 90%-about 130%, and wherein the average A UC observed value with Depakote ER is set at 100%, and
B) average C
MaxValue is in the scope of about 100%-about 160%, wherein with the average C of Depakote ER
MaxObserved value is set at 100%,
Wherein give the fasting mammal with described controlled release preparation.
30. according to the controlled release preparation of claim 29, wherein said mammal is human.
31. according to the controlled release preparation of claim 1, the relative pharmacokinetic curve that it compares with the pharmacokinetic curve of commercially available divalproex sodium ER500mg sheet (Depakote ER) in mammalian body:
A) average A UC value is in the scope of about 85%-about 120%, and wherein the average A UC observed value with Depakote ER is set at 100%,
B) average C
MaxValue is in the scope of about 90%-about 160%, wherein with the average C of Depakote ER
MaxObserved value is set at 100%,
Wherein described controlled release preparation is given the mammal of non-fasting.
32. according to the controlled release preparation of claim 31, wherein said mammal is human.
33. preparation is suitable for the method that is pressed into controlled-release tablet preparation or is packed into capsular particulate composition, may further comprise the steps:
A) will contain the mixture dry mixed of valproate compound, at least two kinds of hydrophilic polymers and binding agent;
B) use aqueous alcohol solutions, i.e. the mixture system of alcohol and water wet granular is to form uniform homogeneous blend;
C) with wet grain drying and screening;
D) with containing the surface coatings of the dispersion of hydrophilic polymer and Pulvis Talci and pure water with dried particles;
E) drying coated granule; And it is optional
F) add fluidizer, coated granule sieves;
G) incite somebody to action coated granule and filler and lubricant dry mixed;
Wherein step a) and b) in each hydrophilic polymer consumption less than about 20% compositions.
34. according to the method for claim 33, wherein said each hydrophilic polymer consumption is less than about 16% compositions.
35. method according to claim 33, wherein said valproate compound is a divalproex sodium, described at least two kinds of hydrophilic polymers are hypromellose and hydroxyethyl-cellulose at least, and described binding agent is pregelatinized Starch, and the hydrophilic polymer of described surface coatings is a hypromellose.
36. be used to be pressed into the method for the particulate composition of controlled-release tablet preparation according to claim 33 preparation, further may further comprise the steps:
F) the optional fluidizer that adds, coated granule sieves;
G) optional coated granule and filler and lubricant dry mixed;
H) in flakes with the granule compacting; And
I) choose usefulness finish coating wantonly with coating tablets,
Wherein step a) and b) in each hydrophilic polymer consumption less than about 20% compositions.
37. method according to claim 36, wherein said valproate compound is a divalproex sodium, described at least two kinds of hydrophilic polymers are hypromellose and hydroxyethyl-cellulose at least, described binding agent is pregelatinized Starch, the hydrophilic polymer of described surface coatings is a hypromellose, described fluidizer is a silicon dioxide, and described filler is a microcrystalline Cellulose, and described lubricant is a stearic acid.
38. a controlled release capsule preparation that comprises particulate composition, it contains:
A) consumption is the valproate compound of about 80% formulation weight of about 40%-, and
B) at least two kinds of polymer, its each plant demand is less than about 20% capsules weight.
39. according to the controlled release capsule preparation of claim 38, wherein at least a polymer is a hydrophilic polymer.
40. according to the controlled release capsule preparation of claim 38, wherein said valproate compound is a divalproex sodium.
41. according to the controlled release capsule preparation of claim 38, wherein the consumption of each polymer is less than about 16% capsules weight.
42. according to the controlled release capsule preparation of claim 38, wherein the consumption of each polymer is about 16% capsules weight of about 10%-.
43. according to the controlled release capsule preparation of claim 38, wherein the consumption of each polymer is about 16% capsules weight of about 12%-.
44. according to the controlled release capsule preparation of claim 38, wherein said polymer is selected from hypromellose (HPMC), hydroxyethyl-cellulose (HEC), polyethylene glycol oxide (Polyox), polyvinylpyrrolidine, hyprolose, methylcellulose, vinyl acetate co-polymer, polysaccharide, methacrylic acid copolymer, maleic anhydride/methyl ethylene ether copolymer and derivant thereof.
45. according to the controlled release capsule preparation of claim 38, wherein said polymer be selected from hypromellose (hypromellose, HPMC), hydroxyethyl-cellulose, polyethylene glycol oxide and Kollicoat 30SR.
46. the controlled release capsule preparation according to claim 38 further comprises additional hydrophobic polymer.
47. according to the controlled release capsule preparation of claim 38, wherein said preparation is the capsular form that comprises the matrix granule that contains the medical surfaces coating.
48. according to the controlled release capsule preparation of claim 47, the matrix granule of wherein said medical surfaces coating contains valproate compound and at least two kinds of hydrophilic polymers.
49. a method for the treatment of the patient, it comprises the valproate compound controlled release preparation for the treatment of effective dose once a day, and it comprises about 80% valproate compound of about 40%-and at least two kinds of each plant demands hydrophilic polymer less than about 20% weight of formulation.
50. according to the method for claim 49, wherein said controlled release preparation is a controlled-release tablet preparation.
51. according to claim 50 treatment patient's method, wherein the consumption of each hydrophilic polymer is less than about 16% weight.
52. according to the method for claim 49, wherein said controlled release preparation is the controlled release capsule preparation.
53. according to claim 52 treatment patient's method, wherein the consumption of each hydrophilic polymer is less than about 16% capsule contents weight.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2006/001201 WO2007081341A1 (en) | 2006-01-11 | 2006-01-11 | Controlled release formulation of divalproic acid and its derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101400342A true CN101400342A (en) | 2009-04-01 |
Family
ID=36939169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800538183A Pending CN101400342A (en) | 2006-01-11 | 2006-01-11 | Controlled release formulation of divalproic acid and its derivatives |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JP2009525953A (en) |
| CN (1) | CN101400342A (en) |
| AU (1) | AU2006335344A1 (en) |
| CA (1) | CA2635949A1 (en) |
| IL (1) | IL192554A0 (en) |
| WO (1) | WO2007081341A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2465478T3 (en) * | 2008-05-30 | 2014-06-05 | Ucb Pharma, S.A. | Pharmaceutical compositions comprising brivaracetam |
| CA2937365C (en) | 2016-03-29 | 2018-09-18 | F. Hoffmann-La Roche Ag | Granulate formulation of 5-methyl-1-phenyl-2-(1h)-pyridone and method of making the same |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE68346T1 (en) * | 1987-07-22 | 1991-11-15 | Farvalsa Ag | MOISTURE-STABLE SOLID VALPROIC ACID PREPARATION AND PROCESS FOR THEIR PRODUCTION. |
| JPH0291018A (en) * | 1988-09-27 | 1990-03-30 | Farval Ag | Solid barproic acid preparation stable to humidity and its production |
| US6287598B1 (en) * | 1993-05-28 | 2001-09-11 | Alza Corporation | Method for providing sustained antiepileptic therapy |
| AT408718B (en) * | 1999-12-02 | 2002-02-25 | Gerot Pharmazeutika | SODIUM VALPROAT GRANULES WITH REDUCED HYGROSCOPICITY |
| JP2004026750A (en) * | 2002-06-27 | 2004-01-29 | Nippon Shinyaku Co Ltd | Method for stabilizing medicine |
-
2006
- 2006-01-11 AU AU2006335344A patent/AU2006335344A1/en not_active Abandoned
- 2006-01-11 JP JP2008550280A patent/JP2009525953A/en active Pending
- 2006-01-11 WO PCT/US2006/001201 patent/WO2007081341A1/en active Application Filing
- 2006-01-11 CN CNA2006800538183A patent/CN101400342A/en active Pending
- 2006-01-11 CA CA002635949A patent/CA2635949A1/en not_active Abandoned
-
2008
- 2008-07-01 IL IL192554A patent/IL192554A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007081341A1 (en) | 2007-07-19 |
| CA2635949A1 (en) | 2007-07-19 |
| IL192554A0 (en) | 2009-02-11 |
| JP2009525953A (en) | 2009-07-16 |
| AU2006335344A1 (en) | 2007-07-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2304110C (en) | Theophylline sustained release tablet | |
| KR101316773B1 (en) | Stabilized pharmaceutical compositions comprising fesoterodine | |
| EP1898886B1 (en) | Novel sustained release dosage form | |
| US5500227A (en) | Immediate release tablet cores of insoluble drugs having sustained-release coating | |
| AU2007242984B2 (en) | Controlled released preparations of oxcarbazepine having sigmoidal release profile | |
| US20130259906A1 (en) | Pharmaceutical composition comprising one or more fumaric acid esters | |
| US10441585B2 (en) | Formulations containing nalbuphine and uses thereof | |
| CN104902880B (en) | Pharmaceutical composition comprising Hydromorphone and naloxone | |
| KR20110116027A (en) | Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix | |
| WO2000009133A1 (en) | Sustained release oral preparations of fasudil hydrochloride | |
| CN105832687A (en) | Pharmaceutical compositions comprising hydromorphone and naloxone | |
| TWI548425B (en) | High-loading, controlled-release magnesium oral dosage forms and methods of making and using same | |
| US8460702B2 (en) | Pharmaceutical compositions | |
| JP2001500150A (en) | Controlled release dosage form of [R- (Z)]-α- (methoxyimino) -α- (1-azabicyclo [2.2.2] oct-3-yl) acetonitrile monohydrochloride | |
| KR20070091960A (en) | Safe controlled release preparation composition containing zolpidem or its salt | |
| EP1839649A1 (en) | Coated formulations for tolterodine | |
| US20070160667A1 (en) | Controlled release formulation of divalproex sodium | |
| CN101400342A (en) | Controlled release formulation of divalproic acid and its derivatives | |
| WO2005046648A1 (en) | Extended release pharmaceutical dosage forms comprising alpha-2 agonist tizanidine | |
| EP1815850B1 (en) | Controlled release formulation of divalproic acid and its derivatives | |
| WO2022061058A1 (en) | Multiparticulate dosage forms comprising deutetrabenazine | |
| JP4754485B2 (en) | Coprecipitation active substance-containing particles | |
| EP1784161B1 (en) | Controlled-release formulation comprising tamsulosin hydrochloride | |
| AU2013200237B2 (en) | Controlled released preparations of oxcarbazepine having sigmoidal release profile | |
| KR20240055160A (en) | Multiparticulate formulation containing deutetrabenazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20090401 |