CN110974823A - Compound controlled release preparation containing topiroxostat - Google Patents
Compound controlled release preparation containing topiroxostat Download PDFInfo
- Publication number
- CN110974823A CN110974823A CN201911265218.9A CN201911265218A CN110974823A CN 110974823 A CN110974823 A CN 110974823A CN 201911265218 A CN201911265218 A CN 201911265218A CN 110974823 A CN110974823 A CN 110974823A
- Authority
- CN
- China
- Prior art keywords
- release
- controlled
- topiroxostat
- controlled release
- febuxostat
- 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.)
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- UBVZQGOVTLIHLH-UHFFFAOYSA-N 4-[5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl]-pyridine-2-carbonitrile Chemical compound C1=NC(C#N)=CC(C=2N=C(NN=2)C=2C=CN=CC=2)=C1 UBVZQGOVTLIHLH-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 229950004176 topiroxostat Drugs 0.000 title claims abstract description 37
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 title claims abstract description 13
- 229960005101 febuxostat Drugs 0.000 claims abstract description 32
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 claims abstract description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 38
- 238000013270 controlled release Methods 0.000 claims description 31
- 239000008187 granular material Substances 0.000 claims description 23
- 235000019359 magnesium stearate Nutrition 0.000 claims description 19
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 18
- 239000008101 lactose Substances 0.000 claims description 18
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 14
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 9
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229960000913 crospovidone Drugs 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 8
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 8
- 239000001856 Ethyl cellulose Substances 0.000 claims description 6
- 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 6
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 6
- 229920001249 ethyl cellulose Polymers 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 3
- 229920002472 Starch Polymers 0.000 claims 3
- 239000008107 starch Substances 0.000 claims 3
- 235000019698 starch Nutrition 0.000 claims 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims 2
- 238000009472 formulation Methods 0.000 claims 2
- 229960001375 lactose Drugs 0.000 claims 2
- 229940057948 magnesium stearate Drugs 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims 2
- -1 polyethylene Polymers 0.000 claims 2
- 229940032147 starch Drugs 0.000 claims 2
- 229920000178 Acrylic resin Polymers 0.000 claims 1
- 239000004925 Acrylic resin Substances 0.000 claims 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims 1
- 229920001353 Dextrin Polymers 0.000 claims 1
- 239000004375 Dextrin Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 229920000881 Modified starch Polymers 0.000 claims 1
- 239000004698 Polyethylene Substances 0.000 claims 1
- 239000004743 Polypropylene Substances 0.000 claims 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
- 229930006000 Sucrose Natural products 0.000 claims 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 239000000853 adhesive Substances 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 claims 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims 1
- 239000001768 carboxy methyl cellulose Substances 0.000 claims 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 235000010980 cellulose Nutrition 0.000 claims 1
- 229960005168 croscarmellose Drugs 0.000 claims 1
- 229960001681 croscarmellose sodium Drugs 0.000 claims 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims 1
- 235000019425 dextrin Nutrition 0.000 claims 1
- 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 1
- 239000007884 disintegrant Substances 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- 239000008103 glucose Substances 0.000 claims 1
- 235000001727 glucose Nutrition 0.000 claims 1
- 229940075507 glyceryl monostearate Drugs 0.000 claims 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims 1
- 239000000314 lubricant Substances 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims 1
- 239000008188 pellet Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 229920000573 polyethylene Polymers 0.000 claims 1
- 229920001155 polypropylene Polymers 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims 1
- 239000005720 sucrose Substances 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 235000000346 sugar Nutrition 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 17
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 3
- 238000009825 accumulation Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 231100000572 poisoning Toxicity 0.000 abstract 1
- 230000000607 poisoning effect Effects 0.000 abstract 1
- 229960003459 allopurinol Drugs 0.000 description 12
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 12
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 11
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 11
- 108010093894 Xanthine oxidase Proteins 0.000 description 11
- 229940116269 uric acid Drugs 0.000 description 11
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 10
- 102100033220 Xanthine oxidase Human genes 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 239000002245 particle Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 201000001431 Hyperuricemia Diseases 0.000 description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
- 201000005569 Gout Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000007873 sieving Methods 0.000 description 4
- 208000001647 Renal Insufficiency Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960002708 antigout preparations Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 201000006370 kidney failure Diseases 0.000 description 3
- 230000004144 purine metabolism Effects 0.000 description 3
- 230000004147 pyrimidine metabolism Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 2
- 108090000489 Carboxy-Lyases Proteins 0.000 description 1
- 108010012029 Guanine Deaminase Proteins 0.000 description 1
- 102000013587 Guanine deaminase Human genes 0.000 description 1
- 102000018251 Hypoxanthine Phosphoribosyltransferase Human genes 0.000 description 1
- 108010091358 Hypoxanthine Phosphoribosyltransferase Proteins 0.000 description 1
- 208000000913 Kidney Calculi Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010029148 Nephrolithiasis Diseases 0.000 description 1
- 101710101148 Probable 6-oxopurine nucleoside phosphorylase Proteins 0.000 description 1
- 102000030764 Purine-nucleoside phosphorylase Human genes 0.000 description 1
- 206010048302 Tubulointerstitial nephritis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000026816 acute arthritis Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000850 chronic interstitial nephritis Toxicity 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000037360 nucleotide metabolism Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical class OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002213 purine nucleotide Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Physical Education & Sports Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a controlled release preparation of a compound medicine containing topiroxostat and febuxostat, and also discloses a preparation method of the controlled release preparation of the compound medicine containing topiroxostat and febuxostat. Compared with the prior art, the controlled release preparation of the compound medicine can slowly release the medicine at a constant speed in a specified release medium, effectively improves the release degree and the bioavailability of the controlled release preparation of the compound medicine, can quickly release and generate the medicine effect at the initial stage of taking, slowly releases at a constant speed at the later stage, maintains the normal blood concentration, maintains the medicine effect for a long time without generating toxic and side effects, does not cause medicine accumulation poisoning, improves the curative effect, and is safe and quick. Meanwhile, the preparation method in the method is suitable for expanded production.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a compound controlled release preparation containing topiroxostat, belonging to the technical field of medicines.
Background
Uric acid is a normal product of purine nucleotide metabolism, and hyperuricemia is formed when uric acid is excessively generated and uric acid excretion is reduced and uric acid in blood is increased beyond a normal range; hyperuricemia and the deposition of uric acid in organ tissues are the basic pathogenesis of gout. The causes of uric acid elevation are complicated and can be divided into primary and secondary categories.
With the improvement of living standard and nutritional conditions of people, the increase of protein and fat intake of animals and the change of living behaviors (drinking, smoking and the like), the incidence rate of hyperuricemia and gout is gradually increased, the incidence age is advanced, the hyperuricemia can cause repeated attack of gouty acute arthritis, formation of tophus, gouty stone arthritis and joint deformity, chronic interstitial nephritis and uric acid kidney stone formation caused by kidney involvement, the pain of patients is often increased, and the life quality of the patients is seriously affected.
At present, gout patients in China are still increasing continuously and show a tendency of spreading towards low-age, so that the anti-gout medicines have great market potential in China, but the anti-gout medicines in the current market are mostly old medicines, although the price is low, the side effect is obvious, and if new medicines are released timely, the market prospect is very considerable.
Topiroxostat has obvious inhibition effect on both oxidized and reduced xanthine oxidase, so that the effect of reducing uric acid is stronger and more durable, and the topiroxostat can be used for treating chronic hyperuricemia of gout. Compared with allopurinol, the method has two advantages: 1) allopurinol only has an inhibiting effect on reduced xanthine oxidase, and topiroxol has a remarkable inhibiting effect on both oxidized and reduced xanthine oxidase, so that the effect of reducing uric acid is more powerful and lasting; 2) since allopurinol is a purine analog, which inevitably causes other enzymatic activities involved in purine and pyridine metabolism, it is necessary to repeatedly administer large doses of allopurinol to maintain a high drug level, thereby causing serious and even fatal adverse reactions due to drug accumulation. And topiroxostat is a non-purine xanthine oxidase inhibitor, so that the safety is better.
Febuxostat is the only drug approved to be on the market for inhibiting the production of uric acid for 20 years, and compared with other anti-gout drugs such as allopurinol, the febuxostat has the following remarkable advantages: 1) the action mechanism is unique. Febuxostat is a strong non-purine selective xanthine oxidase inhibitor, inhibits the activity of enzyme by occupying a hydrophobic port of the enzyme and preventing substrate combination, and has strong inhibition effect on both oxidized and reduced xanthine oxidases. At therapeutic concentrations, febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely: guanine deaminase, hypoxanthine guanine phosphoribosyl transferase, orotate nucleotide decarboxylase or purine nucleoside phosphorylase. Allopurinol lacks selectivity for xanthine oxidase and inhibits enzymes involved in purine or pyrimidine metabolism other than xanthine oxidase. 2) The efficacy of reducing uric acid is better than allopurinol, and the curative effect is more durable. The febuxostat has strong inhibition effect on both oxidized xanthine oxidase and reduced xanthine oxidase and has lasting curative effect, the treatment requirement can be met only by 1-time administration in 1 day in clinic, and the compliance of patients is increased; allopurinol usually needs to be administered 2-3 times a day to maintain the effective blood concentration. 3) The adverse reaction is less. Febuxostat has higher selectivity on xanthine oxidase, and can inhibit enzymes involved in purine or pyrimidine metabolism except xanthine oxidase unlike allopurinol, so that febuxostat is safer than allopurinol. 4) The febuxostat can be eliminated through double channels of the liver and the kidney, and has higher safety for patients with renal insufficiency compared with the elimination of a large amount of allopurinol through renal excretion. Clinically, patients with mild or moderate renal insufficiency do not need to adjust the febuxostat dose, and febuxostat has better curative effect than allopurinol on patients with renal insufficiency.
Disclosure of Invention
The invention discloses a compound controlled release preparation containing topiroxostat, which can achieve the purposes of smooth release of a medicine, stable blood concentration, reduction of administration times, small toxic and side effects and improvement of patient compliance. The invention has the advantages of rapid dissolution, rapid absorption, high bioavailability, good stability, convenient administration, etc.
The preparation method comprises the following steps of crushing and sieving topiroxostat and febuxostat by adopting a common pharmaceutical technology, uniformly mixing controlled-release materials, crushing and sieving, mixing topiroxostat and controlled-release materials to prepare quick-release granules, mixing topiroxostat and febuxostat with controlled-release materials to prepare controlled-release granules, uniformly mixing the quick-release granules and the controlled-release granules, and filling the granules into capsules.
The controlled release preparation changes the original single release form, organically combines the quick release with the controlled release, quickly generates the treatment effect within a certain time and maintains the treatment effect for a longer time. About 40% is released within 1 hour to immediately produce therapeutic effect, and the rest is released within 2-24 hours later, thereby producing continuous therapeutic effect.
Detailed Description
Example 1
Prescription 1 (1000 granules basis)
A. Topiroxostat quick-release granules
Topiroxostat 5g
Microcrystalline cellulose 2.85g
Low-substituted hydroxypropylcellulose 6.0g
0.9g crospovidone
Lactose 3.0g
Magnesium stearate 0.15g
B. Topiroxostat controlled-release particle
Topiroxol 15g
Microcrystalline cellulose 8.5g
Low-substituted hydroxypropylcellulose 7.8g
Crosslinked carboxymethylcellulose 10g
Lactose 9.0g
Magnesium stearate 4.0g
C. Controlled release febuxostat granules
Febuxostat 40g
Hydroxypropyl methylcellulose 38g
Ethyl cellulose 6.0g
Lactose 6.0g
Magnesium stearate 0.3 g.
The preparation method comprises the following steps:
(1) pulverizing topiroxostat and febuxostat, and sieving with a 80-mesh sieve;
(2) uniformly mixing the controlled release materials, crushing and sieving by a 120-mesh sieve;
(3) mixing topiroxostat with a controlled release material to prepare quick release particles;
(4) mixing topiroxostat and febuxostat with a controlled-release material to prepare controlled-release particles;
(5) and finally, uniformly mixing the quick-release granules and the controlled-release granules, and encapsulating to obtain the capsule.
Example 2
Prescription 2 (1000 granules basis)
A. Topiroxostat quick-release granules
Topiroxostat 5g
Microcrystalline cellulose 2.85g
Low-substituted hydroxypropylcellulose 6.0g
0.9g crospovidone
Lactose 3.0g
Magnesium stearate 0.15g
B. Topiroxostat controlled-release particle
Topiroxol 15g
Microcrystalline cellulose 10.5g
Low-substituted hydroxypropylcellulose 8.5g
Crosslinked carboxymethylcellulose 12g
Lactose 8.0g
Magnesium stearate 4.0g
C. Controlled release febuxostat granules
Febuxostat 40g
Hydroxypropyl methylcellulose 45g
Ethyl cellulose 8.0g
Lactose 4.0g
Magnesium stearate 0.3 g.
The preparation method is the same as that of example 1.
Example 3
Prescription 3 (1000 granules basis)
A. Topiroxostat quick-release granules
Topiroxostat 5g
Microcrystalline cellulose 2.85g
Low-substituted hydroxypropylcellulose 6.0g
0.9g crospovidone
Lactose 3.0g
Magnesium stearate 0.15g
B. Topiroxostat controlled-release particle
Topiroxol 15g
Microcrystalline cellulose 8.5g
Low-substituted hydroxypropylcellulose 9.5g
Crosslinked carboxymethylcellulose 10g
Lactose 9.0g
Magnesium stearate 4.5g
C. Controlled release febuxostat granules
Febuxostat 40g
Hydroxypropyl methylcellulose 35g
Ethyl cellulose 6.0g
Lactose 8.0g
Magnesium stearate 0.25 g.
The preparation method is the same as that of example 1.
Example 4
Prescription 4 (1000 granules basis)
A. Topiroxostat quick-release granules
Topiroxostat 5g
Microcrystalline cellulose 2.85g
Low-substituted hydroxypropylcellulose 6.0g
0.9g crospovidone
Lactose 3.0g
Magnesium stearate 0.15g
B. Topiroxostat controlled-release particle
Topiroxol 15g
Microcrystalline cellulose 12.5g
Low-substituted hydroxypropylcellulose 7.8g
Crosslinked carboxymethylcellulose 12g
Lactose 7.0g
Magnesium stearate 4.5g
C. Controlled release febuxostat granules
Febuxostat 40g
Hydroxypropyl methylcellulose 38g
Ethyl cellulose 10g
Lactose 10g
Magnesium stearate 0.3 g.
The preparation method is the same as that of example 1.
Example 5
Prescription 5 (1000 granules basis)
A. Topiroxostat quick-release granules
Topiroxostat 5g
Microcrystalline cellulose 2.85g
Low-substituted hydroxypropylcellulose 6.0g
0.9g crospovidone
Lactose 3.0g
Magnesium stearate 0.15g
B. Topiroxostat controlled-release particle
Topiroxol 15g
Microcrystalline cellulose 6.5g
Low-substituted hydroxypropylcellulose 10g
Cross-linked carboxymethylcellulose 8.0g
Lactose 6.0g
Magnesium stearate 4.0g
C. Controlled release febuxostat granules
Febuxostat 40g
Hydroxypropyl methylcellulose 40g
Ethyl cellulose 8.0g
Lactose 6.0g
Magnesium stearate 0.25 g.
The preparation method is the same as that of example 1.
Test example 1 topiroxostat long-term stability test
A sample to be put on the market is placed at the temperature of 25 ℃ and the relative humidity of 60% for 36 months, and is sampled and measured by a high performance liquid chromatography (0512 in the four ministry of China pharmacopoeia 2015 edition) at the time of 0 month, 3 months, 6 months, 12 months, 24 months and 36 months respectively, octadecylsilane chemically bonded silica is used as a filling agent, 20mmol/L potassium dihydrogen phosphate (pH value is adjusted to 3.2 by phosphoric acid) -acetonitrile (80: 20) is used as a mobile phase, the detection wavelength is 220nm, and the number of theoretical plates is not less than 3000 according to the calculation of a main component peak. The results are shown in table 1, and show that the topiroxostat in the controlled release preparation (example 1) of the compound medicine of the invention has stable quality.
Test example 2 Long-term stability test of febuxostat
The sample to be put on the market is placed at the temperature of 25 ℃ and the relative humidity of 60% for 36 months, and is sampled and measured by high performance liquid chromatography (0512 in the four ministry of the national pharmacopoeia 2015) at the time of 0, 3, 6, 12, 24 and 36 months respectively, and octadecylsilane chemically bonded silica is used as a filler; 0.1% phosphoric acid (triethylamine adjusted to pH 2.5) -methanol (81:19) was used as the mobile phase, and the detection wavelength was 245 nm. The separation degree of the febuxostat peak from the adjacent impurity peak should be not less than 1.5. The results are shown in table 2, and show that the quality of febuxostat in the controlled release preparation (example 1) of the compound medicine of the invention is stable.
It can be seen that the topiroxostat and febuxostat in the controlled release preparation of the compound drug in the embodiment 1 have stable quality, and the bioavailability of the controlled release preparation of the compound drug is effectively improved. Meanwhile, the preparation method in the method is suitable for expanded production.
Claims (5)
1. A compound controlled release preparation containing topiroxostat is characterized in that a controlled release part consists of a quick release part and a controlled release part, wherein the quick release part contains 5mg of topiroxostat, and the controlled release part contains 15mg of topiroxostat and 40mg of febuxostat.
2. The controlled-release preparation according to claim 1, characterized in that the controlled-release part is prepared by mixing topiroxostat and febuxostat respectively after being prepared into controlled-release granules, controlled-release pellets or controlled-release tablets.
3. The controlled-release preparation of claim 2, wherein the controlled-release material is selected from one or more of microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose, lactose, magnesium stearate, ethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, glyceryl monostearate, stearyl alcohol, polyethylene, polypropylene, and acrylic resin.
4. The controlled release formulation of claim 2, wherein the immediate release material is selected from one or more of microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, lactose, magnesium stearate, sucrose, starch, pregelatinized starch, cellulose, powdered sugar, dextrin, glucose, calcium bicarbonate; the disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium; the adhesive is selected from one or more of water, alcohol, polyvinylpyrrolidone and starch slurry; the lubricant is selected from one or more of magnesium stearate, pulvis Talci, silica gel micropowder, sodium laurylsulfate or magnesium.
5. The controlled release formulation of claim 3 or 4, the pharmaceutical excipient being microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose, lactose, magnesium stearate.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110200948A (en) * | 2019-07-19 | 2019-09-06 | 曹郁 | A kind of stomach medication controlled release capsule |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110200948A (en) * | 2019-07-19 | 2019-09-06 | 曹郁 | A kind of stomach medication controlled release capsule |
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