CN108066289A - A kind of posaconazole solid dispersions and preparation method thereof and posaconazole enteric coated preparations - Google Patents
A kind of posaconazole solid dispersions and preparation method thereof and posaconazole enteric coated preparations Download PDFInfo
- Publication number
- CN108066289A CN108066289A CN201711495634.9A CN201711495634A CN108066289A CN 108066289 A CN108066289 A CN 108066289A CN 201711495634 A CN201711495634 A CN 201711495634A CN 108066289 A CN108066289 A CN 108066289A
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- CN
- China
- Prior art keywords
- posaconazole
- enteric
- solid dispersions
- parts
- hydroxypropylcellulose
- 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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- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 157
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 157
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 47
- 239000000463 material Substances 0.000 claims abstract description 58
- 239000004014 plasticizer Substances 0.000 claims abstract description 20
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 14
- 238000010438 heat treatment Methods 0.000 claims abstract description 14
- 239000007921 spray Substances 0.000 claims abstract description 14
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 36
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 35
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 28
- 239000012943 hotmelt Substances 0.000 claims description 26
- 230000008569 process Effects 0.000 claims description 23
- 238000007710 freezing Methods 0.000 claims description 13
- 230000008014 freezing Effects 0.000 claims description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 13
- 229960003943 hypromellose Drugs 0.000 claims description 12
- 229920003081 Povidone K 30 Polymers 0.000 claims description 11
- 238000000889 atomisation Methods 0.000 claims description 11
- 238000001723 curing Methods 0.000 claims description 9
- 239000007884 disintegrant Substances 0.000 claims description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000853 adhesive Substances 0.000 claims description 7
- 230000001070 adhesive effect Effects 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000006069 physical mixture Substances 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000011347 resin Substances 0.000 claims description 5
- 229920005989 resin Polymers 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000004148 curcumin Substances 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims description 2
- 229960001021 lactose monohydrate Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 238000010128 melt processing Methods 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 2
- 229940069328 povidone Drugs 0.000 claims 2
- 239000007767 bonding agent Substances 0.000 claims 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims 1
- 235000013312 flour Nutrition 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group 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 claims 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims 1
- 229940083542 sodium Drugs 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 29
- 239000012535 impurity Substances 0.000 abstract description 12
- 238000011068 loading method Methods 0.000 abstract description 3
- 238000009472 formulation Methods 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 36
- 229940096978 oral tablet Drugs 0.000 description 28
- 239000007935 oral tablet Substances 0.000 description 28
- 230000000052 comparative effect Effects 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000005574 benzylation reaction Methods 0.000 description 7
- 238000009474 hot melt extrusion Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- OPFHZSVWSCMEPV-AYAMJOBCSA-N 4-[4-[4-[4-[[(3r,5r)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-pentan-3-yl-1,2,4-triazol-3-one Chemical compound O=C1N(C(CC)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 OPFHZSVWSCMEPV-AYAMJOBCSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000004925 Acrylic resin Substances 0.000 description 5
- 229920000178 Acrylic resin Polymers 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000003851 azoles Chemical class 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- -1 hydroxypropyl Chemical group 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- HUADITLKOCMHSB-AVQIMAJZSA-N 2-butan-2-yl-4-[4-[4-[4-[[(2s,4r)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 HUADITLKOCMHSB-AVQIMAJZSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- 208000031888 Mycoses Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000031700 light absorption Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 229950005137 saperconazole Drugs 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 241000228212 Aspergillus Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000001125 extrusion Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
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- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYDFXSRVZBYYJV-TYYBGVCCSA-N (e)-but-2-enedioic acid;sodium Chemical compound [Na].OC(=O)\C=C\C(O)=O RYDFXSRVZBYYJV-TYYBGVCCSA-N 0.000 description 1
- QEASJVYPHMYPJM-UHFFFAOYSA-N 1,2-dihydrotriazol-5-one Chemical compound OC1=CNN=N1 QEASJVYPHMYPJM-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- 102100021695 Lanosterol 14-alpha demethylase Human genes 0.000 description 1
- 101710146773 Lanosterol 14-alpha demethylase Proteins 0.000 description 1
- AQLLBJAXUCIJSR-UHFFFAOYSA-N OC(=O)C[Na] Chemical compound OC(=O)C[Na] AQLLBJAXUCIJSR-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 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 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000008686 ergosterol biosynthesis Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229940100691 oral capsule Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000009885 systemic effect Effects 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
- A61K9/14—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
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/14—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
- A61K9/1682—Processes
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of posaconazole solid dispersions and preparation method thereof and posaconazole enteric coated preparations, are related to posaconazole formulations field.It is prepared posaconazole solid dispersions disclosed by the invention by raw material after heating, spray, freeze, and the raw material includes by weight：1~15 part of 100~200 parts of posaconazole active ingredient, 300~400 parts of enteric material and plasticizer.The posaconazole solid dispersions have preferable dissolution rate in enteron aisle, and the impurity component of lower loading improves the bioavilability of posaconazole.
Description
Technical field
The present invention relates to posaconazole formulations field, in particular to a kind of posaconazole solid dispersions and its system
Preparation Method and posaconazole enteric coated preparations.
Background technology
Invasive infections with fungi, also known as deep fungal infection or systemic fungal infection.In recent years, as heavy dose is immune
The abuse of inhibitor, chemotherapeutics and broad-spectrum antibiotic so that immunosuppressive patient gradually increases.
Posaconazole (Posaconazole), trade nameIt is by Schering Plough company of the U.S. (sand of now writing from memory
Eastern pharmacy) develop a kind of Novel triazole antifungal drug, in September in 2006 obtain within 15th FDA approval listing, for intractable
Fungal infection caused by disease or other drugs drug resistance, such as aspergillosis, tulase disease and fusaridiosis.Posaconazole is
First antibacterials for causing lesion by aggressive Aspergillus for prevention by FDA approvals, with other azole antibacterials
Identical, which is also the ferroheme confactor by mould (the CYP51 or Ergllp) active site of 14 α of lanosterol-demethylation
With reference to, inhibit fungi ergosterol biosynthesis, destroy cell membrane formation and integrality and play antibacterial action.
Posaconazole overcomes first generation triazole type medicine narrow antimicrobial spectrum and drug resistance problems, the effect of broad-spectrum antifungal
It is proved there is effect to candida albicans, various Aspergillus and other common and non-common pathomycetes in vivo and in vitro.
Posaconazole is alkaline compound, and solubility is higher in stomach acidity environment, about 0.8mg/ml, but when dissolving
When posaconazole under one's belt reaches enteron aisle (pH is about 6.5), the posaconazole Precipitation largely dissolved, solubility is less than
1μg/ml.And enteron aisle is exactly the main portions that posaconazole absorbs, and the life of posaconazole is caused in the poor dissolubility of enteron aisle
Object availability is low.
Therefore, prepare oral posaconazole preparation and be limited by posaconazole dissolubility poor in enteron aisle so far.
In consideration of it, special propose the present invention.
The content of the invention
It is an object of the invention to provide a kind of posaconazole solid dispersions, by raw material after heating, spray, freeze
It is prepared, which has preferable dissolution rate in enteron aisle, and the impurity component of lower loading improves
The bioavilability of posaconazole.
Another object of the present invention is to provide the preparation method of above-mentioned posaconazole solid dispersions.
Another object of the present invention is to provide a kind of posaconazole enteric coated preparations, including above-mentioned posaconazole solid point
Granular media.
What the present invention was realized in：
A kind of posaconazole solid dispersions are prepared by raw material after heating, spray, freezing and curing, on
State raw material includes by weight：100~200 parts of posaconazole active ingredient, 300~400 parts of enteric material and plasticizer 1
~15 parts.
The preparation method of posaconazole solid dispersions as described above, including：
The physical mixture mixed by posaconazole active ingredient, enteric material and plasticizer is subjected to hot melt
Reason, obtains hot melt blend；
Above-mentioned hot melt blend is disperseed through atomization process, freezing processing and curing process to get posaconazole solid
Body.
A kind of posaconazole enteric coated preparations, including posaconazole solid dispersions as described above and pharmaceutically acceptable
Auxiliary material.
The invention has the advantages that：
Posaconazole solid dispersions provided by the invention are prepared by raw material after heating, spray, freezing and curing
It forms, which includes by weight：100~200 parts of posaconazole active ingredient, 300~400 parts of enteric material and increasing
Mould 1~15 part of agent.The posaconazole solid dispersions have preferable dissolution rate in enteron aisle, improve the biology of posaconazole
Availability；
In addition, the present invention provides the preparation method of posaconazole solid dispersions, hot melt spray chilling technology is used, it will
The physical mixture mixed by posaconazole active ingredient, enteric material and plasticizer carries out hot melt processing, then incites somebody to action
The hot melt blend arrived is through atomization process, freezing processing and curing process to get posaconazole solid dispersions；Pass through the system
Preparation Method causes impurity content to reduce, intermediate it is quality controllable, and it is low to overcome efficiency in hot-melt extrusion process, and loss late is high
The shortcomings that, it is more uniformly distributed with grain graininess, the characteristics of high income.
Description of the drawings
It in order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of scope, for those of ordinary skill in the art, without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is the posaconazole enteric solid oral tablet and posaconazole original triturate that the embodiment of the present invention 1 providesIn Vitro Dissolution curve comparison result；
The posaconazole enteric solid oral tablet and posaconazole that Fig. 2 is 1-3 of the embodiment of the present invention and comparative example 1 provides
Former triturateIn Vitro Dissolution curve comparison result；
Fig. 3 is that the posaconazole enteric solid oral tablet that the embodiment of the present invention 1 and 4 and comparative example 2 provide and pool are husky
Health azoles original triturateIn Vitro Dissolution curve comparison result.
Specific embodiment
It, below will be in the embodiment of the present invention to make the purpose, technical scheme and advantage of the embodiment of the present invention clearer
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, builds according to normal condition or manufacturer
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
Below to a kind of posaconazole solid dispersions of the embodiment of the present invention and preparation method thereof and posaconazole enteric
Preparation is specifically described.
Solid dispersion technology is the method for common increase insoluble drug dissolution rate and bioavilability.Hot-melt extruded skill
Art (Hot Melt Extrusion, HME) is that bulk pharmaceutical chemicals and carrier auxiliary material are mixed the system of extrusion by one kind under high temperature fused state
The solid dispersion technology of standby insoluble medicine solid dispersoid.The posaconazole enteric coatel tablets that Schering Plough company developsUsing torching mark, using enteric material HPMC-AS as hot-melt extruded carrier, it is prepared for posaconazole and consolidates
Body dispersion improves its dissolving and absorption in enteron aisle.
But there are following problems for the prior art：
1st, the shear-mixed process of hot-melt extruded is related to the mechanical force of high intensity, is easily destroyed the molecular structure of material
And be denatured, the content in relation to substance is caused to increase.And the stability of HPMC-AS is used to easily by extrusion be turned during hot-melt extruded
The influence of speed and temperature, the discoveries such as Sarode, during hot-melt extruded, as rotating speed by 100r/min increases to 300r/min,
Temperature increases to 200 DEG C by 160 DEG C, and the free succinic acid of HPMC-AS and the content of acetic acid substantially increase, and the color of extrudate is bright
Aobvious to deepen, the dissolution rate of solid dispersions obtained also accordingly slows down, and reduces the bioavilability of posaconazole；
2nd, the hot-melt extruded intermediate that hot-melt extrusion process obtains need to be ground into particle, and disintegrating process reduces technique entirety
Continuity, and the easy heat production of pulverising step increases the operable difficulty of technique, it is necessary to be interrupted crushing and add in dry ice or protection of liquid nitrogen
Greatly, efficiency reduces.The heat generated during crushing can be such that particle heats again to be attached on cavity wall, and such one is that can cause material
Loss, hardly possible recycling；Second is that the material of glutinous wall is difficult again pulverized thus larger to the control difficulty of granularity.
It is the preparation technique to grow up on the basis of spray drying to heat spray chilling technology, with being spray-dried most
Big difference lies in hot melt spray chilling is come cured article, and without the use of any solvent using cold airflow.It can be by drug
Active ingredient is dispersed in melted material, is sprayed at followed by atomizer in cooling tower, with the air in cooling tower into
Row heat exchange solidify afterwards obtain semifinished or finished goods.
Heating the basic principle of spray chilling technology is：At a certain temperature by uniformly mixed melting auxiliary material and other objects
Material is dispersed into misty liquid droplets by atomizer, and comes into full contact with carry out heat exchange with cold air in refrigerating chamber, makes misty liquid droplets
Quick solidification, completion gas solid separation obtains superfine powder or fine grained semifinished or finished goods in cyclone separator.
Based on this, in order to overcome the problems referred above, the present invention provides a kind of pool formed using hot melt spray chilling technology is husky
Health azoles solid dispersions and preparation method thereof and posaconazole enteric coated preparations.
On the one hand, the present invention provides a kind of posaconazole solid dispersions, by raw material after heating, spray, freeze
It is prepared, raw material includes by weight：100~200 parts of posaconazole active ingredient, 300~400 parts of enteric material and
1~15 part of plasticizer.
Preferably, in some embodiments of the present invention, raw material includes by weight：Posaconazole active ingredient
100~125 parts, 5~10 parts of 300~325 parts of enteric material and plasticizer.
The grain graininess being prepared in this ratio range is uniform, and result of extraction is preferable.
Further, in some embodiments of the present invention, enteric material is selected from cellulosic enteric material and propylene
One or both of acid resin class enteric material.
Preferably, in some embodiments of the present invention, it is fine to be selected from cellulose acetate phthalate for cellulosic enteric material
One or more of dimension element, hypromellose acetate succinate and hypromellose phthalate.
Preferably, in some embodiments of the present invention, crylic acid resin enteric material is selected from trade nameE100、L100-55、L100 andThe acrylic acid tree of S100
One or more of lipid enteric material.
Further, in some embodiments of the present invention, plasticizer is selected from hypromellose E3, hydroxypropyl
Cellulose E5, hypromellose E15, hydroxypropylcellulose EXF, hydroxypropylcellulose ELF, hydroxypropylcellulose LXF, hydroxypropyl fiber
One or more of plain JXF, hydroxypropylcellulose HXF, 30 POVIDONE K 30 BP/USP 17, PVP K30 and 30 POVIDONE K 30 BP/USP 90.
The effect of plasticizer is to adjust dissolution rate, improves the rheological characteristic of fused materials, and main function is embodied in：1) exist
Heating the spraying stage reduces the fusing point of mixed material, softens material, reduces melt viscosity, improves its rheological characteristic, reduces machinery
Resistance, it is easy to produce；2) since the plasticizer of selection is mostly hydrophilic material, hydrophilic channel can be formed in tablet, is played
Draw wet effect, therefore the dissolution of product can be improved in the dissolution stage.
Further, in some embodiments of the present invention, posaconazole active ingredient for posaconazole solvate,
Posaconazole pro-drug, crystal form posaconazole, amorphous posaconazole or crystal form posaconazole and amorphous pool
The mixture of Saperconazole.
But it should be recognized that posaconazole active ingredient is not limited to above-mentioned form or deposits otherwise
Posaconazole, all belong to the scope of protection of the present invention.
On the other hand, the present invention provides the preparation method of above-mentioned posaconazole solid dispersions, including：
The physical mixture mixed by posaconazole active ingredient, enteric material and plasticizer is subjected to hot melt
Reason, obtains hot melt blend；
By hot melt blend through atomization process, freezing processing and curing process to get posaconazole solid dispersions.
The posaconazole solid dispersions and additional auxiliary material obtained by above-mentioned preparation method after mixing, are prepared into phase
The posaconazole enteric coated preparations answered.Posaconazole enteric solid oral tablet is obtained for example with dry method vertical compression or is filled into capsule
Agent.
Further, in some embodiments of the present invention, the temperature for heating processing is 135-145 DEG C；
Preferably, the atomizing pressure of atomization process is 0.18bar~0.24bar；
Preferably；The condensation temperature of freezing processing is -16 DEG C~0 DEG C.
In the value range of above-mentioned parameter, can make to be prepared posaconazole solid dispersions with particle uniformly, recycling
The characteristics such as rate is high, result of extraction is preferable, impurity content is low.
In some embodiments of the present invention, the temperature for heating processing can be 135 DEG C, 136 DEG C, 137 DEG C, 138 DEG C,
Any one in 139 DEG C, 140 DEG C, 141 DEG C, 142 DEG C, 143 DEG C, 144 DEG C and 145 DEG C etc. or arbitrary model between the two
It encloses.
In some embodiments of the present invention, the atomizing pressure of atomization process can be 0.18bar, 0.19bar,
Any one in 0.20bar, 0.21bar, 0.22bar, 0.23bar and 0.24bar etc. or arbitrary scope between the two.
In some embodiments of the present invention, the condensation temperature of freezing processing for -16 DEG C, -14 DEG C, -12 DEG C, -10
DEG C, -8 DEG C, -6 DEG C, -4 DEG C, any one or arbitrary scope between the two in -2 DEG C and 0 DEG C etc..
Preferably, in some embodiments of the present invention, the temperature for heating processing is 140 DEG C, the atomization of atomization process
Pressure is 0.18bar, the condensation temperature of freezing processing is -8 DEG C.
In another aspect, the present invention provides a kind of posaconazole enteric coated preparations, including above-mentioned posaconazole solid point
Granular media and pharmaceutically acceptable auxiliary material.
Further, in some embodiments of the present invention, auxiliary material includes filler, adhesive, disintegrant, lubricant
And coating material.
Preferably, in some embodiments of the present invention, by weight, auxiliary material includes：50~100 parts of filler,
Preferably 50~80 parts；50~100 parts of adhesive is preferably 50~80 parts；10~40 parts of disintegrant, be preferably 20~30 parts with
And 1~10 part of lubricant, it is preferably 2~5 parts.
Preferably, in some embodiments of the present invention, it is fine to be selected from lactose monohydrate, Lactis Anhydrous, crystallite for filler
Tie up one or more of element, starch, partially pregelatinized starch and mannitol.
Preferably, in some embodiments of the present invention, it is fine to be selected from hypromellose E3, hydroxypropyl for adhesive
Tie up element E5, hypromellose E15, hydroxypropylcellulose EXF, hydroxypropylcellulose ELF, hydroxypropylcellulose LXF, hydroxypropylcellulose
One or more of JXF, hydroxypropylcellulose HXF, 30 POVIDONE K 30 BP/USP 17, PVP K30 and 30 POVIDONE K 30 BP/USP 90.
Preferably, in some embodiments of the present invention, low-substituted hydroxypropyl of the disintegrant in cellulose derivative
The crosslinking of base cellulose, croscarmellose sodium, the sodium carboxymethyl starch of starch analog derivative and povidone class gathers dimension
One or more in ketone.
Preferably, in some embodiments of the present invention, disintegrant is selected from croscarmellose sodium and carboxymethyl
One or both of sodium starch.
Preferably, in some embodiments of the present invention, lubricant is selected from magnesium stearate, stearic acid, calcium stearate, hard
One or more of fat fumaric acid sodium, lauryl sodium sulfate, talcum powder and silica.
Further, in some embodiments of invention, above-mentioned posaconazole enteric coated preparations for solid oral tablet or
Capsule.
Preferably, in some embodiments of the present invention, enteric material is to have the function of the acrylic resin of enteric, increase
Modeling agent is hydroxypropyl cellulose, filler is microcrystalline cellulose, adhesive is hydroxypropyl cellulose, disintegrant is cross-linked carboxymethyl
Sodium cellulosate, lubricant are magnesium stearate.
Preferably, in some embodiments of the present invention, acrylic resin can dissolve pH environment as 5.0~pH of pH
7.0；
Wherein, the corresponding marque of acrylic resin as enteric material isE100、S100、L100 orL100-55。
Wherein, the hydroxypropyl cellulose EXF as plasticizer, corresponding trade nameHPC EXF。
Also on the one hand, the present invention provides the preparation method of above-mentioned posaconazole enteric coated preparations, including：
Above-mentioned posaconazole solid dispersions are tentatively mixed with filler, adhesive, disintegrant, what is obtained is first mixed
It closes object addition lubricant always to be mixed, obtains total mixture.
Further, in some embodiments of invention, above-mentioned preparation method further includes：Total mixture is pressed
Label is made in piece, and label is carried out film coating processing, obtains finished tablet.
Certainly, in some embodiments of invention, total mixture is pelletized, by particles filled into capsule, is obtained into
Product capsule.
It is closed it should be noted that the dosage form of posaconazole enteric coated preparations can for example take mode according to actual demand
Reason selection.
To sum up, posaconazole solid dispersions provided by the invention, by raw material through heating, spraying, freezing and curing
After be prepared, the impurity with lower content has such as deshydroxy posaconazole, Benzylation posaconazole in enteron aisle
Preferable dissolution rate is effectively improved the bioavilability of posaconazole.
The preparation method of posaconazole solid dispersions provided by the invention uses hot melt spray chilling technology by raw material
Solid dispersions are made, which causes the impurity content in posaconazole solid dispersions to reduce, the quality of intermediate
Controllably, and the shortcomings that efficiency in hot-melt extrusion process is low, and loss late is high is overcome, is more uniformly distributed with grain graininess, high income
The characteristics of.
Posaconazole solid dispersion preparation provided by the invention, by above-mentioned posaconazole solid dispersions and pharmacy
Upper acceptable auxiliary material is mixed with, and the similary impurity with lower content such as deshydroxy posaconazole, Benzylation are moored
Saperconazole etc. has preferable dissolution rate in enteron aisle, is effectively improved the bioavilability of posaconazole.
The feature and performance of the present invention are described in further detail with reference to embodiments.
Embodiment 1
Present embodiments provide a kind of posaconazole enteric solid oral tablet, by posaconazole solid dispersions with it is auxiliary
Material is mixed；
Wherein, posaconazole solid dispersions by 100g posaconazoles, 325g acrylic resins (L100-
55) and 5g hydroxypropyl celluloses (HPC EXF) it is prepared after heating, spray, freezing and curing；
Auxiliary material includes：70g hydroxypropyl celluloses (HPC EXF), 70g microcrystalline celluloses, 28g cross-linked carboxymethyls
Sodium cellulosate, 2g magnesium stearates, 16gYellow coating material and suitable purified water, purified water are used for coating solution
Preparation.
The preparation method of above-mentioned posaconazole enteric solid oral tablet is present embodiments provided, is included the following steps：
1 prepares posaconazole solid dispersions
1.1. posaconazole, acrylic resin and hydroxypropyl cellulose fat are crossed after 30 mesh screens by above-mentioned formula dosage
It is placed in together in mixing tank body, is mixed 10 minutes with 20rpm/min speed, obtain physical mixture.
1.2. above-mentioned physical mixture is transferred in the mixing chamber of hot melt spray granulator (MS-220 types), hot melting temperature is set
140 DEG C are set to, the pump speed of circulating pump is arranged to 15, starts agitating paddle, and 300rpm/min is stirred 8 minutes, obtains molten mixture.
At the same time, refrigeration system is opened, cryogenic temperature is arranged to -8 DEG C.
1.3. atomizer (two fluid pneumatic atomizers) is started, atomizing pressure is arranged to 0.18Bar, and rotation speed of fan is
2500rpm, collection material is to get posaconazole solid dispersions in barrel.
2 prepare finished product posaconazole enteric coated preparations
2.1 is fine by obtained posaconazole solid dispersions, the microcrystalline cellulose of above-mentioned formula dosage and cross-linked carboxymethyl
The plain sodium of dimension is placed in together in mixing tank body, with the mixing of 20rpm/min speed after ten minutes, is added in magnesium stearate and is lubricated, with
20rpm/min speed mixing after five minutes whole mixture.
Above-mentioned whole mixture is carried out tabletting by 2.2 on rotary pelleting machine (C＆C800), is carried out using 17mm × 8mm molds
Tabletting obtains posaconazole piece, tablet warpYellow takes orally after carrying out film coating to get posaconazole enteric solid
Tablet.
Result of extraction detects
1 dissolution test
By posaconazole enteric solid oral tablet obtained above and posaconazole original triturateCarry out body
Outer dissolution comparison, with reference to the In Vitro Dissolution method that U.S. FDA is recommended, posaconazole enteric solid oral tablet is needed first in 750mL
0.01N hydrochloric acid medium in carry out the dissolution of 2h, then add in 250mL 0.2M phosphate buffer solutions, make the dissolution system be
1000mL pH value is 6.8 ± 0.05, continues to dissolve out 1h, dissolving-out method is as follows：
The dissolution in vitro method announced with reference to U.S. FDA carries out internalist methodology exploitation, uses lauryl sodium sulfate
(SDS) surfactant is used as, operating procedure is as follows：
First stage：6, posaconazole enteric solid oral tablet sample made from example 1 is taken, is tried in above-mentioned dissolution rate
Acid resisting test is carried out under the conditions of testing, when 2 is small after respectively take 10mL media, cross 0.22 μ miillpore filter, discard 8mL and retain 2mL
And be transferred on the quartz colorimetric utensil of 2mm, it is detected under 262nm wavelength, is carried out by 0.1mg/mL contrast solutions of concentration
It calculates, the formula of dissolution rate (acid resistance) detection is as follows：
Dissolution rate (acid resistance) %=(sample light absorption value × reference substance concentration × dissolution medium volume)/(reference substance extinction
Value × labelled amount) × 100%
Second stage：2 it is small when after on former medium add in etc. temperature the phosphoric acid salt medium 250mL containing SDS, surface is made to live
Property agent mass concentration be 0.3% and pH value is 6.8 ± 0.05, respectively take 10mL media in different sampling time points, cross 0.22 μm it is micro-
Hole filter membrane, discards 7mL and retains and 2mL and be transferred on the quartz colorimetric utensil of 2mm, is detected under 262nm wavelength, using concentration as
0.1mg/mL contrast solutions are calculated, and the formula of dissolution rate detection is as follows：
Dissolution rate calculates
Dissolution rate %=(sample light absorption value × reference substance concentration × dissolution medium volume)/(reference substance light absorption value × mark
Amount) × 100%
As a result as shown in Table 1 and Table 2.
Table 1
Table 2
From Tables 1 and 2, using posaconazole enteric coated preparations made from 1 method of the embodiment of the present invention and former triturate
In Vitro Dissolution behavior is consistent, the effect of not interfering with drug while optimize technique.
2 defects inspectings
The impurity that posaconazole technical process generates mainly has following three kinds：Hydroxyl triazole type impurity, deshydroxy posaconazole,
Benzylation posaconazole.Posaconazole enteric coatel tablets made from embodiment 1 and former triturate in terms of related substance to such as
The following table 3.
Table 3
| Related substance | Former triturate | Embodiment 1 |
| Total impurities | 2.2% | 1.5% |
| Hydroxyl triazole type impurity | 0.5% | 0.6% |
| Deshydroxy posaconazole | 0.7% | 0.3% |
| Benzylation posaconazole | 0.5% | 0.3% |
Deshydroxy posaconazole and Benzylation posaconazole may be related with the mechanical force of technical process, the machine of external action
Tool power has been catalyzed the radical reaction of posaconazole.The posaconazole enteric solid oral tablet preparation method that embodiment 1 provides
Influence of the airflow function to posaconazole is much smaller than hot-melt extrusion process, therefore deshydroxy posaconazole and the Benzylation pool generated
Saperconazole is less than former triturate.
Summary result understand, the embodiment of the present invention 1 provide posaconazole enteric solid oral tablet on the market
Posaconazole enteric coated preparations there is consistent result of extraction, but the also such as husky health of deshydroxy pool of the impurity with lower loading simultaneously
Azoles and Benzylation posaconazole.
Embodiment 2
The preparation method of posaconazole enteric solid oral tablet provided in this embodiment is substantially the same manner as Example 1,
Unlike, plasticizer hydroxypropyl cellulose usedThe dosage of HPC EXF is 10g.
The posaconazole enteric solid oral tablet dissolution experimental result that the present embodiment obtains is shown in Fig. 2.
Embodiment 3
The preparation method of posaconazole enteric solid oral tablet provided in this embodiment is substantially the same manner as Example 1,
Unlike, plasticizer hydroxypropyl cellulose usedThe dosage of HPC EXF is 15g.
The posaconazole enteric solid oral tablet dissolution experimental result that the present embodiment obtains is shown in Fig. 2.
Comparative example 1
The preparation method for the posaconazole enteric solid oral tablet that this comparative example provides is substantially the same manner as Example 1,
Unlike, plasticizer hydroxypropyl cellulose usedThe dosage of HPC EXF is 0g.
The posaconazole enteric solid oral tablet dissolution experimental result that this comparative example obtains is shown in Fig. 2.
As can be seen from FIG. 2, the posaconazole enteric solid oral tablet and posaconazole original triturate that embodiment 1 providesWith similar result of extraction, the hydroxypropyl cellulose containing plasticizerThe Bo Shakang of HPC EXF
The result of extraction of azoles enteric solid oral tablet (embodiment 1-3), which is better than, not to be contained the posaconazole enteric solid of plasticizer and takes orally
Tablet (comparative example 1).
Embodiment 4
The preparation method of posaconazole enteric solid oral tablet provided in this embodiment is substantially the same manner as Example 1,
Unlike, in the present embodiment, the atomizing pressure of atomization process is 0.24bar.
The posaconazole enteric solid oral tablet dissolution experimental result that the present embodiment obtains is shown in Fig. 3.
Comparative example 2
The preparation method for the posaconazole enteric solid oral tablet that this comparative example provides is substantially the same manner as Example 1,
Unlike, in the present embodiment, the atomizing pressure of atomization process is 0.12bar.
The posaconazole enteric solid oral tablet dissolution experimental result that this comparative example obtains is shown in Fig. 3.
As can be seen from FIG. 3, the result of extraction for the posaconazole enteric solid oral tablet that embodiment 1 and embodiment 4 provide
With posaconazole original triturateSimilar, embodiment 1 is consolidated with posaconazole enteric prepared by 0.18bar atomizing pressures
The result of extraction for the posaconazole enteric solid oral tablet that body oral tablet and embodiment 4 are prepared with 0.24bar atomizing pressures
It is better than the posaconazole enteric solid oral tablet that comparative example 2 is prepared with 0.12bar atomizing pressures.
To sum up, its preparation method of posaconazole enteric coated preparations provided in an embodiment of the present invention is sprayed by using hot melt
Raw material is first prepared into solid dispersions by Refrigeration Technique, is taken orally it is prepared by mixing into posaconazole enteric solid with auxiliary material
Tablet compared with prior art, has the advantages that：
(1) related content of material reduces, intermediate it is quality controllable.Posaconazole is prepared using hot melt spray chilling technology
Solid dispersions, mix stages carry out in the storage compartment of equipment, by the circulation being stirred with nebulizer gas of agitating paddle
Movement is formed compared to torching mark, and no screw rod protects posaconazole and its auxiliary material in molecule to the shearing force of material
Structural level reduces related substance and generates, improve the quality controllability of intermediate from the destruction of mechanical force.
(2) the shortcomings that efficiency is low, and loss late is high in hot-melt extrusion process is overcome.Solid is prepared using hot-melt extruded to disperse
During body, intermediate obtained need to be ground into particle by pulverizer, and granularity must be controlled by the mesh size of pulverizer, most of feelings
More heat can be generated when being crushed under condition, it is necessary to be interrupted crushing and add in dry ice or protection of liquid nitrogen, make the operable difficulty of technique
Increase, and the heat that generates can be such that particle heats again to be attached on cavity wall when crushing, such one is that can cause loss of material,
Hardly possible recycling；Second is that the material of glutinous wall is difficult again pulverized thus larger to the control difficulty of granularity.And use hot melt cryospray
Granulation, can one-step palletizing, when particle is by spraying atomizing pressure control, so made from grain graininess be more uniformly distributed, high income.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of posaconazole solid dispersions, which is characterized in that it is made by raw material after heating, spray, freezing and curing
Standby to form, the raw material includes by weight：100~200 parts of posaconazole active ingredient, 300~400 parts of enteric material with
And 1~15 part of plasticizer.
2. posaconazole solid dispersions according to claim 1, which is characterized in that the raw material wraps by weight
It includes：100~125 parts of the posaconazole active ingredient, 300~325 parts of the enteric material and the plasticizer 5~10
Part.
3. posaconazole solid dispersions according to claim 1 or 2, which is characterized in that the enteric material is selected from fibre
Dimension plain one or both of class enteric material and crylic acid resin enteric material；
Preferably, the cellulosic enteric material is selected from cellulose acetate phthalate, hypromellose acetic acid amber
One or more of amber acid esters and hypromellose phthalate；
Preferably, the crylic acid resin enteric material is selected from trade nameE100、L100-
55、L100 andOne or more of crylic acid resin enteric material of S100.
4. posaconazole solid dispersions according to claim 1 or 2, which is characterized in that the plasticizer is selected from hydroxypropyl
Methylcellulose E3, hypromellose E5, hypromellose E15, hydroxypropylcellulose EXF, hydroxypropylcellulose ELF,
In hydroxypropylcellulose LXF, hydroxypropylcellulose JXF, hydroxypropylcellulose HXF, 30 POVIDONE K 30 BP/USP 17, PVP K30 and 30 POVIDONE K 30 BP/USP 90
One or more.
5. posaconazole solid dispersions according to claim 1 or 2, which is characterized in that the posaconazole activity into
It is divided into posaconazole solvate, posaconazole pro-drug, crystal form posaconazole, amorphous posaconazole or crystal
The mixture of form posaconazole and amorphous posaconazole.
6. such as the preparation method of claim 1-5 any one of them posaconazole solid dispersions, which is characterized in that it is wrapped
It includes：
The physical mixture mixed by posaconazole active ingredient, enteric material and plasticizer is subjected to hot melt processing,
Obtain hot melt blend；
By the hot melt blend through atomization process, freezing processing and curing process to get posaconazole solid dispersions.
7. preparation method according to claim 6, which is characterized in that the temperature for heating processing is 135-145 DEG C；
Preferably, the atomizing pressure of atomization process is 0.18bar~0.24bar；
Preferably；The condensation temperature of freezing processing is -16 DEG C~0 DEG C.
8. a kind of posaconazole enteric coated preparations, which is characterized in that it includes the posaconazole any one of claim 1-5
Solid dispersions and pharmaceutically acceptable auxiliary material.
9. posaconazole enteric coated preparations according to claim 8, which is characterized in that the auxiliary material includes filler, bonding
Agent, disintegrant, lubricant and coating material；
Preferably, the filler is selected from lactose monohydrate, Lactis Anhydrous, microcrystalline cellulose, starch, partially pregelatinized starch
And one or more of mannitol；
Preferably, described adhesive be selected from hypromellose E3, hypromellose E5, hypromellose E15,
Hydroxypropylcellulose EXF, hydroxypropylcellulose ELF, hydroxypropylcellulose LXF, hydroxypropylcellulose JXF, hydroxypropylcellulose HXF, povidone
One or more of K17, PVP K30 and 30 POVIDONE K 30 BP/USP 90；
Preferably, disintegrant is selected from low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch and friendship
Join the one or more in povidone；
Preferably, lubricant is selected from magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, lauryl sodium sulfate, cunning
One or more of mountain flour and silica.
10. posaconazole enteric coated preparations according to claim 8 or claim 9, which is characterized in that by weight, the auxiliary material
Including：50~100 parts of filler is preferably 50~80 parts；
50~100 parts of adhesive is preferably 50~80 parts；
10~40 parts of disintegrant is preferably 20~30 parts；
And 1~10 part of lubricant, it is preferably 2~5 parts.
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| WO2019240698A3 (en) * | 2017-12-28 | 2020-02-13 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Oral pharmaceutical composition comprising posaconazole |
| CN110960499A (en) * | 2019-12-31 | 2020-04-07 | 卓和药业集团有限公司 | Posaconazole gastric floating tablet and preparation method thereof |
| CN112956699A (en) * | 2021-01-27 | 2021-06-15 | 上海海洋大学 | Hypoglycemic peptide enteric solid dispersion and preparation method thereof |
| WO2023138366A1 (en) * | 2022-01-19 | 2023-07-27 | 四川科伦药物研究院有限公司 | Solid dispersion, preparation method for same, and pharmaceutical composition containing same |
| WO2024041662A1 (en) * | 2023-09-18 | 2024-02-29 | 北京德立福瑞医药科技有限公司 | Posaconazole solid dispersion and preparation method therefor |
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| CN104721827A (en) * | 2013-12-18 | 2015-06-24 | 博瑞生物医药技术(苏州)有限公司 | Insoluble antifungal medicament solid dispersion and preparation method thereof |
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| WO2019240698A3 (en) * | 2017-12-28 | 2020-02-13 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Oral pharmaceutical composition comprising posaconazole |
| CN110960499A (en) * | 2019-12-31 | 2020-04-07 | 卓和药业集团有限公司 | Posaconazole gastric floating tablet and preparation method thereof |
| CN112956699A (en) * | 2021-01-27 | 2021-06-15 | 上海海洋大学 | Hypoglycemic peptide enteric solid dispersion and preparation method thereof |
| WO2023138366A1 (en) * | 2022-01-19 | 2023-07-27 | 四川科伦药物研究院有限公司 | Solid dispersion, preparation method for same, and pharmaceutical composition containing same |
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| CN108066289B (en) | 2021-01-26 |
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