CN114652725B - 一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂 - Google Patents
一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂 Download PDFInfo
- Publication number
- CN114652725B CN114652725B CN202210420844.6A CN202210420844A CN114652725B CN 114652725 B CN114652725 B CN 114652725B CN 202210420844 A CN202210420844 A CN 202210420844A CN 114652725 B CN114652725 B CN 114652725B
- Authority
- CN
- China
- Prior art keywords
- atorvastatin
- maleate
- cyclodextrin
- hydroxypropyl
- inclusion compound
- 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.)
- Active
Links
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 135
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 135
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 134
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 117
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 117
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 64
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 60
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 239000011976 maleic acid Substances 0.000 title claims abstract description 30
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 46
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- 239000000463 material Substances 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 30
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 26
- 229920001531 copovidone Polymers 0.000 claims description 23
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 239000008213 purified water Substances 0.000 claims description 15
- 238000005303 weighing Methods 0.000 claims description 11
- 239000000945 filler Substances 0.000 claims description 10
- 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 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000008101 lactose Substances 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 229940032147 starch Drugs 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- 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 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 239000000853 adhesive Substances 0.000 claims description 3
- 230000001070 adhesive effect Effects 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- 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 description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 2
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 5
- 239000007884 disintegrant Substances 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000000654 additive Substances 0.000 abstract 1
- 230000000996 additive effect Effects 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 abstract 1
- 239000008187 granular material Substances 0.000 description 30
- 239000000243 solution Substances 0.000 description 23
- 239000011248 coating agent Substances 0.000 description 20
- 238000000576 coating method Methods 0.000 description 20
- 238000004090 dissolution Methods 0.000 description 20
- 239000007788 liquid Substances 0.000 description 14
- 238000002156 mixing Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 208000019423 liver disease Diseases 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 206010043554 thrombocytopenia Diseases 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- 229920003081 Povidone K 30 Polymers 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 238000005063 solubilization Methods 0.000 description 6
- 230000007928 solubilization Effects 0.000 description 6
- 230000009466 transformation Effects 0.000 description 6
- 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 5
- 239000002775 capsule Substances 0.000 description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 5
- 238000010008 shearing Methods 0.000 description 5
- 238000007873 sieving Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- MISPBGHDNZYFNM-BTJKTKAUSA-N (z)-but-2-enedioic acid;1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid Chemical compound OC(=O)\C=C/C(O)=O.C1CC(C(=O)O)CCN1C1=NC=C(C(=O)NC=2SC(=C(C=3SC=C(Cl)C=3)N=2)N2CCN(CC2)C2CCCCC2)C=C1Cl MISPBGHDNZYFNM-BTJKTKAUSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000005763 Thrombopoietin Receptors Human genes 0.000 description 2
- 108010070774 Thrombopoietin Receptors Proteins 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- -1 cyclic oligosaccharides Chemical class 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 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 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 239000003390 Chinese drug Substances 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 241001506137 Rapa Species 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method 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
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Images
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
- A61K31/495—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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明属于药物制剂领域,具体涉及一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂。所述马来酸阿伐曲泊帕环糊精包合物包含马来酸阿伐曲泊帕、环糊精或其衍生物,以及高分子添加剂共聚维酮。本发明环糊精包合物可以明显增加药物溶解度,且环糊精用量少、包合效率高,从而提高了药物生物利用度,且制造过程简单、成本低,产品稳定性更好,药物制剂受包材和环境湿度等因素影响小。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂。
技术背景
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
马来酸阿伐曲泊帕(Avatrombopag maleate)是一种血小板生成素受体(TPO)激动剂,该药物由AkaRx Inc研发,并于2018年5月获美国FDA批准上市,商品名为Doptelet,规格为20mg,用于治疗计划接受医疗或牙科手术的慢性肝病(CLD)成人患者的低血小板计数(血小板减少症CIT)。2020年4月,马来酸阿伐曲泊帕片获中国药品监督管理局批准,商品名为苏可欣,用于择期行诊断性操作或者手术的慢性肝病相关血小板减少症的成年患者治疗。血小板减少症,是慢性肝病患者常见的并发症之一,此前国内被批准用于CLD相关血小板减少症的治疗方案仅有血小板输注一种,作为国内首款针对CLD相关血小板减少症的治疗药物,马来酸阿伐曲泊帕片在中国的上市填补了国内该领域的用药空白,为中国CLD相关血小板减少症患者引入了全球领先的“强效持久、安全方便”的诊疗新方案。
马来酸阿伐曲泊帕的化学名为1-(3-氯代-5-{[4-(4-氯噻吩-2-基)-5-(4-环己基哌嗪-1-基)-1,3-噻唑-2-基]氨基甲酰基}吡啶-2-基)哌啶-4-羧酸马来酸盐,分子式为C29H34Cl2N6O3S2·C4H4O4,化学结构式如下:
马来酸阿伐曲泊帕属于生物药剂学分类(BCS)IV类药物,几乎不溶于水和盐酸溶液,在pH1.0~pH11.0缓冲液中也几乎不溶,其中,在0.1mol/L盐酸和pH7.0介质中的饱和溶解度分别仅为0.58μg/mL和0.027μg/mL,因此,考虑到马来酸阿伐曲泊帕在生理pH范围内溶解度较低,如何保证药物在吸收部位的有效溶出才是保证其生物利用度的关键所在。同时,马来酸阿伐曲泊帕为多晶型药物,该药物在一定湿度环境下容易发生转晶,使其在贮库中可能因为环境中水分原因,导致药物转晶,所形成的转晶药物溶解性更低,进一步降低了药物溶出度,存在不稳定性问题,因此,如何保证所生产的马来酸阿伐曲泊帕制剂具有良好稳定性是需要解决的另一个重要问题。
专利文献CN 112022825 A公开了将原料药微粉化后,采用干法制粒方式制备马来酸阿伐曲泊帕片,虽然该方式避免了制备过程中使用水可能导致的转晶问题,但是由于原料药水溶解性差,对原料药粒度控制较为严格,也增加了粉碎操作难度,且在放置中可能因为片剂吸湿性而存在潜在稳定性问题,需要进行较厚的包衣或阻湿性能较好的包材,也增加了制造成本。
专利文献CN 114010638 A公开了将原料药与填充剂采用球磨机进行干法共研磨的方式,使原料药粒径分布更均一、均匀度更好,然后再通过干法制粒后压片,或填充胶囊。该方式也避免了制备过程中水分的加入可能导致的转晶问题,但是,考察到原料药难溶特征,原料药粒度直接决定产品溶出特征,而原料药与填充剂以共研磨方式,因为辅料的存在而难以有效监控原料药粒径,且所制备的片剂或胶囊剂也存在制剂吸湿可能导致的溶出度下降问题。
发明内容
为了克服现有技术的不足,本发明旨在提供一种在吸收部位溶解度好、生物利用度高,且稳定性好的马来酸阿伐曲泊帕制剂,为马来酸阿伐曲泊帕在慢性肝病患者血小板减少症的治疗中提供更加可靠的技术支持。
环糊精是由酶改性的淀粉衍生物,由与α-1,4糖苷键连接的葡萄糖单元组成的环状低聚糖,通常含有6~12个D-吡喃葡萄糖单元结构,其中研究得较多并且具有重要实际意义的是含有6、7、8个葡萄糖单元的分子,分别称为α-、β-和γ-环糊精。环糊精的外形像一个锥柱状空桶,一边端口口径宽,一边端口口径窄,中间是一个空腔,环糊精筒状结构的两端具有亲水性,空腔内有葡萄糖基氧桥和-CH-基团,故空腔内具有疏水性。可利用药物分子与环糊精间的范德华力,将大小合适的药物分子包合在疏水区内形成包合物。
本发明将马来酸阿伐曲泊帕与环糊精和共聚维酮包合后,马来酸阿伐曲泊帕失去了原有的结晶性,以分子状态进入到包合物的空隙中,药物具有很高的分散度,且包合材料含有多个亲水性的醇羟基,使得包合物具有良好的可湿润性,从而达到对药物的增溶作用,大幅度增加了药物溶解度,分子态的药物易透过生物膜,进而提高药物生物利用度。本发明通过大量的筛选试验发现,在常用的环糊精种类中,羟丙基-β-环糊精与马来酸阿伐曲泊帕包合效果相对较好,尤其当马来酸阿伐曲泊帕与加入的羟丙基-β-环糊精的摩尔比为1:2.4时,对药物的包合效果最佳,但是,即便按最优比例制备的马来酸阿伐曲泊帕包合物,仍存在包合效率较低,按最优摩尔比1:2.4的包合方式计算,相当于包合每克药物需要约4.8g环糊精,包合物体积或质量过大,不利于包合物药物的进一步制备,且所形成的包合物稳定性较差,同时,因为包合过程中环糊精用量较大,制备成本也较高,不利于日常生产制备。在进一步地研究中意外发现,当在羟丙基-β-环糊精包合物的制备中加入一定量的共聚维酮,尤其共聚维酮为羟丙基-β-环糊精质量的3.0~7.0%时,环糊精的包合效率显著提升,可使羟丙基-β-环糊精的使用量减少约一半量,且对阿伐曲泊帕的增溶效果和稳定作用最好,这也是本发明的创新性所在。
具体地,本发明的技术方案如下所述:
本发明提供一种有效提高马来酸阿伐曲泊帕溶解度、且不受外界环境水分等影响,具有良好溶出特征和稳定性的马来酸阿伐曲泊帕环糊精包合物及其药物制剂。
所述马来酸阿伐曲泊帕环糊精包合物包含马来酸阿伐曲泊帕、环糊精和共聚维酮,所述环糊精为β-环糊精或其衍生物,优选羟丙基-β-环糊精,马来酸阿伐曲泊帕、环糊精和共聚维酮的质量比为1:2~3:0.1~0.15。所述马来酸阿伐曲泊帕药物制剂包含马来酸阿伐曲泊帕环糊精包合物和药学上可接受的辅料。
进一步地,本发明的马来酸阿伐曲泊帕药物制剂,所述药学上可接受的辅料包含填充剂、粘合剂、崩解剂、润滑剂中的一种或几种。所述填充剂选自微晶纤维素、甘露醇、乳糖、蔗糖、预胶化淀粉、淀粉、山梨醇的一种或其组合物;所述粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素中的一种或几种;所述崩解剂选自交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、低取代羟丙纤维素的一种或其组合物;所述润滑剂选自硬脂酸镁、硬脂富马酸钠、二氧化硅、滑石粉中的一种或其几种。
一个具体的示例,所述药物制剂中各组分的质量百分比如下:
马来酸阿伐曲泊帕环糊精包合物60-120份,填充剂20~160份,粘合剂1~10份,崩解剂1~10份,润滑剂1~4份。
同时,本发明提供了所述含马来酸阿伐曲泊帕环糊精包合物及其药物制剂的制备方法,包括以下步骤:
(1)称取处方量环糊精,用纯化水溶解后,再加入共聚维酮,制备成含共聚维酮的环糊精溶液;
(2)称取处方量的马来酸阿伐曲泊帕,用浓度大于或等于95%(W/V)的乙醇水溶液溶解,制备马来酸阿伐曲泊帕药物溶液;
(3)将马来酸阿伐曲泊帕药物溶液加入至上述环糊精溶液中,搅拌,离心,取上清液,再将上清液冷冻干燥,即得马来酸阿伐曲泊帕包合物。
(4)将上述干燥的马来酸阿伐曲泊帕包合物与填充剂、润滑剂等混合制备成散剂;或与填充剂等混合均匀后制粒,然后加入崩解剂、润滑剂等后均匀混合,包装成颗粒剂,或压制成片剂,或充填成胶囊剂。
与现有技术相比,本发明的优点在于:
(1)本发明的马来酸阿伐曲泊药物制剂,采用环糊精方式将药物以分子状态包合进亲水性的羟丙基-β-环糊精中,增加了药物溶解度。同时,在羟丙基-β-环糊精包合作用基础上,加入适量共聚维酮,利用其增溶、抑晶和氢键缔合等作用,显著增加了羟丙基-β-环糊精的包合效果,大大减少了环糊精的用量并提高了包合物稳定性,也有利于包合物药物的进一步制剂加工。
(2)本发明的马来酸阿伐曲泊帕制剂的制备过程中,避免了原料药的微粉化处理,同时,对外界湿度等条件更稳定,避免了药物转晶等问题,减少了额外采用阻湿性能要求较高的包材需求,降低了生产成本,且制备工艺更加简单,更加适宜于工业化生产。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明所制备马来酸阿伐曲泊帕药物制剂的体外溶出曲线对比图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。
除非另行定义,文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。本发明所使用的试剂或原料均可通过常规途径购买获得,如无特殊说明,本发明所使用的试剂或原料均按照本领域常规方式使用或者按照产品说明书使用。此外,任何与所记载内容相似或均等的方法或材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1马来酸阿伐曲泊片剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000片计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入羟丙基-β-环糊精64.5g,加入纯化水搅拌溶解后,加入共聚维酮3.2g,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物;
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量乳糖、聚维酮K30置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与羧甲淀粉钠和硬脂酸镁均匀混合,压片即得;
3)采用纯化水配制12%包衣液,采用包衣机包衣增重至3%,即得马来酸阿伐曲泊帕片剂。
实施例2马来酸阿伐曲泊帕颗粒剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000袋计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入处方量羟丙基-β-环糊精64.5g,加入纯化水搅拌溶解后,加入共聚维酮4.5g,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物。
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量乳糖、聚维酮置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与阿司帕坦和二氧化硅均匀混合,装袋即得。
实施例3马来酸阿伐曲泊胶囊剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000粒计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入羟丙基-β-环糊精64.5g,加入纯化水搅拌溶解后,加入共聚维酮1.94g,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物。
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量甘露醇、羟丙纤维素置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与硬脂酸镁均匀混合,充填胶囊即得。
对比例1马来酸阿伐曲泊片剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000片计):
制备工艺:
1)采用气流粉碎机将马来酸阿伐曲泊帕粉碎,控制原料药粒径D90小于30μm,得到马来酸阿伐曲泊帕微粉物;
2)将马来酸阿伐曲泊帕微粉物23.6g、乳糖110.4g、胶态二氧化硅2.0g、和交联聚维酮3.0g均匀混合,采用干法制粒机制粒;
3)将干法制粒后颗粒采用20目筛整粒后,与微晶纤维素15.0g、交联聚维酮3.0g和硬脂酸镁3.0g混合均匀,然后采用压片机压片,制备成马来酸阿伐曲泊帕素片;
4)采用纯化水配制12%包衣液,采用包衣机包衣增重至7~9%,即得马来酸阿伐曲泊帕片剂。
对比例2马来酸阿伐曲泊片剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000片计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入羟丙基-β-环糊精128.5g,加入纯化水搅拌溶解后,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物。
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量乳糖、聚维酮K30置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与羧甲淀粉钠和硬脂酸镁均匀混合,压片即得。
3)采用纯化水配制12%包衣液,采用包衣机包衣增重至3%,即得马来酸阿伐曲泊帕片剂。对比例3马来酸阿伐曲泊片剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000片计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入羟丙基-β-环糊精64.5g,加入纯化水搅拌溶解后,加入共聚维酮6.0g,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物;
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量乳糖、聚维酮K30置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与羧甲淀粉钠和硬脂酸镁均匀混合,压片即得;
3)采用纯化水配制12%包衣液,采用包衣机包衣增重至3%,即得马来酸阿伐曲泊帕片剂。对比例4马来酸阿伐曲泊片剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000片计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入羟丙基-β-环糊精64.5g,加入纯化水搅拌溶解后,加入羟丙甲纤维素3.2g,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物。
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量乳糖、聚维酮K30置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与羧甲淀粉钠和硬脂酸镁均匀混合,压片即得。
3)采用纯化水配制12%包衣液,采用包衣机包衣增重至3%,即得马来酸阿伐曲泊帕片剂。
对比例5马来酸阿伐曲泊片剂(规格:20mg,按阿伐曲泊帕计)
处方组成(以1000片计):
制备工艺:
1)马来酸阿伐曲泊帕羟丙基-β-环糊精包合物的制备:向反应釜中加入羟丙基-β-环糊精64.5g,加入纯化水搅拌溶解后,加入聚维酮K30 3.2g,保持釜内温度维持在35℃,搅拌制得澄清的环糊精溶液;称取23.6g马来酸阿伐曲泊帕,用无水乙醇溶解后,缓慢加入上述搅拌中的环糊精溶液,加液完成后继续搅拌1h后,冷却静置,抽滤,将滤出物放置真空干燥箱干燥,得马来酸阿伐曲泊帕包合物。
2)马来酸阿伐曲泊帕颗粒剂的制备:将制得的马来酸阿伐曲包合物整粒,过60目筛,与处方量乳糖、聚维酮K30置于湿法制粒机中均匀混合,然后加入适量水,高速剪切制粒,干燥后30目整粒,然后与羧甲淀粉钠和硬脂酸镁均匀混合,压片即得。
3)采用纯化水配制12%包衣液,采用包衣机包衣增重至3%,即得马来酸阿伐曲泊帕片剂。
实施例4体外溶出曲线评价
取实施例1~3、对比例1~5,以及市售原研制剂苏可欣,测定上述马来酸阿伐曲泊帕制剂的体外溶出特征,选择对产品处方工艺具有区分力的体外溶出曲线方法,即:桨法,以磷酸氢二钠溶液(取无水磷酸氢二钠7.1g,加水1000ml使溶解,用磷酸调节pH值至6.8,加十六烷基三甲基溴化铵2.5g使溶解,摇匀)900ml为溶出介质,转速为每分钟50转,温度37.0℃,依法操作,分别于5、10、15、30、45、60和90分钟取样,按产品质量标准含量项下检测方法测定,溶出试验结果见下表:
该结果显示,与原研制剂体外溶出曲线相比,本发明所述处方(实施例1~3)所制备的马来酸阿伐曲泊帕制剂各时间点的体外溶出度均高于原研制剂苏可欣和原研制剂制备工艺(对比例1),其中,实施例2和实施例3溶出度显著高于原研片剂,可能在于其为颗粒剂或胶囊剂,溶出过程中无明显的崩解过程。与对比例2相比,实施例1的体外溶出度相对较高,表明环糊精包合液中加入共聚维酮后,进一步提高了环糊精的增溶效果,而缺少共聚维酮的条件下,仅通过提高环糊精的用量提高药物的溶出速度的效果很有限。但是当加入过量共聚维酮后,药物溶出度(对比例3)反而显著降低,表明共聚维酮用量对药物的包合影响较大,在包合制备中应控制共聚维酮用量。对比例4和对比例5中虽然也加入了亲水性高分子材料羟丙甲纤维素或聚维酮K30,但是并没有明显增溶的效果,这也说明环糊精溶液中共聚维酮的促溶作用与其独特的分子结构特征有关。
实施例5溶出度稳定性评价
将实施例1、对比例1~5中制备的马来酸阿伐曲泊帕片用铝塑泡罩包装,置于温度40±2℃,湿度75±5%加速试验条件下,按马来酸阿伐曲泊帕片质量标准项下方法进行检测,考察马来酸阿伐曲泊帕片的加速稳定性,实验结果如下:
试验结果表明,与各对比例所制备的马来酸阿伐曲泊帕片相比,实施例1的片剂稳定性较好,在加速6月条件下药物溶出度没有明显变化,稳定性优于市售原研制剂,这可能是由于马来酸阿伐曲泊帕在经环糊精包合后,药物以分子状态分散于环糊精分子中,不受外界湿度或温度影响,且经共聚维酮的缔合、抑晶等作用,大大提高了包合物稳定性。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,尽管参照前述实施例对本申请进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (9)
1.一种马来酸阿伐曲泊帕环糊精包合物,其特征在于,所述马来酸阿伐曲泊帕环糊精包合物由马来酸阿伐曲泊帕、羟丙基-β-环糊精和共聚维酮组成,马来酸阿伐曲泊帕、羟丙基-β-环糊精和共聚维酮的质量比为1:2~3:0.1~0.15。
2.一种含马来酸阿伐曲泊帕的药物制剂,其特征在于,包含权利要求1所述的马来酸阿伐曲泊帕环糊精包合物和药学上可接受的辅料。
3.根据权利要求2所述的含马来酸阿伐曲泊帕的药物制剂,其特征在于,所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂中的一种或几种。
4.根据权利要求3所述的含马来酸阿伐曲泊帕的药物制剂,其特征在于,所述填充剂选自微晶纤维素、甘露醇、乳糖、蔗糖、预胶化淀粉、淀粉、山梨醇中的一种或几种。
5.根据权利要求3所述的含马来酸阿伐曲泊帕的药物制剂,其特征在于,所述粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素中的一种或几种。
6.根据权利要求3所述的含马来酸阿伐曲泊帕的药物制剂,其特征在于,所述崩解剂选自交联羧甲基纤维素钠、羧甲基淀粉钠、交联聚维酮、低取代羟丙纤维素中的一种或几种。
7.根据权利要求3所述的含马来酸阿伐曲泊帕的药物制剂,其特征在于,所述润滑剂选自硬脂酸镁、硬脂富马酸钠、二氧化硅、滑石粉中的一种或几种。
8.根据权利要求2-7任一项所述的含马来酸阿伐曲泊帕的药物制剂,其特征在于各组分重量份如下:马来酸阿伐曲泊帕环糊精包合物60-120份,填充剂20~160份,粘合剂1~10份,崩解剂1~10份,润滑剂1~4份。
9.根据权利要求1所述含马来酸阿伐曲泊帕环糊精包合物的制备方法,其特征在于包含如下步骤:
(1)称取处方量羟丙基-β-环糊精,用纯化水溶解后,再加入共聚维酮,制备成含共聚维酮的环糊精溶液;
(2)称取处方量的马来酸阿伐曲泊帕,用浓度大于等于95%的乙醇水溶液溶解,制备马来酸阿伐曲泊帕药物溶液;
(3)将马来酸阿伐曲泊帕药物溶液加入至步骤(1)的环糊精溶液中,搅拌,离心,取上清液,再将上清液冷冻干燥,即得马来酸阿伐曲泊帕环糊精包合物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210420844.6A CN114652725B (zh) | 2022-04-20 | 2022-04-20 | 一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210420844.6A CN114652725B (zh) | 2022-04-20 | 2022-04-20 | 一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114652725A CN114652725A (zh) | 2022-06-24 |
CN114652725B true CN114652725B (zh) | 2023-06-06 |
Family
ID=82036881
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210420844.6A Active CN114652725B (zh) | 2022-04-20 | 2022-04-20 | 一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN114652725B (zh) |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106880598B (zh) * | 2015-12-14 | 2021-08-31 | 山东新时代药业有限公司 | 一种依折麦布片剂 |
CN106860408B (zh) * | 2015-12-14 | 2021-06-22 | 山东新时代药业有限公司 | 一种格列美脲片 |
CN111184692B (zh) * | 2020-02-14 | 2021-10-26 | 南京大渊医美生物技术有限公司 | 一种白藜芦醇的制剂及其制备方法 |
CN112022825B (zh) * | 2020-08-24 | 2024-03-22 | 瑞阳制药股份有限公司 | 马来酸阿伐曲泊帕片剂及其制备方法 |
CN113476415A (zh) * | 2021-07-26 | 2021-10-08 | 北京丰科睿泰医药科技有限公司 | 一种盐酸鲁拉西酮片剂及其制备方法 |
-
2022
- 2022-04-20 CN CN202210420844.6A patent/CN114652725B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN114652725A (zh) | 2022-06-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI778983B (zh) | 包含2-羥基-6-((2-(1-異丙基-1h-吡唑-5-基)吡啶-3-基)甲氧基)-苯甲醛之片劑 | |
US20200345766A1 (en) | Pharmaceutical compositions | |
NO174996B (no) | Fremgangsmåte for fremstilling av et granulat og en tablett inneholdende granulatet | |
EP2167046B1 (en) | Pharmaceutical solid preparation comprising benzazepines and production method thereof | |
CN101801347A (zh) | 包含二氢吡啶类钙通道拮抗剂的改进的药物组合物及其制备方法 | |
CN106572977A (zh) | 可直接压制的聚乙烯醇类 | |
CN113413388B (zh) | 含有枸橼酸西地那非的药物组合物、制备方法及其应用 | |
US20100016378A1 (en) | Method of preventing dihydropyridine compound from degradation | |
CN107913411B (zh) | 艾曲泊帕包合物及其制剂和制备方法 | |
CN108186581B (zh) | 一种伏立康唑制剂及其制备方法 | |
KR20150003726A (ko) | 프라수그렐을 함유하는 안정한 즉시방출형 경구 약제학적 조성물 | |
US11517569B2 (en) | Vilazodone inclusion complexes, compositions and preparation thereof | |
EP4079295A1 (en) | Composition having improved solubility and bioavailability of olaparib | |
CN114652725B (zh) | 一种马来酸阿伐曲泊帕环糊精包合物及其药物制剂 | |
JP4890657B1 (ja) | リマプロストとβ−シクロデキストリンを含有する錠剤 | |
CN114377147A (zh) | 一种阿伐曲泊帕包合物、组合物及其制备方法 | |
CN106880611A (zh) | 一种含微粉化的托伐普坦和水溶性辅料的托伐普坦制剂 | |
JP2003238393A (ja) | 施錠性が改善された錠剤及びその製造方法 | |
WO2016029494A1 (zh) | 微晶纤维素在制备美索舒利制剂中的用途及其制备方法 | |
CN115869264A (zh) | 一种美洛昔康固体分散体及其制备方法 | |
CN102218071A (zh) | 一种微粉化地夫可特口服制剂及其制备方法 | |
WO2007141806A1 (en) | Pharmaceutical formulations comprising oxcarbazepine and methods thereof | |
WO2017093890A1 (en) | Clobazam tablet formulation and process for its preparation | |
US20090012146A1 (en) | Solubility-enhanced pharmaceutical compositions comprising zafirlukast | |
US20210205301A1 (en) | Vilazodone inclusion complexes, compositions and preparation thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |