CN106924206A - A kind of net oral solid formulations of Yi Gelie and preparation method thereof - Google Patents
A kind of net oral solid formulations of Yi Gelie and preparation method thereof Download PDFInfo
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- CN106924206A CN106924206A CN201511027692.XA CN201511027692A CN106924206A CN 106924206 A CN106924206 A CN 106924206A CN 201511027692 A CN201511027692 A CN 201511027692A CN 106924206 A CN106924206 A CN 106924206A
- Authority
- CN
- China
- Prior art keywords
- gelie
- net
- oral solid
- proline
- filler
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- 239000000203 mixture Substances 0.000 title claims abstract description 78
- 239000007787 solid Substances 0.000 title claims abstract description 41
- 238000009472 formulation Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title description 32
- 239000002775 capsule Substances 0.000 claims abstract description 32
- 239000003826 tablet Substances 0.000 claims abstract description 29
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- 238000000576 coating method Methods 0.000 claims abstract description 27
- 239000000945 filler Substances 0.000 claims abstract description 26
- 239000000843 powder Substances 0.000 claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 20
- 239000000853 adhesive Substances 0.000 claims abstract description 18
- 230000001070 adhesive effect Effects 0.000 claims abstract description 18
- 235000010603 pastilles Nutrition 0.000 claims abstract description 18
- 239000007884 disintegrant Substances 0.000 claims abstract description 16
- 239000000314 lubricant Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000012856 packing Methods 0.000 claims abstract description 5
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 36
- 230000005496 eutectics Effects 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 18
- 238000004090 dissolution Methods 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 210000002784 stomach Anatomy 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- -1 hydroxy-propyl Chemical group 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 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 claims description 3
- 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 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
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 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
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 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
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000007888 film coating Substances 0.000 claims description 2
- 238000009501 film coating Methods 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- 229960003943 hypromellose Drugs 0.000 claims 1
- 229960001375 lactose Drugs 0.000 claims 1
- 229960001855 mannitol Drugs 0.000 claims 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- 102000034534 Cotransporters Human genes 0.000 description 1
- 108020003264 Cotransporters Proteins 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 229910003978 SiClx Inorganic materials 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 235000015177 dried meat Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of net oral solid formulations of Yi Gelie, and it can be the form of tablet, powder or capsule, and it includes antiplastering aid, filler and optional disintegrant, adhesive, lubricant and coating material.Correspondingly, the present invention also provides the method for preparing the oral solid formulation.In the case where the oral solid formulation is tablet, methods described includes the step of forming pre-composition, formation pastille mixture, compressing tablet, coating.In the case where the oral solid formulation is capsule, the pastille mixture is filled in capsule shells.In the case where the oral solid formulation is powder, the pastille mixture is encapsulated in packing container.
Description
Technical field
The present invention relates to field of pharmaceutical preparations.Specifically, the present invention provide a kind of net oral solid formulations of Yi Gelie and
Its preparation method.
Background technology
Glucose cotransporter (SLGT) is a class memebrane protein, can be by glucose transport to intracellular.SLGT has
There are 2 kinds of hypotypes, SLGT1 and SLGT2 is distributed in mucous membrane of small intestine and renal tubule respectively.SLGT2 inhales again in proximal tubular glucose
Key effect is played in receipts.
Yi Gelie is the net class SLGT2 inhibitor of row only, and it passes through the known SLGT2 of selectivity, makes the glucose in renal tubule
Blood can not be entered by reabsorption, but be discharged with urine, so as to reduce blood sugar concentration.Yi Gelie purification scientific name be referred to as (1S)-
1,5- dehydration -1- { 3- [(1- benzothiophene -2- bases) methyl] -4- fluorophenyls }-D-Glucose alcohol, Yi Gelie is only and L-PROLINE
Shown in the structure such as formula (I) of the eutectic thing of formation.
Be dissolved or dispersed in for SLGT2 inhibitor, crystallizing inhibitor, filler a certain amount of by the A of Chinese patent CN 104382859
In water-containing organic solvent, using the method for spray drying, the particle comprising SLGT2 inhibitor, crystallizing inhibitor and filler is prepared, used
In being further prepared into the preparations such as tablet, capsule, granule；The preparation method solve SLGT2 inhibitor poorly water-soluble and
Cause dissolution rate and the low problem of bioavilability.
Chinese patent CN 102596206B disclose a kind of solid pharmaceutical composition, it is characterised in that comprising (1S) -1,
5- is dehydrated the co-crystal thereof of -1- { 3- [(1- benzothiophene -2- bases) methyl] -4- fluorophenyls }-D-Glucose alcohol and L-PROLINE
And avicel cellulose.In manufacture capsule preparations of the co-crystal thereof of net and L-PROLINE comprising Yi Gelie, it was found that due to
Strong compendency that net and L-PROLINE the co-crystal thereofs of Yi Gelie have and disintegrative is poor, result causes medicine dissolution rate becomes
Slow problem.If the disintegrative of preparation is poor, medicine dissolution rate is slack-off, it is likely that produce bioavilability reduction, nothing
The problems such as method obtains sufficient therapeutic effect pharmacologically.Manufacture method disclosed in the patent is by Yi Gelie is net and L- dried meat ammonia
The co-crystal thereof of acid mixes with avicel cellulose, the operation of wet type granulation is carried out to gained mixture.
The net class SLGT2 inhibitor generally existing poor solubility of visible columns or disintegrative are poor, so as to cause such medicine biological
The low problem of availability.In order to solve the above technical problems, the invention provides a kind of one kind different from existing public technology more
Simple oral solid formulation and its easier preparation process comprising the net eutectic things of L-PROLINE Yi Gelie, while improve
Disintegrative, the dissolution in vitro of the net eutectic things of L-PROLINE Yi Gelie.
The content of the invention
The present invention provides a kind of net oral solid formulations of Yi Gelie, and it includes net eutectic things of L-PROLINE Yi Gelie, anti-stick
Agent, filler, and optional disintegrant, adhesive, lubricant, coating material and capsule shells.
The net oral solid formulations of Yi Gelie of the invention are tablet, powder or capsule.
Correspondingly, the present invention also provides the Yi Gelie of the invention preparation methods of net oral solid formulation.
Brief description of the drawings
Fig. 1 is the drug-eluting amount-time plot of the tablet of embodiment 2-4.
Fig. 2 is the drug-eluting amount-time plot of the capsule of embodiment 5-7.
Specific embodiment
The present invention provides a kind of net oral solid formulations of Yi Gelie, and it includes net eutectic things of L-PROLINE Yi Gelie, anti-stick
Agent, filler, optionally also include adhesive, lubricant and disintegrant；The net oral solid formulations of Yi Gelie of the invention are also wrapped
Containing any one in coating material and capsule shells.
The net oral solid formulations of Yi Gelie of the invention are tablet, powder or capsule.
In the context of the present invention, antiplastering aid refers to and is usually used in pharmaceutical preparation reducing bulk drug or auxiliary material viscosity
A kind of material.Because L-PROLINE Yi Gelie has strong compendency only, it is therefore desirable to add antiplastering aid, prevent bulk drug from assembling knot
Block.Herein, the antiplastering aid can be aerosil or talcum powder, but not limited to this.Preferably use gas phase dioxy
SiClx is used as antiplastering aid.
In the context of the present invention, the filler refers to the weight or volume for being mainly used in filling tablet, consequently facilitating
The pharmaceutic adjuvant of compressing tablet.Conventional filler is starch, carbohydrate, cellulose family and inorganic salts etc..Herein, it is described to fill out
Agent is filled for such as starch, lactose, mannitol, xylitol, sucrose, microcrystalline cellulose, but not limited to this.Preferably use microcrystalline cellulose
Element is used as filler.
In the context of the present invention, described adhesive refers to that addition to drug powder makes it be glued together in production process
Stickum.Herein, described adhesive can be such as polyvinylpyrrolidone (PVP), Hydroxypropyl methylcellulose
(HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose (CMC-Na), but not limited to this.Preferably use polyvinyl pyrrole
Alkanone is used as adhesive.
In the context of the present invention, the lubricant can be such as magnesium stearate, calcium stearate or stearyl fumarate
Sodium, but not limited to this.Magnesium stearate is preferably used as lubricant.
In the context of the present invention, disintegrant refers to that can generally make that tablet splits rapidly in gastro-intestinal Fluid is broken into fine particle
Material, so that the rapid solution absorption of functional component, plays a role.Herein, the disintegrant is, such as CMS
Sodium, PVPP (PVPP), low-substituted hydroxypropyl cellulose (L-HPC), pregelatinized starch, but not limited to this.
PVPP is preferably used as disintegrant.
In the context of the present invention, the coating material can be conventional stomach dissolution type coating material, such as hydroxypropyl first
Cellulose, polyvinyl alcohol or its mixture, orStomach dissolution type coating powder, but not limited to this.Preferably use
Serial stomach dissolution type coating powder is used as coating material.
In a preferred embodiment of the invention, the net oral solid formulations of the Yi Gelie are tablets, based on described
The gross weight meter of tablet, it includes the net eutectic thing 10-25% of L-PROLINE Yi Gelie, disintegrant 1-4.5%, antiplastering aid 0.5-
5%, filler 55-80%, adhesive 5-9%, lubricant 0.01-2%, and coating material 0.5-4%；
L-PROLINE Yi Gelie net eutectic thing 12-22%, disintegrant 1.5-4%, antiplastering aid 0.7-3% are preferably comprised, is filled out
Fill agent 60-75%, adhesive 6-8%, lubricant 0.3-1.5% and coating material 1-3%；
L-PROLINE Yi Gelie net eutectic thing 15-20%, disintegrant 2.5-3.5%, antiplastering aid 1-2% are most preferably comprised,
Filler 65-70%, adhesive 6.5-7.5%, lubricant 0.5-1.2% and coating material 1.5-2.5%.
In a preferred embodiment of the invention, the net oral solid formulations of Yi Gelie of the invention are tablet, its tool
The coating membrane that useful stomach dissolution type coating material is packed.
In a preferred embodiment of the invention, the net oral solid formulations of the Yi Gelie are capsule or powder,
The powder of the net eutectic things of wherein filling bag Yi Gelie containing L-PROLINE, based on the gross weight meter of the pastille powder, it includes L-
Proline Yi Gelie net eutectic thing 10-25%, antiplastering aid 0.5-5%, filler 70-89%；
Most preferably comprise the net eutectic thing 12-22% of L-PROLINE Yi Gelie, antiplastering aid 0.7-3%, filler 75-85%.
Correspondingly, the present invention also provides the Yi Gelie of the invention preparation methods of net oral solid formulation.
In the case where the net oral solid formulations of Yi Gelie of the invention are tablet, the preparation method includes following step
Suddenly：
(1) the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid are well mixed, form the pre-composition of bulk drug；
(2) filler, adhesive, disintegrant are added into the pre-composition of the bulk drug, is well mixed, formed
Pastille mixture；
(3) by the pastille mixture and mix lubricant, compressing tablet of step (2), plain piece is obtained；
(4) film-coating is packed with stomach dissolution type coating material.
In the case where the net oral solid formulations of Yi Gelie of the invention are capsule, the preparation method includes：
(1) the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid are well mixed, form the pre-composition of bulk drug；
(2) filler is added into the pre-composition of the bulk drug, is well mixed, form pastille mixture；
(3) the pastille mixture of step (2) is loaded into capsule shells.
In the case where the net oral solid formulations of Yi Gelie of the invention are powder, the preparation method includes：
(1) the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid are well mixed, form the pre-composition of bulk drug；
(2) filler is added into the pre-composition of the bulk drug, is well mixed, form pastille mixture；
(3) the pastille mixture of step (2) is encapsulated in suitable packing container.
In a preferred embodiment of the invention, the packing container can be bottle, hermetic bag or Fresco Bag, or other
The sealing container that can be used.
Embodiment
The present invention is described in further detail with reference to embodiments.Following examples are not necessarily to be construed as to this hair
Bright limitation.All technologies realized based on present invention belong to the scope of the present invention.
Embodiment 1：L-PROLINE Yi Gelie net preparation
In the present embodiment, raw materials used and reagent is all commercially available.
The preparation of the compound of formula 3：
Compound 1 (160.6g, 0.5mol) is added in 3L round bottom there-necked flasks, adds 400mlTHF and 800ml toluene molten
Solution, argon gas protection.It is cooled to -78 DEG C, the hexane solution (184ml, 0.5mol) of 2.5M n-BuLis is added dropwise, keeping temperature is not high
In -70 DEG C.30min is stirred at -78 DEG C.Then reaction solution is slowly transferred to the 2,3,4,6- for being pre-chilled to -78 DEG C with double needle
Toluene (1.1L) solution of four-O- trimethyls silicon substrates-D-Glucose acid lactone (236g, 0.5mol), keeping temperature is not higher than -70
℃.Methanesulfonic acid (1L, 0.6N MeOH) is added after stirring 30min at -78 DEG C, room temperature is warmed naturally to and is continued stirring reaction 16h.
PH is adjusted to 7.5 with saturated sodium bicarbonate solution (about 200ml), organic phase is separated, with ethyl acetate (150ml × 3) extraction water
Phase, merges organic phase, wash with saturated brine (150ml), filtering after anhydrous sodium sulfate drying, removes under reduced pressure molten in filtrate
Agent, by residue with being poured into 1L n-hexanes after 150ml toluene heating for dissolving, obtains the white crystal of the compound of 171g formulas 3, receives
Rate 78.7%.
The preparation of Yi Gelie net (compound of formula 4)：
300ml dichloromethane is added in a container, the compound of 0.3mol formulas 3 is weighed, dichloromethane is slowly added to by several times
In to prevent from being lumpd after adding, it is stirring while adding to being completely dissolved, to adding 96ml triethyl silicanes, stirring clarification in the solution
In adding dropping funel afterwards, then rinsed with a small amount of dichloromethane and also add dropping funel after bottle wall, it is standby.
By in 300ml dichloromethane addition reactor, stir.Purged 10 minutes with nitrogen.Under nitrogen protection, lower the temperature
To less than -15 DEG C, by 78ml BFEEs addition reactor.Finish, the solution of intermediate 3 in dropping funel be added dropwise,
Keep Nei Wen -20~-10 DEG C.Completion of dropping, closes cooling, continues to stir 2 hours, to dropwise addition 300ml saturated carbons in reaction solution
Sour hydrogen sodium solution, after stirring, vacuum distillation removes organic solvent.It is extracted twice with methyl tertiary butyl ether(MTBE), merges methyl- tert
Butyl ether, then add purifying water washing.Stand to thoroughly layering, release lower floor's water phase, used after t-butyl methyl ether solution is dried
Rotary Evaporators remove solvent, obtain syrupy shape solid 120g, weight yield 99%.
Add Yi Gelie net in 3L reactors and each 0.2mol of proline, add ethanol in proper amount and water to be dissolved.
Under Quick mechanical stirring, 30min is heated to reflux, appropriate n-hexane is added dropwise after being cooled to room temperature, be cooled to -5 DEG C, and stir 3h,
Filtering.Filter cake is washed with 90% cold ethanol water and n-hexane respectively, is vacuum dried.Then with 90% ethanol and just oneself
Alkane is recrystallized once, vacuum drying, obtains final product the net eutectic things of L-PROLINE Yi Gelie.
Embodiment 2：The preparation of the net coated tablets of Yi Gelie
Table 1：The composition of the net coated tablets of Yi Gelie
Preparation method：Mix about 5min, mistake during the net eutectic things of L-PROLINE Yi Gelie, aerosil are put into mixer
60 mesh sieves, it is standby；Microcrystalline cellulose 102, PVPP, PVP K30 are added, mixes about 15min, it is standby；It is eventually adding stearic acid
Magnesium mixing 3min, compressing tablet is coated using Opadry and obtained final product.
Embodiment 3：The preparation of the net coated tablets of Yi Gelie
Table 2：The composition of the net coated tablets of Yi Gelie
Preparation method：In the present embodiment, with talcum powder as antiplastering aid, with sodium carboxymethyl starch as disintegrant, with hydroxypropyl
Base cellulose is adhesive, and the net oral solid formulations of Yi Gelie of the invention are prepared in the same manner as in Example 1.
Embodiment 4：The preparation of the net coated tablets of Yi Gelie
Table 3：The composition of the net coated tablets of Yi Gelie
Preparation method：In the present embodiment, with PVP K30 as adhesive, with MCC as filler, with
The identical method of embodiment 1 prepares the net oral solid formulations of Yi Gelie of the invention.
Embodiment 5：The preparation of the net capsules of Yi Gelie
Table 4：The composition of the net capsules of Yi Gelie
Preparation method：By the net eutectic things of L-PROLINE Yi Gelie, aerosil mixing 5min, 60 mesh sieves are crossed, then add
Enter the mixing 10min of microcrystalline cellulose 102, be filled directly into capsule shells, obtain final product the net oral solid formulations of Yi Gelie of the invention.
Embodiment 6：The preparation of the net capsules of Yi Gelie
Table 5：The composition of the net capsules of Yi Gelie
Preparation method：By the net eutectic things of L-PROLINE Yi Gelie, aerosil mixing 5min, 60 mesh sieves are crossed, then add
Enter the mixing 10min of microcrystalline cellulose 102, be filled directly into capsule shells, obtain final product the net oral solid formulations of Yi Gelie of the invention.
Embodiment 7：The preparation of the net capsules of Yi Gelie
Table 6：The composition of the net capsules of Yi Gelie
Preparation method：By the net eutectic things of L-PROLINE Yi Gelie, talcum powder mixing 5min, 60 mesh sieves are crossed, add crystallite
Cellulose 102 mixes 10min, is filled directly into capsule shells, obtains final product the net oral solid formulations of Yi Gelie of the invention.
Embodiment 8：The preparation of the net powders of Yi Gelie
The composition of the net powders of the present embodiment Yi Gelie is identical with the net capsules of the Yi Gelie of embodiment 5, as described in embodiment 5
Method by each component it is well mixed after, load hermetic bag, that is, obtain the net powders of Yi Gelie.
Embodiment 9
Disintegration experiment is carried out to coating tablet prepared by embodiment 2, embodiment 3, embodiment 4.By hanging basket by upper end
Stainless steel shaft is hung on metallic support, in immersion 1000ml beakers, and adjusts when hanging basket position declines it screen cloth away from beaker
Bottom 25mm, fills the water that temperature is 37 DEG C ± 1 DEG C in beaker, screen cloth is in underwater when regulation height of water level rises hanging basket
At 15mm.Each 6 of the coating tablet that respectively prepared by Example 2, embodiment 3, embodiment 4, in putting the glass tube of above-mentioned hanging basket, plus
Baffle plate, starts disintegration tester and is checked, records disintegration time, the results are shown in Table 7.
Table 7：Coating tablet disintegration time record sheet (unit：Second)
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| Embodiment 2 | 9 | 8 | 9 | 10 | 9 | 8 |
| Embodiment 3 | 10 | 11 | 11 | 10 | 11 | 10 |
| Embodiment 4 | 10 | 10 | 9 | 10 | 10 | 9 |
Embodiment 10
The coating tablet or capsule prepared to embodiment 2, embodiment 3, embodiment 4, embodiment 5, embodiment 6, embodiment 7 enter
Row Dissolution Rate Testing.Dissolution Rate Testing uses paddle method, 50rpm, using the 0.1N hydrochloric acid solutions of 900mL as dissolution medium, distinguishes
Yi Gelie net content, draws the dissolution of stripping quantity percentage-time in 10,15,30,45min sampling detection dissolution mediums
Curve.Result is shown in Fig. 1, Fig. 2.
The Yi Gelie net coating tablets or capsule of the preparation of the embodiment of the present invention 2~7 are can be seen that by the result of Fig. 1, Fig. 2
Dissolution rate has reached more than 80% in 30min.As can be seen here, it is of the invention comprising the net eutectic things of L-PROLINE Yi Gelie
Solid pharmaceutical preparation realizes good technique effect, but the composition and preparation method of preparation are simpler than prior art, be easier behaviour
Make, it is more energy efficient.
Obviously, the above of the invention, according to the ordinary technical knowledge and customary means of this area, is not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be carried out, is replaced or is changed.People from this area
Member is it is understood that each feature of technical solution of the present invention described herein can as needed carry out appropriate combination.
Claims (10)
1. net oral solid formulations of a kind of Yi Gelie, it includes the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid, filler, with
And optional disintegrant, adhesive, lubricant；The net oral solid formulations of Yi Gelie are also comprising in coating material or capsule shells
Any one.
2. net oral solid formulations of Yi Gelie according to claim 1, wherein, the net oral solid formulations of Yi Gelie are
Tablet, powder or capsule.
3. net oral solid formulations of Yi Gelie according to claim 1 and 2, wherein the antiplastering aid is aerosil
Or talcum powder, preferred aerosil；The filler is microcrystalline cellulose, lactose, mannitol, xylitol, sucrose, shallow lake
Powder, preferably microcrystalline cellulose；The disintegrant is sodium carboxymethyl starch, PVPP, low substituted hydroxy-propyl fibre
Dimension element, preferably pregelatinized starch, PVPP；Described adhesive is polyvinylpyrrolidone, hypromellose
Element, hydroxypropyl cellulose, sodium carboxymethylcellulose, preferably polyvinylpyrrolidone；The lubricant is magnesium stearate, stearic acid
Calcium or sodium stearyl fumarate, preferably magnesium stearate；The coating material is Hydroxypropyl methylcellulose, polyvinyl alcohol or its mixture,
OrStomach dissolution type coating powder, preferablyThe capsule shells are stomach dissolution type capsule shells.
4. the net oral solid formulations of Yi Gelie according to any one of claims 1 to 3, wherein, the Yi Gelie is only oral
Solid pharmaceutical preparation is tablet, and based on the gross weight meter of the tablet, it includes the net eutectic thing 10-25% of L-PROLINE Yi Gelie, collapses
Solution agent 1-4.5%, antiplastering aid 0.5-5%, filler 55-80%, adhesive 5-9%, lubricant 0.01-2%, and coating material
0.5-4%；
Preferably comprise L-PROLINE Yi Gelie net eutectic thing 12-22%, disintegrant 1.5-4%, antiplastering aid 0.7-3%, filler
60-75%, adhesive 6-8%, lubricant 0.3-1.5% and coating material 1-3%；
L-PROLINE Yi Gelie net eutectic thing 15-20%, disintegrant 2.5-3.5%, antiplastering aid 1-2% are most preferably comprised, is filled
Agent 65-70%, adhesive 6.5-7.5%, lubricant 0.5-1.2% and coating material 1.5-2.5%.
5. the method for preparing the net oral solid formulations of Yi Gelie of claim 4, including：
(1) the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid are well mixed, form the pre-composition of bulk drug；
(2) filler, disintegrant, adhesive are added into the pre-composition of the bulk drug, is well mixed, form pastille
Mixture；
(3) by the pastille mixture and mix lubricant, compressing tablet of step (2), plain piece is obtained；
(4) film-coating is packed with coating material.
6. the net oral solid formulations of Yi Gelie according to any one of claims 1 to 3, wherein, the Yi Gelie is only oral
Solid pharmaceutical preparation is capsule or powder, and it contains the pastille comprising the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid and filler
Powder.
7. net oral solid formulations of Yi Gelie according to claim 6, wherein, the gross weight based on the pastille powder
Meter, it includes the net eutectic thing 10-25% of L-PROLINE Yi Gelie, antiplastering aid 0.5-5%, filler 70-89%；
Most preferably comprise the net eutectic thing 12-22% of L-PROLINE Yi Gelie, antiplastering aid 0.7-3%, filler 75-85%.
8. the method for preparing the capsule described in claim 6 or 7, including：
(1) the net eutectic things of L-PROLINE Yi Gelie, antiplastering aid are well mixed, form the pre-composition of bulk drug；
(2) filler is added into the pre-composition of the bulk drug, is well mixed, form pastille mixture；
(3) the pastille mixture of step (2) is filled to capsule shells.
9. the method for preparing the powder described in claim 6 or 7, including：(1) by net eutectic things of L-PROLINE Yi Gelie, anti-stick
Agent is well mixed, and forms the pre-composition of bulk drug；
(2) filler is added into the pre-composition of the bulk drug, is well mixed, form pastille mixture；
(3) the pastille mixture of step (2) is packaged in packing container.
10. method according to claim 9, wherein the packing container is bottle, hermetic bag or Fresco Bag.
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| CN201511027692.XA CN106924206A (en) | 2015-12-31 | 2015-12-31 | A kind of net oral solid formulations of Yi Gelie and preparation method thereof |
| PCT/CN2016/111034 WO2017114228A1 (en) | 2015-12-31 | 2016-12-20 | Ipragliflozin oral solid preparation and preparation method thereof |
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Cited By (2)
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| CN112891315A (en) * | 2020-02-03 | 2021-06-04 | 北京阳光诺和药物研究股份有限公司 | Method for preparing pitavastatin calcium tablet |
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| CN112891315A (en) * | 2020-02-03 | 2021-06-04 | 北京阳光诺和药物研究股份有限公司 | Method for preparing pitavastatin calcium tablet |
| CN112891315B (en) * | 2020-02-03 | 2022-04-08 | 北京阳光诺和药物研究股份有限公司 | Method for preparing pitavastatin calcium tablet |
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Application publication date: 20170707 |