CN107343887A - A kind of unformed half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions and preparation method thereof - Google Patents
A kind of unformed half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions and preparation method thereof Download PDFInfo
- Publication number
- CN107343887A CN107343887A CN201610296500.3A CN201610296500A CN107343887A CN 107343887 A CN107343887 A CN 107343887A CN 201610296500 A CN201610296500 A CN 201610296500A CN 107343887 A CN107343887 A CN 107343887A
- Authority
- CN
- China
- Prior art keywords
- fanselin
- tartaric acid
- pharmaceutic adjuvant
- half tartaric
- solid dispersions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 title claims abstract description 171
- 235000002906 tartaric acid Nutrition 0.000 title claims abstract description 171
- 239000011975 tartaric acid Substances 0.000 title claims abstract description 171
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 109
- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 83
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000013078 crystal Substances 0.000 claims abstract description 49
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 45
- 239000003814 drug Substances 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000463 material Substances 0.000 claims description 19
- -1 filmogen Substances 0.000 claims description 17
- 229920001661 Chitosan Polymers 0.000 claims description 14
- 229920002472 Starch Polymers 0.000 claims description 14
- 235000019698 starch Nutrition 0.000 claims description 14
- 239000008107 starch Substances 0.000 claims description 14
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 239000004925 Acrylic resin Substances 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 239000001856 Ethyl cellulose Substances 0.000 claims description 8
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 8
- 229920002125 Sokalan® Polymers 0.000 claims description 8
- 229920001249 ethyl cellulose Polymers 0.000 claims description 8
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 8
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 7
- 241000206575 Chondrus crispus Species 0.000 claims description 7
- 102000008186 Collagen Human genes 0.000 claims description 7
- 108010035532 Collagen Proteins 0.000 claims description 7
- 229920001353 Dextrin Polymers 0.000 claims description 7
- 239000004375 Dextrin Substances 0.000 claims description 7
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 claims description 7
- 229920000615 alginic acid Polymers 0.000 claims description 7
- 235000010443 alginic acid Nutrition 0.000 claims description 7
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 7
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 7
- 229920001436 collagen Polymers 0.000 claims description 7
- 235000019425 dextrin Nutrition 0.000 claims description 7
- 239000002502 liposome Substances 0.000 claims description 7
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 7
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 7
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 7
- 239000011118 polyvinyl acetate Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 6
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 6
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003456 ion exchange resin Substances 0.000 claims description 5
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 5
- 229920001206 natural gum Polymers 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 238000001228 spectrum Methods 0.000 claims description 3
- 208000027089 Parkinsonian disease Diseases 0.000 claims description 2
- 206010034010 Parkinsonism Diseases 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 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 2
- 229920000858 Cyclodextrin Polymers 0.000 claims 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 2
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims 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 2
- 229920002678 cellulose Polymers 0.000 claims 2
- 239000001913 cellulose Substances 0.000 claims 2
- 235000010980 cellulose Nutrition 0.000 claims 2
- 239000008101 lactose Substances 0.000 claims 2
- 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 claims 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- 241000220324 Pyrus Species 0.000 claims 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims 1
- 229920002301 cellulose acetate Polymers 0.000 claims 1
- 238000004132 cross linking Methods 0.000 claims 1
- 150000002085 enols Chemical class 0.000 claims 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 235000021017 pears Nutrition 0.000 claims 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 1
- 239000004584 polyacrylic acid Substances 0.000 claims 1
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- 239000013049 sediment Substances 0.000 claims 1
- 239000000811 xylitol Substances 0.000 claims 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims 1
- 229960002675 xylitol Drugs 0.000 claims 1
- 235000010447 xylitol Nutrition 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000012360 testing method Methods 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 151
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 230000015572 biosynthetic process Effects 0.000 description 46
- 238000005755 formation reaction Methods 0.000 description 46
- 238000003756 stirring Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 238000005352 clarification Methods 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 11
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 238000001914 filtration Methods 0.000 description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229960004592 isopropanol Drugs 0.000 description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 6
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- RGSULKHNAKTFIZ-CEAXSRTFSA-N pimavanserin tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1.C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RGSULKHNAKTFIZ-CEAXSRTFSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920003139 Eudragit® L 100 Polymers 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
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- 229940081837 nuplazid Drugs 0.000 description 3
- 241000894007 species Species 0.000 description 3
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- 229920003149 Eudragit® E 100 Polymers 0.000 description 2
- 229920003141 Eudragit® S 100 Polymers 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 229920002538 Polyethylene Glycol 20000 Polymers 0.000 description 2
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 2
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 2
- 229940043234 carbomer-940 Drugs 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000012943 hotmelt Substances 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
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- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 229940081770 pimavanserin tartrate Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000002469 receptor inverse agonist Substances 0.000 description 1
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- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
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- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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Abstract
A kind of unformed half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions and its manufacture method, it includes half tartaric acid Mo Fanselin and pharmaceutic adjuvant, and both weight ratios are 1:0.1~100, wherein, half tartaric acid Mo Fanselin is unformed shape, and the characteristic peak of the crystal without half tartaric acid Mo Fanselin after the background peaks of pharmaceutic adjuvant is deducted in the X ray Powder Diffraction patterns of the solid dispersions.The half tartaric acid Mo Fanselin of the present invention and the solid dispersions stability and favorable dispersibility of pharmaceutic adjuvant, add half tartaric acid Mo Fanselin dissolution rate, it is more beneficial for improving the absorption of the bioavilability and body of pharmaceutical preparation to medicine, under the conditions of accelerated test, good physical stability and chemical stability can be kept.The preparation method of the unformed solid dispersions of the present invention is simple to operate, and cost is cheap, favorable reproducibility, it is easy to accomplish, it is adapted to industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of unformed half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions and preparation method thereof.
Background technology
Half tartaric acid Mo Fanselin (Pimavanserin Tartrate), the entitled tartrate of 1- (4- luorobenzyls) -3- (4- isobutoxies benzyl) -1- (1- methyl piperidine -4- bases) urea half of chemistry, trade name Nuplazid, it is a kind of serotonin 2A receptor inverse agonists of drugmaker of Acadia of the U.S. (Acadia Pharmaceuticals) research and development, occur the Parkinson's disease patients of the mental illnesses such as illusion or paranoea for treating, on April 29th, 2016, U.S.'s food and Drug Administration office (FDA) approval listing are obtained.Industry is also very good to Nuplazid commercial promise, and the estimated medicines of Evaluate Pharma are up to 8.41 hundred million dollars in the sales volume of the year two thousand twenty, separately there is the heavy pound medicine that the estimated Nuplazid of analyst will turn into 1,000,000,000 dollars of year pin in 5 years.Shown in the structure of the medicine such as formula (I)：
Although the effect of half tartaric acid Mo Fanselin, has been widely recognized as, but still some defects be present.Patent CN102103505 discloses half tartaric acid Mo Fanselin six kinds of crystal formations：Crystal formation A, crystal formation B, crystal formation C, crystal formation D (iso-propanol solvate), crystal formation E (methyl tert-butyl ether solvent compound) and crystal formation F (tetrahydrofuran solvent compound), wherein crystal formation C is the most stable form of the crystal formation of found crystal formation, and stable type is good.But solubility of the thermodynamically stable crystal formation in water can reduce, so as to influence the bioavilability of medicine.
The solid forms of medicine directly affect the rate of dissolution of bulk drug, the dissolution rate of preparation and bioavilability; in order to improve the bioavilability of medicine; reduce dosage, reduce toxic side effect; the new solid forms of medicine would generally be developed; therefore, develop the solid form that the drug solubility is more preferable, bioavilability is higher and just seem necessary.
The solid forms of medicine are in addition to crystalline state, also unformed state, a kind of specific form of the unformed state of medicine as solid matter, typically with more preferable dissolubility, there is important purposes in medicine preparation.Therefore, the stability of unformed shape medicine is improved by multiple technologies means and method, the medicine being possessed of good qualities is made and just seems very necessary.
The content of the invention
It is an object of the invention to provide solid dispersions of a kind of half tartaric acid Mo Fanselin and pharmaceutic adjuvant and preparation method thereof, obtain half tartaric acid Mo Fanselin of the unformed shape of stability and favorable dispersibility and the solid dispersions of pharmaceutic adjuvant, add half tartaric acid Mo Fanselin dissolution rate, the preparation method is not limited by drying process, also do not limited by solvent species and quantity of solvent, easy to operate, cost is cheap, it is easily achieved, industrialized production can be achieved.
In order to achieve the above object, technical scheme is as follows：
A kind of half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions, the solid dispersions include half tartaric acid Mo Fanselin and pharmaceutic adjuvant, and both weight ratios are 1:0.1~100, wherein, half described tartaric acid Mo Fanselin is unformed shape, in the X-ray powder diffraction spectrum of the solid dispersions, deducts the characteristic peak of the crystal without half tartaric acid Mo Fanselin after the background peaks of pharmaceutic adjuvant.
Further, the pharmaceutic adjuvant is selected from least one of diluent, lubricant, adhesive, disintegrant, surfactant, filmogen, coating material and capsule material.
Preferably, described pharmaceutic adjuvant is selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan, at least one of ion exchange resin and collagen.
The present invention provides a kind of preparation method of half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions, comprises the following steps：
1) half tartaric acid Mo Fanselin and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50~150 DEG C, solution or suspension containing half tartaric acid Mo Fanselin and pharmaceutic adjuvant are formed, wherein, the weight ratio of half tartaric acid Mo Fanselin and solvent is 0.001~100:The weight ratio of 1, half tartaric acid Mo Fanselin and pharmaceutic adjuvant is 1:0.1~100；
2) removing step 1) solvent in obtained solution or suspension, obtain half tartaric acid Mo Fanselin of unformed shape and the solid dispersions of pharmaceutic adjuvant.
Further, the pharmaceutic adjuvant is selected from least one of diluent, lubricant, adhesive, disintegrant, surfactant, filmogen, coating material and capsule material.
Preferably, pharmaceutic adjuvant described in step 1) is selected from HPMC, hydroxypropyl cellulose, PVP, microcrystalline cellulose, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl cellulose phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan, at least one of ion exchange resin and collagen.
Also, the step 1) solvent is selected from least one of alcohols, phenols, ethers, halogenated hydrocarbons, ketone, aldehydes, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water containing less than 12 carbon atoms, the method that step 2) removes solvent includes：Evaporation, vacuum evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.
Present invention also offers a kind of Pharmaceutical composition, the Pharmaceutical composition includes the solid dispersions of the tartaric acid Mo Fanselin containing amorphous state and at least one pharmaceutically acceptable auxiliary material.
Further, the composition described in any of the above is used to prepare treatment parkinsonism medicine.
The half tartaric acid Mo Fanselin of the present invention and the solid dispersions of pharmaceutic adjuvant, radiated using Cu-K α, characteristic peak of the background peaks of pharmaceutic adjuvant without half tartaric acid Mo Fanselin crystalline states is deducted in the X-ray powder diffraction spectrum represented with 2 θ of degree, it is unformed state to show half tartaric acid Mo Fanselin.Half tartaric acid Mo Fanselin crystalline state is typically used in the prior art, has no the report of its unformed shape.Normally due to the orderly and periodic arrangement of amorphous material molecule, reduce the energy of intermolecular interaction, energy is relatively low, and the half tartaric acid Mo Fanselin of the present invention is unformed shape, molecule is in height disordered state, and the surface free energy of material is bigger, molecule in solid matter has higher energy compared with the molecule in crystalline solid material, easily disperse, increase its dissolution rate, improve half tartaric acid Mo Fanselin bioavilability.
After half tartaric acid Mo Fanselin and pharmaceutic adjuvant are well mixed by the present invention, " solid dispersion " method is used, is obstructed drug molecule by the polymer network structure of pharmaceutic adjuvant, suppress the generation of crystallization, make its holding scattered and unformed state.Present invention use is widely used, is cheap, the pharmaceutic adjuvant that dissolubility is good, these pharmaceutic adjuvants mix with half tartaric acid Mo Fanselin, evaporation, spray drying, freeze-drying and the technology such as hot-melt extruded is coordinated to obtain half tartaric acid Mo Fanselin amorphous forms, the stability of the unformed shape of half tartaric acid Mo Fanselin in half tartaric acid Mo Fanselin of increase present invention solid dispersions.
The present invention selects pharmaceutically widely used, cheap auxiliary material, obtain the solid dispersions of half tartaric acid Mo Fanselin and pharmaceutic adjuvant, it is easy to develop pharmaceutical formulation, the preparation method of the present invention is not limited by drying process, also do not limited by solvent species and quantity of solvent, easy to operate, cost is cheap, it is easily achieved, industrialized production can be achieved.
Compared with prior art, the beneficial effects of the invention are as follows：
1) unformed half tartaric acid Mo Fanselin and pharmaceutic adjuvant prepared by the present invention solid dispersions have high dispersion and stability, after solid pharmaceutical preparation is made, the degree of scatter of drug particle can be made more preferable by disintegration, scattered and dissolution rate faster, is advantageous to the absorption of medicine.Therefore, the dissolution rate of unformed state medicine substantially increases, and is more beneficial for absorption of the body to medicine, improves the bioavilability of medicine, allows medicament to preferably play clinical disease treatment effect.
2) preparation method of the solid dispersions of half tartaric acid Mo Fanselin of the unformed state of the present invention and pharmaceutic adjuvant is not limited by drying process, also do not limited by solvent species and quantity of solvent, easy to operate, cost is cheap, it is easily achieved, industrialized production can be achieved.
3) half tartaric acid Mo Fanselin of unformed state prepared by the present invention and the solid dispersions of pharmaceutic adjuvant can keep good physical stability and chemical stability under the conditions of accelerated test (40 ± 2 DEG C, humidity 75% ± 5%).Therefore, the present invention will have broad application prospects.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the unformed half tartaric acid Mo Fanselin and PVP-K30 of the embodiment of the present invention 1 solid dispersions.
Fig. 2 is the X-ray powder diffraction figure of unformed half tartaric acid Mo Fanselin and polyacrylic resin the Eudragit L100 of the embodiment of the present invention 10 solid dispersions.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited by the following examples.
X-ray powder diffraction figure of the present invention gathers on Ultima IV x-ray diffractometers.The method parameter of X-ray powder diffraction of the present invention is as follows：
X-ray powder parameter：Cu-Kα
Kα：1.5418
Voltage：40 kilovolts
Electric current：40 milliamperes
Divergent slit：Automatically
Scan pattern：Continuously
Scanning range：From 2.0 to 60.0 degree
Sampling step length：0.0200 degree
Sweep speed：60 degrees/min
Embodiment 1
(10 grams) of half tartaric acid Mo Fanselin (5 grams) and PVP K30 are added in water (300 milliliters), are heated to 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is dried with JISL mini spray dryers LSD-48, maintain 60 DEG C of inlet temperature, 50 DEG C of outlet temperature, outlet material is collected, obtains white solid, further vacuum drying obtains unformed half tartaric acid Mo Fanselin and PVP-K30 solid dispersions.X-ray powder diffraction figure deducts the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant as shown in figure 1, in the X-ray powder diffraction figure of the solid dispersions.
Embodiment 2
Half tartaric acid Mo Fanselin (1 gram) and HPMC E50 (0.2 gram) are added in water (10 milliliters), are heated to 40 DEG C of stirring dissolved clarifications.Above-mentioned solution is freeze-dried, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and HPMC E50 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 3
Half tartaric acid Mo Fanselin (1 gram) and PEG 8000 (50 grams) are heated to melt, room temperature is quickly cooled under stirring, obtains white solid.Above-mentioned solid is crushed, obtain white powdery solids, i.e. unformed half tartaric acid Mo Fanselin and PEG 8000 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 4
Half tartaric acid Mo Fanselin (1 gram) and PEG20000 (100 grams) are heated to 240 DEG C, is well mixed, is quickly cooled to room temperature, obtains white solid.Above-mentioned solid is crushed, obtain white powdery solids, i.e. unformed half tartaric acid Mo Fanselin and PEG20000 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 5
Half tartaric acid Mo Fanselin (1 gram), isopropanol (20 grams) and liposome (4 grams) mixture are heated to 90 DEG C, stirring, it is well mixed, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, i.e. unformed half tartaric acid Mo Fanselin and liposome solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 6
Half tartaric acid Mo Fanselin (1 gram), methanol (20 grams) and methacrylic acid copolymer A types (4 grams) mixture are heated to 50 DEG C, stirring, dissolved clarification, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, i.e. unformed half tartaric acid Mo Fanselin and the solid dispersions of methacrylic acid copolymer A types, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 7
Half tartaric acid Mo Fanselin (1 gram), isopropanol (20 grams) and ethyl cellulose (2 grams) mixture are heated to 30 DEG C, stirring, it is well mixed, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, i.e. unformed half tartaric acid Mo Fanselin and ethyl cellulose solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant.
Embodiment 8
Half tartaric acid Mo Fanselin (1 gram), methanol (20 grams) and hydroxypropyl cellulose SSL (4 grams) mixture are heated to 30 DEG C, stir dissolved clarification, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, i.e. unformed half tartaric acid Mo Fanselin and hydroxypropyl cellulose SSL solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 9
The mixture of half tartaric acid Mo Fanselin (1 gram), methanol (20 grams), water (10 grams) and polyvinyl acetate (4 grams) is heated to 30 DEG C, stir dissolved clarification, it is evaporated in vacuo and removes solvent, it is cooled to room temperature and obtains white solid, i.e. unformed half tartaric acid Mo Fanselin and polyvinyl acetate solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 10
Half tartaric acid Mo Fanselin (50 milligrams) and polyacrylic resin Eudragit L100 (100 milligrams) are added to methanol (750 microlitres), stir dissolved clarification at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and polyacrylic resin Eudragit L100 solid dispersions, the X-ray powder diffraction figures of the solid dispersions is as shown in Fig. 2 deduct the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant in X-ray powder diffraction figure.
Embodiment 11
Half tartaric acid Mo Fanselin (50 milligrams) and polyacrylic resin Eudragit S100 (5 milligrams) are added to methanol (4 milliliters) and ethyl acetate (1 milliliter), dissolved clarification is stirred at -30 DEG C.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, i.e. unformed half tartaric acid Mo Fanselin and polyacrylic resin Eudragit S100 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 12
Half tartaric acid Mo Fanselin (50 milligrams) and carbopol Carbomer 940 (50 milligrams) are added to methanol (4 milliliters) and tetrahydrofuran (1 milliliter), are uniformly mixed at -30 DEG C.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, i.e. unformed half tartaric acid Mo Fanselin and carbopol Carbomer 940 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 13
Half tartaric acid Mo Fanselin (50 milligrams) and pregelatinized starch Pharma-Gel (100 milligrams) are added to methanol (4 milliliters) and water (1 milliliter), are well mixed at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, i.e. unformed half tartaric acid Mo Fanselin and Pharma-Gel pregelatinized starch solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 14
Half tartaric acid Mo Fanselin (50 milligrams) and high side chain crosslinked starch (50 milligrams) are added to methanol (4 milliliters) and water (1 milliliter), dissolved clarification is stirred at room temperature, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, stirring is lower to separate out white solid, i.e. unformed half tartaric acid Mo Fanselin and high side chain crosslinked starch solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 15
Half tartaric acid Mo Fanselin (50 milligrams) and sodium carboxymethylcellulose SCMC (500 milligrams) are added to dimethyl sulfoxide (DMSO) (5 milliliters), stir dissolved clarification at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and sodium carboxymethylcellulose SCMC solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 16
Half tartaric acid Mo Fanselin (50 milligrams) and chitosan (500 milligrams) are added to ethanol (5 milliliters), dissolved clarification is stirred at room temperature, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and chitosan solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 17
Half tartaric acid Mo Fanselin (50 milligrams) and sodium carboxymethyl starch Explotab (500 milligrams) are added to ethanol (5 milliliters), it is uniformly mixed at room temperature, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and sodium carboxymethyl starch Explotab solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 18
Half tartaric acid Mo Fanselin (50 milligrams) and alginates E401 (500 milligrams) are added to ethanol (5 milliliters), are uniformly mixed at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and alginates E401 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 19
Half tartaric acid Mo Fanselin (50 milligrams) and carboxymethyl cellulose phthalic acid ester Agucoat CPD (5 grams) are suspended in methanol (30 milliliters), 50 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, filtering, dry, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and carboxymethyl cellulose phthalic acid ester Agucoat CPD solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 20
Half tartaric acid Mo Fanselin (50 milligrams) and carragheen E407 (500 milligrams) are suspended in methanol (30 milliliters), 50 DEG C are heated to be uniformly mixed, by above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, filtering, dry, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and carragheen E407 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 21
Half tartaric acid Mo Fanselin (50 milligrams) and chitosan (5 grams) are suspended in methanol (50 milliliters), 50 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, filtering, dry, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and chitosan solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 22
Half tartaric acid Mo Fanselin (30 milligrams) and polyacrylic resin Eudragit E100 (30 milligrams) are dissolved in isopropanol (600 microlitres) and N, in dinethylformamide (600 microlitres), it is heated to 50 DEG C of stirring dissolved clarifications, above-mentioned solution is cooled to 10 DEG C, separate out white solid, filtering, dry, obtain unformed half tartaric acid Mo Fanselin and polyacrylic resin Eudragit E100 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of deduction pharmaceutic adjuvant.
Embodiment 23
Half tartaric acid Mo Fanselin (30 milligrams) and collagen Peptan (300 milligrams) are dissolved in isopropanol (600 microlitres) and acetonitrile (600 microlitres), are heated to 50 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 10 DEG C, separate out white solid, filtering, dry, obtain unformed half tartaric acid Mo Fanselin and collagen Peptan solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 24
Half tartaric acid Mo Fanselin (30 milligrams) and gummy Galactosol (300 milligrams) are dissolved in isopropanol (600 microlitres) and methanol (600 microlitres), are heated to 50 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 10 DEG C, separate out white solid, filtering, dry, obtain unformed half tartaric acid Mo Fanselin and gummy Galactosol solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 25
Half tartaric acid Mo Fanselin (30 milligrams) and hydroxypropyl methylcellulose phthalate HPMCP (30 milligrams) are added to ethanol (750 microlitres) and water (750 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and hydroxypropyl methylcellulose phthalate HPMCP solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 26
Half tartaric acid Mo Fanselin (30 milligrams) and ion exchange resin Amberlite IRA-400 (300 milligrams) are added to ethanol (750 microlitres) and water (750 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain brown solid, i.e. unformed half tartaric acid Mo Fanselin and ion exchange resin Amberlite IRA-400 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 27
Half tartaric acid Mo Fanselin (30 milligrams) and caprolactone (300 milligrams) are added to ethanol (750 microlitres) and water (750 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain brown solid, i.e. unformed half tartaric acid Mo Fanselin and caprolactone solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 28
Half tartaric acid Mo Fanselin (30 milligrams) and dextrin Maltrin M100 (300 milligrams) are added to ethanol (750 microlitres) and water (750 microlitres), 80 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain brown solid, i.e. unformed half tartaric acid Mo Fanselin and dextrin Maltrin M100 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 29
Half tartaric acid Mo Fanselin (30 milligrams) and sodium carboxymethylcellulose SCMS (3 milligrams) are added to water (30 milliliters), 100 DEG C is heated to and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and sodium carboxymethylcellulose SCMC solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 30
Half tartaric acid Mo Fanselin (30 milligrams) and beta-schardinger dextrin (30 milligrams) are added to methanol (300 microlitres) and water (300 microlitres), stir dissolved clarification at room temperature.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and beta-schardinger dextrin solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 31
Half tartaric acid Mo Fanselin (30 milligrams) and sodium carboxymethylcellulose SCMC (30 milligrams) are added to methanol (300 microlitres) and water (60 microlitres), are uniformly mixed at 60 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and sodium carboxymethylcellulose SCMC solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 32
Half tartaric acid Mo Fanselin (5 milligrams) and PEO Polyox WSR301 (60 milligrams) are added to methanol (300 microlitres) and water (60 microlitres), are uniformly mixed at 60 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and PEO Polyox WSR301 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 33
Half tartaric acid Mo Fanselin (30 milligrams) and polyvinyl alcohol EG-40 (60 milligrams) are added to methanol (300 microlitres) and water (60 microlitres), dissolved clarification is stirred at 60 DEG C, by above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and polyvinyl alcohol EG-40 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 34
Half tartaric acid Mo Fanselin (50 milligrams) and HPMC acetate succinate Agoat MG (2 grams) are added to ethanol (10 milliliters) and water (2 milliliters), it is uniformly mixed at 80 DEG C, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and HPMC acetate succinate Agoat MG solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of deduction pharmaceutic adjuvant.
Embodiment 35
Half tartaric acid Mo Fanselin (50 milligrams) and carboxymethylethylcellulose (2 grams) are added to ethanol (10 milliliters) and water (1 milliliter), it is uniformly mixed at 80 DEG C, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e. unformed half tartaric acid Mo Fanselin and carboxymethylethylcellulose solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, the characteristic peak without half tartaric acid Mo Fanselin crystal formations after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 36：Unformed half tartaric acid Mo Fanselin and PVP K30 solid dispersions influence factor are tested
Material：The unformed half tartaric acid Mo Fanselin of the gained of embodiment 1 and PVP K30 solid dispersions
Table 1：
Table 1 illustrates：Unformed half tartaric acid Mo Fanselin under high temperature, super-humid conditions, is placed 10 days with PVP K30 solid dispersions, and relevant material separates out without significantly changing without half tartaric acid Mo Fanselin crystallizations.
Embodiment 37：Unformed half tartaric acid Mo Fanselin and PVP K30 solid dispersions influence factor are tested
Material：The unformed half tartaric acid Mo Fanselin of the gained of embodiment 1 and PVP K30 solid dispersions
Experiment condition：40 DEG C ± 2 DEG C of temperature, humidity 75% ± 5%
Table 2：
Table 2 illustrates：Unformed half tartaric acid Mo Fanselin under the conditions of accelerated test, is placed 6 months with PVP K30 solid dispersions, and relevant material separates out without significantly changing without half tartaric acid Mo Fanselin crystallizations.
The half tartaric acid Mo Fanselin of the present invention and the unformed solid dispersions of pharmaceutic adjuvant, its dissolution rate substantially increases, it is more beneficial for improving the bioavilability of medicine, allow medicament to preferably play clinical disease treatment effect, the amorphous article is (40 ± 2 DEG C under the conditions of accelerated test, humidity 75% ± 5%), good physical stability and chemical stability can be kept.
Claims (9)
1. a kind of half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions, its feature exist
Half tartaric acid Mo Fanselin and pharmaceutic adjuvant are included in, solid dispersions, two
The weight ratio of person is 1:0.1~100, wherein, half described tartaric acid Mo Fanselin is
Unformed shape, in the X-ray powder diffraction spectrum of the solid dispersions, deduct medicine
With the characteristic peak without half tartaric acid Mo Fanselin crystal after the background peaks of auxiliary material.
2. half tartaric acid Mo Fanselin according to claim 1 and pharmaceutic adjuvant solid
Dispersion, it is characterised in that at least one of described pharmaceutic adjuvant be selected from diluent,
Lubricant, adhesive, disintegrant, surfactant, filmogen, coating material
At least one of with capsule material.
3. half tartaric acid Mo Fanselin according to claim 1 and pharmaceutic adjuvant solid
Dispersion, it is characterised in that at least one of described pharmaceutic adjuvant is selected from hydroxypropyl first
Base cellulose, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose,
Microcrystalline cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxylic first
Base ethyl cellulose, carboxymethyl cellulose phthalic acid ester, HPMC
Phthalic acid ester, HPMC acetate succinate, polyacrylic acid tree
Fat, carbopol, alginates, carragheen, caprolactone, natural gum, poly- second
Enol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polycyclic oxygen
In ethane, chitosan, chitosan, ion exchange resin and collagen at least
It is a kind of.
A kind of 4. preparation side of the solid dispersions of half tartaric acid Mo Fanselin and pharmaceutic adjuvant
Method, comprise the following steps：
1) half tartaric acid Mo Fanselin and pharmaceutic adjuvant are mixed in a solvent, mixing temperature
For -50~150 DEG C, the solution containing half tartaric acid Mo Fanselin and pharmaceutic adjuvant is formed
Or suspension, wherein, the weight ratio of half tartaric acid Mo Fanselin and solvent is
0.001~100:The weight ratio of 1, half tartaric acid Mo Fanselin and pharmaceutic adjuvant is
1:0.1~100；
2) removing step 1) solvent in obtained solution or suspension, obtain unformed shape
Half tartaric acid Mo Fanselin and pharmaceutic adjuvant solid dispersions.
5. half tartaric acid Mo Fanselin according to claim 4 and pharmaceutic adjuvant solid
The preparation method of dispersion, it is characterised in that the pharmaceutic adjuvant be selected from diluent,
Lubricant, adhesive, disintegrant, surfactant, filmogen, coating material
At least one of with capsule material.
6. half tartaric acid Mo Fanselin according to claim 4 and pharmaceutic adjuvant solid
The preparation method of dispersion, it is characterised in that described pharmaceutic adjuvant is selected from hydroxypropyl first
Base cellulose, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose,
Liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose,
Carboxymethyl cellulose phthalic acid ester, hydroxypropyl methylcellulose phthalate,
HPMC acetate succinate, polyacrylic resin, carbopol,
Alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinated form sediment
Powder, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, chitosan,
Chitosan and collagen, cyclodextrin, lactose, galactolipin, PEARLITOL 25C, mountain
At least one of pears alcohol, xylitol, urea.
7. a kind of Pharmaceutical composition, it is characterised in that the Pharmaceutical composition contains claim 1
Described solid dispersions and at least one pharmaceutically acceptable auxiliary material.
8. Pharmaceutical composition according to claim 7, it is characterised in that the pharmaceutical compositions
It is fine that at least one of pharmaceutic adjuvant in thing is selected from HPMC, hydroxypropyl
Tie up element, PVP, polyethylene glycol, ethyl cellulose, microcrystalline cellulose, liposome,
Methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl
Cellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl first
Base cellulose acetate succinate, polyacrylic resin, carbopol, alginates,
Carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinking
Starch, sodium carboxymethyl starch, dextrin, PEO, chitosan, chitosan,
Collagen, cyclodextrin, lactose, galactolipin, PEARLITOL 25C, sorbierite, xylose
At least one of alcohol, urea.
9. claim 7-8 it is any as described in composition, for prepare treat parkinsonism medicine
The purposes of thing.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109432016A (en) * | 2018-12-26 | 2019-03-08 | 广州中医药大学(广州中医药研究院) | A kind of tertiary solid preparation and preparation method thereof of the miscellaneous Shandong amine of grace |
| CN111297805A (en) * | 2019-12-19 | 2020-06-19 | 赵洁 | Liposome of pimavanserin and preparation process thereof |
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| CN1816524A (en) * | 2003-01-16 | 2006-08-09 | 阿卡蒂亚药品公司 | Selective serotonin 2A/2C receptor inverse agonists for the treatment of neurodegenerative diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109432016A (en) * | 2018-12-26 | 2019-03-08 | 广州中医药大学(广州中医药研究院) | A kind of tertiary solid preparation and preparation method thereof of the miscellaneous Shandong amine of grace |
| CN109432016B (en) * | 2018-12-26 | 2021-03-02 | 广州中医药大学(广州中医药研究院) | Enzalutamide ternary solid preparation and preparation method thereof |
| CN111297805A (en) * | 2019-12-19 | 2020-06-19 | 赵洁 | Liposome of pimavanserin and preparation process thereof |
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Application publication date: 20171114 |