CN108498470A - A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof - Google Patents
A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN108498470A CN108498470A CN201710103673.3A CN201710103673A CN108498470A CN 108498470 A CN108498470 A CN 108498470A CN 201710103673 A CN201710103673 A CN 201710103673A CN 108498470 A CN108498470 A CN 108498470A
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- CN
- China
- Prior art keywords
- melitracen
- flupentixol
- pharmaceutical composition
- hydrochloride
- stabilizer
- Prior art date
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- 229960002419 flupentixol Drugs 0.000 title claims abstract description 70
- 229960004794 melitracen Drugs 0.000 title claims abstract description 67
- GWWLWDURRGNSRS-UHFFFAOYSA-N melitracen Chemical compound C1=CC=C2C(=CCCN(C)C)C3=CC=CC=C3C(C)(C)C2=C1 GWWLWDURRGNSRS-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- NJMYODHXAKYRHW-DVZOWYKESA-N cis-flupenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 NJMYODHXAKYRHW-DVZOWYKESA-N 0.000 title claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003381 stabilizer Substances 0.000 claims abstract description 14
- 239000000945 filler Substances 0.000 claims abstract description 13
- 239000000853 adhesive Substances 0.000 claims abstract description 11
- 230000001070 adhesive effect Effects 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- 235000020985 whole grains Nutrition 0.000 claims abstract description 10
- 239000007888 film coating Substances 0.000 claims abstract description 5
- 238000009501 film coating Methods 0.000 claims abstract description 5
- 238000007906 compression Methods 0.000 claims abstract description 4
- 230000006835 compression Effects 0.000 claims abstract description 4
- 239000008187 granular material Substances 0.000 claims abstract description 4
- 239000011248 coating agent Substances 0.000 claims description 17
- 238000000576 coating method Methods 0.000 claims description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000000463 material Substances 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 229920003081 Povidone K 30 Polymers 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 7
- 239000008107 starch Substances 0.000 claims description 7
- 235000019698 starch Nutrition 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229960003511 macrogol Drugs 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 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 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- -1 hydroxypropyl methyl Chemical group 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 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 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 238000005461 lubrication Methods 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
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002518 antifoaming agent Substances 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 239000012456 homogeneous solution Substances 0.000 claims description 2
- 239000003605 opacifier Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims 2
- 210000000481 breast Anatomy 0.000 claims 1
- 239000001913 cellulose Substances 0.000 claims 1
- 235000010980 cellulose Nutrition 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 239000004014 plasticizer Substances 0.000 claims 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 claims 1
- 230000001629 suppression Effects 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000470 constituent Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract description 2
- 238000005469 granulation Methods 0.000 abstract 1
- 230000003179 granulation Effects 0.000 abstract 1
- NJMYODHXAKYRHW-BLLMUTORSA-N 2-[4-[(3e)-3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol Chemical compound C1CN(CCO)CCN1CC\C=C/1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2\1 NJMYODHXAKYRHW-BLLMUTORSA-N 0.000 description 51
- 230000000052 comparative effect Effects 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- 238000010348 incorporation Methods 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- 239000004677 Nylon Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229920001778 nylon Polymers 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000006641 stabilisation Effects 0.000 description 3
- 238000011105 stabilization Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 230000003153 cholinolytic effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- GWFCYDIAPRIMLA-UHFFFAOYSA-N 10,10-dimethylanthracen-9-one Chemical compound C1=CC=C2C(C)(C)C3=CC=CC=C3C(=O)C2=C1 GWFCYDIAPRIMLA-UHFFFAOYSA-N 0.000 description 1
- OOAPSVJLHZBWDR-UHFFFAOYSA-N 2-(trifluoromethyl)-9h-thioxanthene Chemical compound C1=CC=C2CC3=CC(C(F)(F)F)=CC=C3SC2=C1 OOAPSVJLHZBWDR-UHFFFAOYSA-N 0.000 description 1
- NEWRXGDGZGIHIS-UHFFFAOYSA-N 2-(trifluoromethyl)thioxanthen-9-one Chemical compound C1=CC=C2C(=O)C3=CC(C(F)(F)F)=CC=C3SC2=C1 NEWRXGDGZGIHIS-UHFFFAOYSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- WPDAVTSOEQEGMS-UHFFFAOYSA-N 9,10-dihydroanthracene Chemical compound C1=CC=C2CC3=CC=CC=C3CC2=C1 WPDAVTSOEQEGMS-UHFFFAOYSA-N 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 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 description 1
- 206010002942 Apathy Diseases 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-UHFFFAOYSA-N 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 206010029333 Neurosis Diseases 0.000 description 1
- 208000035755 Psychosomatic disease Diseases 0.000 description 1
- DAWRNEWHSBIWMT-UHFFFAOYSA-N S1C=NC=C1.N1CCNCC1.[F] Chemical compound S1C=NC=C1.N1CCNCC1.[F] DAWRNEWHSBIWMT-UHFFFAOYSA-N 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 230000004308 accommodation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 229940050842 flupentixol hydrochloride Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 208000015238 neurotic disease Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000005075 thioxanthenes Chemical class 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention designs a kind of pharmaceutical composition and preparation method thereof of antidepressants flupentixol and melitracen.The composition includes Flupenthixol Hydrochloride, melitracen hydrochloride, filler, adhesive, lubricant, and stabilizer is prepared using wet granule compression tablet.Its method includes granulation, dry, and whole grain is always mixed, tabletting, film coating and etc..Technical process efficiently solves two drug content differences big caused dissolution and content homogeneity question, while protecting the stability of active constituent, prepared Flupentixol and Melitracen Tablets stable quality, and safety and effectiveness is good.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of flupentixol and melitracen pharmaceutical composition and its preparation side
A kind of method, and in particular to coated preparation pharmaceutical composition of hydrochloric Flupentixol and melitracen hydrochloride.
Background technology
Flupenthixol Hydrochloride（flupentixol）Belong to thioxanthene class atypical antipsychotic drug, by blocking
Brain-limbic system and midbrain-cortex system dopamine receptor effect, chemistry are entitled：(Z) -4- [3- [2- (trifluoromethyl) -
9H- thioxanthene -9- subunits] propyl] -1- piperazine ethanol dihydrochlorides, structural formula is as follows：
Melitracen hydrochloride（melitracen）Belong to tricyclic（Heterocycle）Class antidepressant, by inhibiting norepinephrine and 5-
The reuptake of hydroxytryptamine increases the concentration of synaptic cleft both mediators and plays antidepressant effect, and chemistry is entitled：3-[10,
10- dimethyl -9 (10H)-anthracene subunit]-N, N- dimethyl propylene amine hydrochlorates.Its structural formula is as follows：
Since there may be the side effects for being outside centrum for Flupenthixol Hydrochloride, and there is melitracen hydrochloride the secondary of cholinolytic to make
With, therefore by the two use in conjunction, it is refreshing that synaptic cleft dopamine, norepinephrine and serotonin etc. on the one hand can be improved
Concentration through mediator generates synergistic effect, enhances its antidepression, antianxiety and firing properties；On the other hand, Flupenthixol Hydrochloride
Melitracen hydrochloride cholinolytic effect can be weakened, melitracen hydrochloride can fight the issuable centrum of Flupenthixol Hydrochloride
Outer system's side effect.So being at present combined both Flupenthixol Hydrochloride, melitracen hydrochloride, reach collaboration, synergy, attenuation
Effect.
Have more documents at present and discloses flupentixol and melitracen compound preparation and preparation method thereof.
Patent application CN200510043966.4, entitled " compound melitracen Flupentixol capsule ", the skill
Art scheme quotes organic solvent in preparation process and carrys out hydrotropy Flupenthixol Hydrochloride, and such dissolution rate is relatively low, and dispersing uniformity
It is poor, certain influence is brought to the drug effect of preparation, and organic impurities may be introduced.
Patent document CN105663062A discloses a kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof.
In the flupentixol and melitracen composition, Flupenthixol Hydrochloride and melitracen hydrochloride are mixed as follows：
Under the air-flow crushing that liquidates, melitracen hydrochloride is equably added in Flupenthixol Hydrochloride in batches and is mixed, then made
Standby particle, defect are that incorporation time is longer, and hybrid parameter is difficult to control.
Patent document CN104288153A discloses a kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof.
Its open method for having used equal increments prepares the pharmaceutical composition, and specifically, the equal increments hybrid mode is as follows：It takes
The melitracen hydrochloride of equivalent is added in recipe quantity Flupenthixol Hydrochloride, is sieved, is stirred, then takes the salt with mixture equivalent
Sour melitracen continues to mix, and continuously adds after mixing and is remixed with the melitracen hydrochloride of mixture equivalent, until will
The melitracen hydrochloride of whole recipe quantities is mixed with Flupenthixol Hydrochloride to be finished.It is long that this method equally exists incorporation time, raw
The uncontrollable problem of hybrid parameter during production.
The above-mentioned normal wet pelletizing press sheet that is all made of in the prior art prepares Flupentixol and Melitracen Tablets agent.Research is aobvious
Show, Flupenthixol Hydrochloride, melitracen hydrochloride are reduced in the wet heat condition stability inferior of wet granule compression tablet technique, degradation impurity
There is increase trend, and then security risks can be increased.The common adverse reactions of fluorine piperazine thiazole melitracen piece are at present：Dizzy,
It trembles, agitation, sleep disturbance, insufficiency of accommodation and gastrointestinal reaction etc., and as the increase of dosage gradually aggravates.Further research card
Real, the generation of above-mentioned adverse reaction has certain correlation with the content of related impurities.
Therefore, how to select suitable excipient and preparation process for the uniformity of raising Flupentixol and melitracen
And stability, the content of related impurities in production process is reduced, becoming currently there are important technological problems to be solved.
Invention content
Defect based on the prior art, the purpose of the present invention is to provide a kind of flupentixol and melitracen drugs of stabilization
Composition, the flupentixol and melitracen coated tablet pharmaceutical composition of especially a kind of stabilization.
Pharmaceutical composition of the present invention uses wet granulation technology, technique reproducibility and has good stability, obtained
Tablet in low specification ingredient Flupenthixol Hydrochloride uniformity of dosage units it is good, active constituent has good stability in tablet, correlative
Matter content is low.
An object of the present invention provides a kind of wet granule compression tablet technique and prepares flupentixol and melitracen medicine group
Close object.The Flupenthixol Hydrochloride of low content is scattered in binder solution by this method, and the U.S. profit of hydrochloric acid for adding premixing is bent
Pungent and filler, stabilizer carry out wet granulation, efficiently solve the problems, such as uniformity of dosage units.The poly- second of stabilizer is added simultaneously
Glycol 6000 is to improve the stability of product.Preparation method simple possible of the present invention, in obtained tablet low specification at
Divide Flupenthixol Hydrochloride uniformity of dosage units good, tablet active constituent has good stability.
The flupentixol and melitracen pharmaceutical composition of the present invention, is mainly made of label and coating material, the label
Including Flupenthixol Hydrochloride, melitracen hydrochloride and pharmaceutically acceptable excipient, above-mentioned excipient include filler, bonding
Agent, lubricant, stabilizer.
As one of preferred embodiment, flupentixol and melitracen pharmaceutical composition of the invention is based on plate core weight
Gauge, including Flupenthixol Hydrochloride 0.2%-0.9%, melitracen hydrochloride 5%-15%, filler 65%-95%, appropriate adhesive, profit
Lubrication prescription 0.1%-0.5%, stabilizer 2%-7%.
As one of preferred embodiment, flupentixol and melitracen pharmaceutical composition of the invention is based on plate core weight
Gauge, including Flupenthixol Hydrochloride 0.4%-0.6%, melitracen hydrochloride 8%-12%, filler 70%-90%, appropriate adhesive, profit
Lubrication prescription 0.2%-0.4%, stabilizer 3-6%.
In above-mentioned flupentixol and melitracen pharmaceutical composition, filler is selected from lactose, starch, microcrystalline cellulose, pre- glue
Change the one or more of starch；It is one or more in wherein preferred newborn sugar and starch.
In above-mentioned flupentixol and melitracen pharmaceutical composition, adhesive is selected from PVP K30, one kind or more in ethyl alcohol
Kind, preferably PVP K30.
In above-mentioned flupentixol and melitracen pharmaceutical composition, lubricant is selected from silica, talcum powder, in magnesium stearate
One or more, preferred magnesium stearate.
In above-mentioned flupentixol and melitracen pharmaceutical composition, stabilizer is selected from Macrogol 6000, Macrogol 4000
One or more, preferred Macrogol 6000.
As one of specific embodiments of the present invention, selected coating material accounts for plain piece label 2%-6%, preferably 3%-5%.It is wrapped
Clothing material is selected from Opadry II, and Opadry 200 is one or more in hydroxypropyl grade methylcellulose, preferably Opadry II.
It is further preferred that the Opadry II is mixture, including optional film forming agent, antiplastering aid, plasticising
Agent, thickener, colorant, antifoaming agent and opacifier.
An object of the present invention provides a kind of method preparing above-mentioned flupentixol and melitracen pharmaceutical composition,
Include the following steps：(1) dispensing；(2) it pelletizes；(3) dry；(4) whole grain is always mixed；(5) tabletting；(6) film coating.
Specifically, preparation method of the present invention, includes the following steps：
(1) dispensing：The Flupenthixol Hydrochloride and melitracen hydrochloride for taking recipe quantity, sieve with 100 mesh sieve, spare；
(2) it pelletizes：The U.S. profit of hydrochloric acid is bent, and filler, stabilizer is mixed, and mixture 1 is obtained；Adhesive is dissolved in solvent to be made
Binder solution, then Flupenthixol Hydrochloride is added thereto and forms homogeneous solution, obtain mixture 2；Mixture is added in mixture 2
1 prepares wet granular；
(3) dry：By step（2）Wet granular obtained is by being dried to obtain dry particl；
(4) whole grain is always mixed：By step（3）Dry particl obtained uses conventional method whole grain, then into the dry particl after arrangement
Lubricant is added and disintegrant carries out total mix and obtains mixture 3；
(5) tabletting：By step（4）Mixing 3 is obtained by routine techniques tabletting；
(6) film coating：Recipe quantity coating material is scattered in water, certain density coating solution is made, by step（5）Obtain piece
Core is placed in coating pan, spray coating solution be coated to get.
As specific embodiment, step（1）In incorporation time be generally 3-15 minutes, preferably 3-8 minutes, mixing
Machine rotating speed is low speed.
Step（2）The addition time of middle adhesive is to be added in 1-3 minutes, preferably 2 minutes.Incorporation time is generally 5-15
Minute, preferably 5-10 minutes, mixing machine rotating speed was low speed.Using 20 mesh nylon screens, wet is made by oscillating granulator
Grain.
Step（3）In drying use fluidized drying method, setting inlet air temperature be 60-100 DEG C, preferably 70~80 DEG C,
Time is about 10~20min.
Step（4）In whole grain process using 20 mesh nylon wires through granulator whole grain；Journey is always sneaked out, incorporation time is generally
10-30 minutes, preferably 15-25 minutes, it was 5rpm that mixing machine, which adjusts rotating cylinder rotating speed,.
Step（5）By step（4）It obtains mixture and passes through routine techniques tabletting；
In addition, further by step（6）Obtained coating tablet carries out aluminum-plastic packaged.
An object of the present invention, provide above-mentioned flupentixol and melitracen pharmaceutical composition prepare treatment it is light, in
Degree depression and anxiety.Neurasthenia, psychogenic depression, depressed sexual neurosis, masked depression, psychosomatic disease with anxiety and
It is apathy, involutional depression, be addicted to drink and the drug of the diseases such as the lather of drug-addict and depression in purposes.
Specific implementation mode
The following examples are further illustrations of the invention, it but never limits the scope of the present invention.Referring to
Embodiment is further elaborated on the present invention, it should be appreciated to those skilled in the art that the present invention is not limited to these implementations
Example and the preparation method used.Moreover, those skilled in the art's description according to the present invention can be equal to the present invention
It replaces, combination, improve or modify, but these are intended to be included in the scope of the present invention.
Embodiment 1
Prescription：Specification is：Flupenthixol Hydrochloride（In terms of Flupentixol）0.2mg；Melitracen hydrochloride（In terms of melitracen）5mg
（10000 batches）
Preparation method is：
(1) dispensing：The Flupenthixol Hydrochloride and melitracen hydrochloride for taking recipe quantity, sieve with 100 mesh sieve, spare；
(2) it pelletizes：Melitracen hydrochloride, lactose, starch, the Macrogol 6000 weighed puts into efficient wet mixer-granulator
In, stirring at low speed mixes about 5min, obtains mixture 1；PVP K30 is taken, is added in medicinal alcohol, stirring and dissolving is configured to 3%
PVP K30 solution；Flupenthixol Hydrochloride is weighed, is added in prepared binder solution, obtains mixture 2；By mixture 2
Softwood processed in the mixture 1 of efficient wet mixer-granulator is at the uniform velocity added；20 mesh nylon screens are crossed, oscillating granulator is made wet
Particle；
(3) dry：By step（2）Wet granular obtained pours into HighefficientFluidbeddrier, and setting inlet air temperature is 70 DEG C, in outlet air
When temperature is up to 45 DEG C, heat source is closed, continues air blast to cool down material, obtains dry particl；
(4) whole grain is always mixed：By step（3）Dry particl obtained is through 20 mesh nylon screen whole grains of granulator, then to after arrangement
Dry particl in lubricant and disintegrant is added carries out always mixing in mixing machine and obtain mixture 3；
(5) tabletting：By step（4）Mixing 3 is obtained by routine techniques tabletting；
(6) film coating：Recipe quantity coating material is dissolved in water, coating solution is made, by step（5）It obtains label and is placed in coating pan
In, spray coating solution be coated to get.
Embodiment 2
Prescription：Specification is：Flupenthixol Hydrochloride（In terms of Flupentixol）0.9mg；Melitracen hydrochloride（In terms of melitracen）
15mg（10000）
It is made using preparation method same as Example 1.
Comparative example 1：
It is prepared into flupentixol and melitracen coating tablet according to the embodiment 5 of CN103877088A；
Comparative example 2：
The tablet of 4 flupentixol and melitracens is prepared according to the embodiment of CN104177330A, then just uses the coating of embodiment 1
Liquid is coated.
1 Content uniformity test of test example
High performance liquid chromatography, chromatographic column：Cyanoalkysilane bonded silica gel；Phosphate buffer pH5.5- methanol-acetonitriles（30:60:
10）For mobile phase, Detection wavelength 230nm.
Test result
Conclusion (of pressure testing) this patent embodiment 1,2 uniformity of dosage units of embodiment are better than comparative example 1, comparative example 2.
2 dissolution test of test example
Dissolution determination method：Paddle method, dissolution medium：Hydrochloric acid solution（1→2000）, rotating speed is 50 turns per minute.
Detection method：High performance liquid chromatography, chromatographic column：Cyanoalkysilane bonded silica gel；Phosphate buffer pH 5.5- first
Alcohol-acetonitrile（30:60:10）For mobile phase, Detection wavelength 230nm,
Conclusion (of pressure testing) this patent embodiment 1,2 dissolution determination value of embodiment and comparative example 1, comparative example 2 are suitable.
3 Related substances separation of test example
High effective liquid chromatography for detecting（1）Chromatographic column：Cyanoalkysilane bonded silica gel；Phosphate buffer pH 5.5- first
Alcohol-acetonitrile（30:60:10）For mobile phase, Detection wavelength 230nm.For the detection in relation to material impurities A, B.
Detection method（2）Chromatographic column：Octadecylsilane chemically bonded silica；Phosphate buffer pH3.0- mixed solvents（It takes
Methanol, acetonitrile and the isometric mixing of tetrahydrofuran）（35：65）For mobile phase；Detection wavelength is 254nm.It is miscellaneous for related substance
The detection of matter C, D, E,
Note detection method 1：Impurity A:Maximum single impurity；Impurity B:Total impurities；
Detection method 2：Impurity C:10,10- dimethyl anthrone peaks；Impurity D:2-(Trifluoromethyl)thioxanthen-9-one；Impurity E:Other are each
The sum of impurity peak area.
Conclusion (of pressure testing) this patent embodiment 1,2 related substance of embodiment illustrate this patent less than comparative example 1, comparative example 2
Preparation method is conducive to the stabilization of principal component.
4 assay of test example
High effective liquid chromatography for detecting chromatographic column：Cyanoalkysilane bonded silica gel；Phosphate buffer pH 5.5- methanol-
Acetonitrile（30:60:10）For mobile phase, Detection wavelength 230nm,
Conclusion (of pressure testing) this patent embodiment 1,2 assay value of embodiment are slightly above comparative example 1, comparative example 2, this patent method
The assay value for preparing sample is essentially 100%；Flupentixol and melitracen content are one high and one low in comparative example 1, not at line
Property increase and reduce, and sample Flupentixol made from this patent method increases simultaneously with melitracen content value, illustrates to use
Two main composition homogeneity prepared by this method are good.
Claims (10)
1. a kind of flupentixol and melitracen pharmaceutical composition, is mainly made of label and coating material, is characterized in that, described
Core includes Flupenthixol Hydrochloride, melitracen hydrochloride and pharmaceutically acceptable excipient.
2. flupentixol and melitracen pharmaceutical composition according to claim 1, which is characterized in that excipient includes filling
Agent, adhesive, lubricant, stabilizer.
3. the flupentixol and melitracen pharmaceutical composition according to claim 1-2, which is characterized in that wherein filler selects
From lactose, starch, microcrystalline cellulose, pregelatinized starch it is one or more；Adhesive is selected from PVP K30, and one in ethyl alcohol
Kind is a variety of；Lubricant is selected from silica, and talcum powder is one or more in magnesium stearate, and stabilizer is selected from polyethylene glycol
6000, Macrogol 4000 it is one or more.
4. according to the flupentixol and melitracen pharmaceutical composition described in claim 3, it is characterised in that：Filler is selected from breast
Sugar, starch, microcrystalline cellulose, pregelatinized starch it is one or more；It is one or more in wherein preferred newborn sugar and starch；It is viscous
Mixture is selected from PVP K30, one or more in ethyl alcohol, preferably PVP K30；Lubricant be selected from silica, talcum powder,
It is one or more in magnesium stearate, preferred magnesium stearate；Stabilizer is selected from Macrogol 6000, one kind of Macrogol 4000
Or a variety of, preferred Macrogol 6000.
5. the flupentixol and melitracen pharmaceutical composition according to claim 1-3, it is characterised in that：Based on plate core weight
Gauge, including Flupenthixol Hydrochloride 0.2%-0.9%, melitracen hydrochloride 5%-15%, filler 65%-95%, appropriate adhesive, profit
Lubrication prescription 0.1%-0.5%, stabilizer 2%-7%.
6. according to the flupentixol and melitracen pharmaceutical composition described in claim 5, it is characterised in that：Based on label weight
Meter, including Flupenthixol Hydrochloride 0.4%-0.6%, melitracen hydrochloride 8%-12%, filler 70%-90%, appropriate adhesive, lubrication
Agent 0.2%-0.4%, stabilizer 3%-6%.
7. a kind of preparation method of flupentixol and melitracen pharmaceutical composition as claimed in any one of claims 1-3,
It is characterized in that using wet granule compression tablet method, include the following steps：
(1) dispensing：The Flupenthixol Hydrochloride and melitracen hydrochloride for taking recipe quantity, sieve with 100 mesh sieve, spare；
(2) it pelletizes：The U.S. profit of hydrochloric acid is bent, and filler, stabilizer is mixed, and mixture 1 is obtained；Adhesive is dissolved in solvent to be made
Binder solution, then Flupenthixol Hydrochloride is added thereto and is mixed to form homogeneous solution, obtain mixture 2；Mixture 2 is added mixed
It closes object 1 and prepares wet granular；
(3) dry：By step（2）Wet granular obtained is by being dried to obtain dry particl；
(4) whole grain is always mixed：By step（3）Dry particl obtained uses conventional method whole grain, then into the dry particl after arrangement
Lubricant is added and disintegrant carries out total mix and obtains mixture 3；
(5) tabletting：By step（4）Mixing 3 is obtained by routine techniques tabletting；
(6) film coating：Recipe quantity coating material is dissolved in water, certain density coating solution is made, by step（5）Obtain label
Be placed in coating pan, spray coating solution be coated to get.
8. the preparation method of flupentixol and melitracen pharmaceutical composition according to claim 7, it is characterised in that：It is selected
Coating material accounts for plain piece label 2%-6%, and preferably 3%-5%, coating material is selected from Opadry II, Opadry 200, hydroxypropyl methyl
It is one or more in cellulose, preferred Opadry II.
9. the preparation method of flupentixol and melitracen pharmaceutical composition according to claim 8, it is characterised in that：It is described
Opadry II, including optional film forming agent, antiplastering aid, plasticizer, thickener, colorant, antifoaming agent and opacifier.
10. the flupentixol and melitracen pharmaceutical composition described in any one of claim 1-2 treats light, moderate suppression in preparation
Purposes in strongly fragrant and anxiety agent.
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| CN201710103673.3A CN108498470A (en) | 2017-02-24 | 2017-02-24 | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof |
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|---|---|---|---|
| CN201710103673.3A CN108498470A (en) | 2017-02-24 | 2017-02-24 | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof |
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| CN109771386A (en) * | 2019-01-10 | 2019-05-21 | 广东赛烽医药科技有限公司 | A kind of Flupentixol and Melitracen Tablets agent and preparation method thereof |
| CN112300119A (en) * | 2019-08-02 | 2021-02-02 | 江苏恩华药业股份有限公司 | Eutectic crystal of melitracen and flupentixol and preparation method thereof |
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| CN109771386B (en) * | 2019-01-10 | 2021-10-08 | 广东赛烽医药科技有限公司 | Flupentixol melitracen tablet and preparation method thereof |
| GB2595140B (en) * | 2019-01-10 | 2023-06-14 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol/melitracen pharmaceutical composition and preparation thereof |
| WO2020143395A1 (en) * | 2019-01-10 | 2020-07-16 | 广东赛烽医药科技有限公司 | Flupentixol melitracen tablet and preparation method therefor |
| WO2020143394A1 (en) * | 2019-01-10 | 2020-07-16 | 广东赛烽医药科技有限公司 | Flupentixol/melitracen pharmaceutical composition and preparation thereof |
| CN109674754B (en) * | 2019-01-10 | 2021-10-08 | 广东赛烽医药科技有限公司 | Flupentixol and melitracen pharmaceutical composition and preparation thereof |
| GB2595141B (en) * | 2019-01-10 | 2023-06-14 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol melitracen tablet and preparation method therefor |
| CN109771386A (en) * | 2019-01-10 | 2019-05-21 | 广东赛烽医药科技有限公司 | A kind of Flupentixol and Melitracen Tablets agent and preparation method thereof |
| GB2595141A (en) * | 2019-01-10 | 2021-11-17 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol melitracen tablet and preparation method therefor |
| CN109674754A (en) * | 2019-01-10 | 2019-04-26 | 广东赛烽医药科技有限公司 | A kind of flupentixol and melitracen pharmaceutical composition and its preparation |
| GB2595140A (en) * | 2019-01-10 | 2021-11-17 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol/melitracen pharmaceutical composition and preparation thereof |
| CN112300119A (en) * | 2019-08-02 | 2021-02-02 | 江苏恩华药业股份有限公司 | Eutectic crystal of melitracen and flupentixol and preparation method thereof |
| CN113677671B (en) * | 2019-08-02 | 2023-01-17 | 苏州恩华生物医药科技有限公司 | Eutectic crystal of melitracen and flupentixol and preparation method thereof |
| CN113677671A (en) * | 2019-08-02 | 2021-11-19 | 苏州恩华生物医药科技有限公司 | Eutectic crystal of melitracen and flupentixol and preparation method thereof |
| WO2021023119A1 (en) * | 2019-08-02 | 2021-02-11 | 江苏恩华药业股份有限公司 | Co-crystal of melitracen and flupentixol and preparation method therefor |
| CN112300119B (en) * | 2019-08-02 | 2024-04-16 | 苏州恩华生物医药科技有限公司 | Metliquxin and flupentixol eutectic and preparation method thereof |
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