CN105663062A - Flupentixol and melitracen medicine composition and preparation method thereof - Google Patents
Flupentixol and melitracen medicine composition and preparation method thereof Download PDFInfo
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- CN105663062A CN105663062A CN201610089571.6A CN201610089571A CN105663062A CN 105663062 A CN105663062 A CN 105663062A CN 201610089571 A CN201610089571 A CN 201610089571A CN 105663062 A CN105663062 A CN 105663062A
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- CN
- China
- Prior art keywords
- flupentixol
- melitracen
- disintegrating agent
- pharmaceutical composition
- tablets
- Prior art date
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- 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 141
- 229960002419 flupentixol Drugs 0.000 title claims abstract description 141
- 229960004794 melitracen Drugs 0.000 title claims abstract description 131
- 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 130
- 239000000203 mixture Substances 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 27
- 239000008187 granular material Substances 0.000 claims description 45
- 239000008194 pharmaceutical composition Substances 0.000 claims description 37
- 239000003795 chemical substances by application Substances 0.000 claims description 34
- 239000011230 binding agent Substances 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 22
- 239000007779 soft material Substances 0.000 claims description 22
- 239000000945 filler Substances 0.000 claims description 16
- 239000000314 lubricant Substances 0.000 claims description 16
- 229920002472 Starch Polymers 0.000 claims description 13
- 239000008107 starch Substances 0.000 claims description 13
- 235000019698 starch Nutrition 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 10
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 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 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 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 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 5
- 239000004703 cross-linked polyethylene Substances 0.000 claims description 5
- 229920003020 cross-linked polyethylene Polymers 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 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
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 22
- 238000010298 pulverizing process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 17
- 230000000052 comparative effect Effects 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000013558 reference substance Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000010413 mother solution 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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 230000003153 cholinolytic effect Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 238000004128 high performance liquid chromatography 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
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical group [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- WPDAVTSOEQEGMS-UHFFFAOYSA-N 9,10-dihydroanthracene Chemical compound C1=CC=C2CC3=CC=CC=C3CC2=C1 WPDAVTSOEQEGMS-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- -1 melitracen compound Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000008014 pharmaceutical binder Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000005075 thioxanthenes Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a flupentixol and melitracen medicine composition, a preparation method thereof and flupentixol and melitracen tablets prepared from the composition. In the flupentixol and melitracen medicine composition, flupentixol and melitracen are mixed according to the method that melitracen is uniformly added into flupentixol in batches to be mixed with flupentixol under counter air jet pulverization. The operation method is simple and low in cost, the uniformity of the flupentixol and melitracen medicine composition can be significantly improved, and the dissolution rate of flupentixol and melitracen is also significantly increased.
Description
Technical field
The invention belongs to technical field of medicine, in particular it relates to a kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof, and the Flupentixol and Melitracen Tablets being made up of described compositions.
Background technology
Flupentixol (flupentixol) belongs to thioxanthene class atypical antipsychotic, work by blocking midbrain-limbic system and midbrain-cortex system dopamine receptor, its chemistry is by name: α-trifluoromethyl-9-{3-[4-(2-ethoxy)-1-diethylene diamidogen]-propane }-thioxanthene, structure is such as shown in formula I:
Melitracen (melitracen) belongs to three rings (heterocycle) class antidepressant drug, by suppressing the reuptake of norepinephrine and 5-hydroxy tryptamine, increase the concentration of synaptic space both mediators and play antidepressant effect, its chemistry is by name: 3-[10,10-dimethyl-9 (10H)-anthracene subunit]-N, N-dimethyl-1-propylamine, structure is such as shown in formula II:
Owing to flupentixol is likely to produce the side effect of extrapyramidal system, and melitracen has cholinolytic side effect, therefore, by flupentixol and melitracen use in conjunction, the concentration of the neurotransmitteies such as synaptic space dopamine, norepinephrine and 5-hydroxy tryptamine can be improved on the one hand, produce synergism, strengthen its antidepressant, anxiety and firing properties; On the other hand, flupentixol can weaken melitracen cholinolytic effect, and melitracen can resist the side effect of the issuable extrapyramidal system of flupentixol. So, flupentixol, the coupling of both melitracens, reach the effect of collaborative, potentiation, attenuation.
Existing many sections of documents disclose flupentixol and melitracen compound preparation and preparation method thereof at present.
CN1732940A discloses a kind of compound recipe melitracen flupentixol capsule and preparation method thereof: U-24973A, diluent, disintegrating agent are fully mixed, and prepares powder; After Flupenthixol Hydrochloride is dissolved with the solvent pharmacologically allowed, uniformly it is added in above-mentioned powder, dry; Dried always mix with binding agent wet granulation, dry, granulate, addition lubricant again, load capsule and get final product; The weight ratio of melitracen and flupentixol is 40～8: 1; The weight ratio of diluent, disintegrating agent and flupentixol is 850～60: 150～5: 1.
The preparation method that CN101125131A discloses a kind of flupentixol and melitracen capsule, it is characterized in that taking ball mill that the flupentixol of recipe quantity/U.S. profit Qu Xin and diluent are carried out the mode of mixed grinding, preparation method includes the steps such as weighing, ball mill ball milling mixing 22-26 hour, River Bank Stability, granulation, dry, total mixed, capsule charge.
CN104288153A discloses a kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof, its method openly employing equal increments prepares this pharmaceutical composition, specifically, described equal increments hybrid mode is as follows: take recipe quantity flupentixol, add the melitracen of equivalent, sieve, stir or move mixing, take the melitracen with mixture equivalent again to continue to mix, continuously add the melitracen with mixture equivalent after mixing to mix, until mixing complete with flupentixol by the melitracen of whole recipe quantities. Although the method improves the stability of product, but the uniformity of the capsule containing flupentixol and melitracen pharmaceutical composition prepared by this equivalent increment method is very low, in prescription, the consumption of flupentixol and melitracen differs greatly, difficulty is brought to the mixing of supplementary material, thus the uniformity of product is very low, have impact on the curative effect of this medicine.
In order to solve the problems referred to above, it is badly in need of developing the preparation method that a kind of cost is low, operational approach simple and can be effectively improved the flupentixol and melitracen pharmaceutical composition uniformity.
Summary of the invention
Present invention aim at the preparation method that a kind of flupentixol and melitracen pharmaceutical composition is provided, the problem mainly solving the uniformity difference of flupentixol and melitracen pharmaceutical composition prepared by the preparation method of existing flupentixol and melitracen pharmaceutical composition.
A first aspect of the present invention, the preparation method that a kind of flupentixol and melitracen pharmaceutical composition is provided, the step that gained compound carries out mixing again is mixed with the filler being optionally present and/or disintegrating agent including flupentixol and melitracen, wherein said flupentixol and melitracen mix as follows: under the comminution by gas stream that liquidates, and are joined in flupentixol in batches equably by melitracen and mix.
Preferably, melitracen is evenly divided into 2-5 batch join in flupentixol and mix.
In order to improve the uniformity of flupentixol and melitracen pharmaceutical composition further, it is preferable that 40-100 mesh sieve crossed before mixing by described flupentixol and melitracen, filler and disintegrating agent, it is preferable that cross 60-100 mesh sieve.
Preferably, flupentixol is 1-3 weight portion, and melitracen is 7-75 weight portion, and filler is 150-300 weight portion, and disintegrating agent is 8-20 weight portion.
Preferably, described flupentixol is 1:10-25 with the amount ratio of described melitracen; More preferably 1:18-25.
In the present invention, the selection of described filler is not particularly limited, it is preferable that described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, magnesium carbonate, mannitol and sorbitol. It addition, to the selection of described disintegrating agent also without special restriction, it is preferable that one or more in carboxymethyl starch sodium, sodium carboxymethyl cellulose, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose of described disintegrating agent.
A second aspect of the present invention, it is provided that a kind of flupentixol and melitracen pharmaceutical composition prepared by said method.
A third aspect of the present invention, it is provided that a kind of Flupentixol and Melitracen Tablets, this Flupentixol and Melitracen Tablets contains above-mentioned flupentixol and melitracen pharmaceutical composition and the following adjuvant being optionally present: binding agent, disintegrating agent or lubricant.
Preferably, calculate by weight, in described Flupentixol and Melitracen Tablets, flupentixol and melitracen pharmaceutical composition 8-78 part, binding agent 1-10 part, disintegrating agent 8-20 part, lubricant 1-10 part.
Described binding agent is preferably selected from one or more in polyvinylpyrrolidone, hydroxypropylcellulose, starch, hypromellose, sodium carboxymethyl cellulose and gelatin;
Described disintegrating agent is preferably selected from one or more in carboxymethyl starch sodium, sodium carboxymethyl cellulose, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose;
Described lubricant is preferably selected from one or more in Pulvis Talci, magnesium stearate, calcium stearate, sodium stearyl fumarate, silicon dioxide and stearic acid.
A fourth aspect of the present invention, it is provided that the preparation method of a kind of above-mentioned Flupentixol and Melitracen Tablets, the method comprises the following steps:
(1) described binding agent is configured to binder solution, then carries out mixing soft material processed with described flupentixol and melitracen pharmaceutical composition;
(2) soft material step (1) obtained adopts 24-18 mesh sieve to granulate, then the dry 0.5-3h when 40-70 DEG C;
(3) dry granule step (2) obtained adopts 20-14 mesh sieve to carry out dry granulate; Then by the dry granule obtained and disintegrating agent and mix lubricant uniformly rear tabletting.
According to the fourth aspect of the invention, in step (1), preparation solvent used by binding agent is preferably selected from least one in water, ethanol, isopropanol; It is further preferred that the weight consumption of described flupentixol and melitracen pharmaceutical composition and binding agent is than for 20:1-5:1.
In step (3), described disintegrating agent is preferably selected from one or more in carboxymethyl starch sodium, sodium carboxymethyl cellulose, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose, and described lubricant is preferably selected from one or more in Pulvis Talci, magnesium stearate, sodium stearyl fumarate, silicon dioxide and stearic acid.
The present inventor finds through deep research, join in flupentixol crude drug with (being preferably divided into 2-5 to criticize) equably in batches by melitracen crude drug, and the mode combining the comminution by gas stream that liquidates mixes, adopt this kind of specific preparation method can obtain the uniformity more tablet, it is ensured that drug effect. And equal increments mode disclosed in patent of invention CN104288153A is mainly a small amount of component raw material and mixes from few order equal increments one by one at most according to prescription weight with a large amount of component raw material and adjuvant, its operating process is complicated, loaded down with trivial details, and compared with the said method of the application, the uniformity of the flupentixol and melitracen pharmaceutical composition preparing gained is relatively low, affects this curative effect of medication.
Accompanying drawing explanation
Fig. 1 is embodiment 1 and the Dissolution profiles figure of melitracen in commercially available Flupentixol and Melitracen Tablets.
Fig. 2 is embodiment 2 and the Dissolution profiles figure of melitracen in commercially available Flupentixol and Melitracen Tablets.
Fig. 3 is embodiment 3 and the Dissolution profiles figure of melitracen in commercially available Flupentixol and Melitracen Tablets.
Fig. 4 is comparative example 3 and the Dissolution profiles figure of melitracen in commercially available Flupentixol and Melitracen Tablets.
Fig. 5 is embodiment 1 and the Dissolution profiles figure of flupentixol in commercially available Flupentixol and Melitracen Tablets.
Fig. 6 is embodiment 2 and the Dissolution profiles figure of flupentixol in commercially available Flupentixol and Melitracen Tablets.
Fig. 7 is embodiment 3 and the Dissolution profiles figure of flupentixol in commercially available Flupentixol and Melitracen Tablets.
Fig. 8 is comparative example 3 and the Dissolution profiles figure of flupentixol in commercially available Flupentixol and Melitracen Tablets.
Detailed description of the invention
The present invention is described in detail by the following examples. It should be appreciated that being merely cited for property of embodiments herein the present invention will be described, be not used to limit the invention.
Embodiment 1
Prescription:
| Title | Consumption |
| Flupenthixol Hydrochloride | 0.1168g |
| U-24973A | 2.25g |
| Lactose | 195.71g |
| Starch | 5.68g |
| Cross-linking sodium carboxymethyl cellulose | 1.48g |
| Hypromellose | 0.1800g |
| Pulvis Talci | 0.3455g |
| Magnesium stearate | 0.1745g |
| Amount to | 205.94g |
Preparation method:
(1) flupentixol and melitracen pharmaceutical composition is prepared in premixing: the flupentixol of recipe quantity and melitracen are crossed 80 mesh sieves, then under the comminution by gas stream that liquidates, the melitracen of recipe quantity is uniformly divided into 5 parts be dividedly in some parts in flupentixol and mix, then the compound obtained is mixed homogeneously with the filler of mistake 80 mesh sieve of recipe quantity, disintegrating agent, obtain flupentixol and melitracen pharmaceutical composition.
(2) soft material processed: the solvent of the binding agent of recipe quantity and 29 weight portions is configured to binder solution, then carries out mixing soft material processed with above-mentioned flupentixol and melitracen pharmaceutical composition;
(3) granulate, dry: the soft material that step (2) obtains is crossed 24 mesh sieves and granulates, dry 1h in baking oven;
(4) granulate: the dry granule that step (3) obtains is crossed 18 mesh sieves and carries out dry granulate;
(5) total mixed, tabletting: dry granule step (4) obtained and disintegrating agent, mix lubricant be rear tabletting uniformly.
Embodiment 2
Prescription:
| Title | Consumption |
| Flupenthixol Hydrochloride | 0.1168g |
| U-24973A | 2.25g |
| Lactose | 115.14g |
| Starch | 25.87g |
| Cross-linking sodium carboxymethyl cellulose | 0.95g |
| Hypromellose | 0.1254g |
| Pulvis Talci | 0.2641g |
| Silicon dioxide | 0.0897g |
| Amount to | 144.81g |
Preparation method:
(1) flupentixol and melitracen pharmaceutical composition is prepared in premixing: the flupentixol of recipe quantity and melitracen are crossed 60 mesh sieves, then under the comminution by gas stream that liquidates, the melitracen of recipe quantity is uniformly divided into 2 parts and is dividedly in some parts in flupentixol, then the compound obtained is mixed homogeneously with the filler of mistake 80 mesh sieve of recipe quantity, disintegrating agent, obtain flupentixol and melitracen pharmaceutical composition.
(2) soft material processed: the solvent of the binding agent of recipe quantity and 36 weight portions is configured to binder solution, then carries out mixing soft material processed with above-mentioned flupentixol and melitracen pharmaceutical composition;
(3) granulate, dry: the soft material that step (2) obtains is crossed 20 mesh sieves and granulates, dry 1h in baking oven;
(4) granulate: the dry granule that step (3) obtains is crossed 18 mesh sieves and carries out dry granulate;
(5) total mixed, tabletting: dry granule step (4) obtained and disintegrating agent, mix lubricant be rear tabletting uniformly.
Embodiment 3
Prescription:
| Title | Consumption |
| Flupenthixol Hydrochloride | 0.2554g |
| U-24973A | 1.7541g |
| Microcrystalline Cellulose | 200g |
| Mannitol | 43.4g |
| Carboxymethyl starch sodium | 0.8669g |
| Polyvinylpyrrolidone | 0.2354g |
| Pulvis Talci | 0.3061g |
| Magnesium stearate | 0.1497g |
| Amount to | 246.97g |
Preparation method:
(1) flupentixol and melitracen pharmaceutical composition is prepared in premixing: in prescription ratio, the flupentixol of recipe quantity and melitracen are crossed 100 mesh sieves, then under the comminution by gas stream that liquidates, the melitracen of recipe quantity is uniformly divided into 3 parts join in batches in flupentixol, then the compound obtained is mixed homogeneously with the filler of mistake 100 mesh sieve of recipe quantity, disintegrating agent, obtain flupentixol and melitracen pharmaceutical composition.
(2) soft material processed: the solvent of the binding agent of recipe quantity and 50 weight portions is configured to binder solution, then carries out mixing soft material processed with above-mentioned flupentixol and melitracen pharmaceutical composition;
(3) granulate, dry: the soft material that step (2) obtains is crossed 24 mesh sieves and granulates, dry 1h in baking oven;
(4) granulate: the dry granule that step (3) obtains is crossed 20 mesh sieves and carries out dry granulate;
(5) total mixed, tabletting: dry granule step (4) obtained and disintegrating agent, mix lubricant be rear tabletting uniformly.
Comparative example 1
Prescription:
Preparation method:
(1) flupentixol and melitracen pharmaceutical composition is prepared in premixing: the flupentixol of recipe quantity and melitracen are crossed 80 mesh sieves, then under the grinding of ball mill, the melitracen of recipe quantity is uniformly divided into 5 parts be dividedly in some parts in flupentixol and mix, then the compound obtained is mixed homogeneously with the filler of mistake 80 mesh sieve of recipe quantity, disintegrating agent, obtain flupentixol and melitracen pharmaceutical composition.
(2) soft material processed: the solvent of the binding agent of recipe quantity and 29 weight portions is configured to binder solution, then carries out mixing soft material processed with above-mentioned flupentixol and melitracen pharmaceutical composition;
(3) granulate, dry: the soft material that step (2) obtains is crossed 24 mesh sieves and granulates, dry 1h in baking oven;
(4) granulate: the dry granule that step (3) obtains is crossed 18 mesh sieves and carries out dry granulate;
(5) total mixed, tabletting: dry granule step (4) obtained and disintegrating agent, mix lubricant be rear tabletting uniformly.
Comparative example 2
Prescription:
Preparation method:
(1) flupentixol and melitracen pharmaceutical composition is prepared in premixing: the flupentixol of recipe quantity and recipe quantity melitracen are crossed 80 mesh sieves, then mix under the comminution by gas stream that liquidates, then the compound obtained is mixed homogeneously with the filler of mistake 80 mesh sieve of recipe quantity, disintegrating agent, obtain flupentixol and melitracen pharmaceutical composition.
(2) soft material processed: the solvent of the binding agent of recipe quantity and 29 weight portions is configured to binder solution, then carries out mixing soft material processed with above-mentioned flupentixol and melitracen pharmaceutical composition;
(3) granulate, dry: the soft material that step (2) obtains is crossed 24 mesh sieves and granulates, dry 1h in baking oven;
(4) granulate: the dry granule that step (3) obtains is crossed 18 mesh sieves and carries out dry granulate;
(5) total mixed, tabletting: dry granule step (4) obtained and disintegrating agent, mix lubricant be rear tabletting uniformly.
Comparative example 3
Prescription:
Preparation method:
(1) flupentixol of recipe quantity and cross-linking sodium carboxymethyl cellulose carry out four equivalent progressively increase mixing, cross 80 mesh sieves, obtain mixture 1.;
(2) 1. mixture carries out with U-24973A secondary equivalent progressively increase and mix, cross 80 mesh sieves, obtain mixture 2.;
(3) 2. mixture carries out with starch secondary equivalent progressively increase and mix, cross 80 mesh sieves, obtain mixture 3.;
(4) 3. mixture carries out with lactose secondary equivalent progressively increase and mix, cross 80 mesh sieves, obtain mixture 4.;
(5) 4. mixture is put into three-dimensional motion mixer with residue lactose, cross 40 mesh sieves, obtain mixture 5.;
(6) 5. soft material processed: the solvent of the binding agent of recipe quantity and 29 weight portions is configured to binder solution, then carry out with mixture mixing soft material processed;
(7) granulate, dry: the soft material that step (6) obtains is crossed 24 mesh sieves and granulates, dry 1h in baking oven;
(8) granulate: the dry granule that step (7) obtains is crossed 18 mesh sieves and carries out dry granulate;
(9) total mixed, tabletting: dry granule step (8) obtained and disintegrating agent, mix lubricant be rear tabletting uniformly.
Test example 1 uniformity of dosage units is tested
Method: each 1 of the tablet of Example 1-3 and comparative example 1 and 2 preparation, put in 25mL measuring bottle respectively, add water appropriate, after jolting makes disintegration of tablet, add methanol and make dissolving in right amount, ultrasonic 40 minutes, with methanol dilution to scale, shake up, filter, measure according to high performance liquid chromatography (Chinese Pharmacopoeia four chromatographys 0512 of version in 2015). It is the filler chromatographic column of equal usefulness (XBridgeTMphenyl, 4.6 × 150mm, 5 μm or) with phenyl silane bonded silica gel; (ammonium formate 2.52g is taken with 0.04mol/L Ammonium formate buffer, add water and make dissolving in right amount, add triethylamine 10mL, mixing, adding water to 1000mL, adjust pH to 7.5 with formic acid)-methanol (20: 80) is mobile phase, column temperature is 35 DEG C, detection wavelength 270nm, flow velocity is 1.0mL/min. Taking U-24973A reference substance, add methanol and dissolve and quantitatively the solution containing about 0.6mg is made in every 1mL in dilution, take 10 μ L, inject chromatograph of liquid, record chromatogram, theoretical cam curve calculates by melitracen peak and is not less than 2000, and tailing factor meets the requirements. Precision measures need testing solution 10 μ L and injects chromatograph of liquid, records chromatogram; Separately take U-24973A reference substance and Flupenthixol Hydrochloride reference substance appropriate, accurately weighed, add methanol and dissolve and dilute the solution made in every 1mL containing about melitracen 0.6mg Yu flupentixol 0.03mg, be measured in the same method, by external standard method with calculated by peak area, to obtain final product.
Table 1 air blending method (embodiment 1,2,3) and equal increments method (comparative example 3) product uniformity effect
Table 2 comparative example 1,2 product uniformity effect
Remarks: S: standard deviation, A: every with labelled amount be 100 relative amount for x, its average is X, A=| 100-X |,
" Chinese Pharmacopoeia " (version in 2015) specifies:
If A+2.2S≤L, then the uniformity of dosage units of test sample meets regulation;
If A+S is > L, then against regulation;
If A+2.2S is > L, and A+S < L, then should separately take 20 retrials of test sample.
In above-mentioned formula, L is setting. Unless otherwise specified, L=15.0.
From the results shown in Table 1, join in flupentixol crude drug while melitracen crude drug (is preferably divided into 2 batches, 3 batches, 5 batches) equably in batches, and the mode combining the comminution by gas stream that liquidates mixes, the uniformity of the Flupentixol and Melitracen Tablets agent obtained is superior to the uniformity of the Flupentixol and Melitracen Tablets agent that the equal increments mixing method described in patent of invention CN104288153A prepares. Under the air-flow that liquidates, melitracen crude drug divides 5 batches of ground join in flupentixol crude drug equably, it is thus achieved that the uniformity effect of Flupentixol and Melitracen Tablets agent have more apparent raising. It addition, ground and mixed method and disposable mixture content uniformity effect are all unable to reach pharmacopoeial requirements.
Test example 2 dissolution is investigated
Method: each 1 of the tablet of Example 1-3 and comparative example 3 preparation, measures according to high performance liquid chromatography (Chinese Pharmacopoeia four chromatographys 0512 of version in 2015). According to dissolution method (Chinese Pharmacopoeia version four general rules 0,931 second method in 2015) with pH1.2 hydrochloric acid solution 900mL for solvent, rotating speed is 50 turns per minute, operates in accordance with the law, takes solution appropriate through 30 minutes time, filter, take subsequent filtrate as need testing solution; It is the filler chromatographic column of equal usefulness (XBridgeTMphenyl, 4.6 × 150mm, 5 μm or) with phenyl silane bonded silica gel; (ammonium formate 2.52g is taken with 0.04mol/L Ammonium formate buffer, add water and make dissolving in right amount, add triethylamine 10mL, mixing, adding water to 1000mL, adjust pH to 7.5 with formic acid)-methanol (20: 80) is mobile phase, column temperature is 35 DEG C, detection wavelength 270nm, flow velocity is 1.0mL/min. Taking U-24973A reference substance, add methanol and dissolve and quantitatively the solution containing about 0.6mg is made in every 1mL in dilution, take 10 μ L, inject chromatograph of liquid, record chromatogram, theoretical cam curve calculates by melitracen peak and is not less than 2000, and tailing factor meets the requirements. Precision measures need testing solution 10 μ L and injects chromatograph of liquid, records chromatogram; Separately take U-24973A (conversion factor of melitracen and U-24973A is 0.8887) reference substance and be about 11.3mg, accurately weighed, put in 25mL volumetric flask, precision measures 5mL, put in 10mL volumetric flask, add methanol dilution to scale, shake up, as U-24973A reference substance mother solution; Take Flupenthixol Hydrochloride (conversion factor of flupentixol and Flupenthixol Hydrochloride is 0.8562) reference substance and be about 11.8mg, accurately weighed, put in 25mL measuring bottle, adding methanol dissolve and be diluted to scale, shake up, precision measures 5mL, put in 200mL volumetric flask, add methanol dilution to scale, shake up, as Flupenthixol Hydrochloride reference substance mother liquor solution; Precision measures U-24973A reference substance mother solution and the Flupenthixol Hydrochloride each 1mL of reference substance mother solution respectively, puts in 20mL volumetric flask, adds dissolution medium to scale, shake up, as reference substance solution.It is measured in the same method, calculates the stripping quantity of every middle flupentixol and melitracen. Limit is the 80% of labelled amount, should meet regulation.
Table 1 embodiment 1 compares with the dissolution of melitracen in commercially available Flupentixol and Melitracen Tablets
Table 2 embodiment 2 compares with the dissolution of melitracen in commercially available Flupentixol and Melitracen Tablets
Table 3 embodiment 3 compares with the dissolution of melitracen in commercially available Flupentixol and Melitracen Tablets
Table 4 comparative example 3 compares with the dissolution of melitracen in commercially available Flupentixol and Melitracen Tablets
| Time min | Sheet 1 | Sheet 2 | Sheet 3 | Sheet 4 | Sheet 5 | Sheet 6 | On average | RSD% | Commercially available product |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 5 | 52.41 | 44.64 | 58.74 | 62.56 | 59.77 | 60.78 | 56.48 | 11.96 | 39.65 |
| 10 | 74.18 | 82.53 | 86.37 | 90.67 | 84.51 | 87.97 | 84.37 | 6.79 | 78.92 |
| 15 | 93.17 | 91.68 | 92.11 | 95.48 | 94.03 | 96.75 | 93.87 | 2.09 | 90.29 |
| 20 | 94.53 | 96.47 | 92.54 | 95.18 | 95.65 | 96.23 | 95.10 | 1.51 | 95.08 |
| 30 | 94.15 | 96.12 | 92.20 | 95.39 | 95.74 | 96.42 | 95.00 | 1.67 | 94.17 |
| 45 | 93.82 | 95.43 | 92.09 | 95.74 | 95.23 | 96.15 | 94.74 | 1.61 | 94.34 |
Table 5 embodiment 1 compares with flupentixol dissolution in commercially available Flupentixol and Melitracen Tablets
Table 6 embodiment 2 compares with flupentixol dissolution in commercially available Flupentixol and Melitracen Tablets
| Time min | Sheet 1 | Sheet 2 | Sheet 3 | Sheet 4 | Sheet 5 | Sheet 6 | On average | RSD% | Commercially available product |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 5 | 80.16 | 76.57 | 84.48 | 78.76 | 83.62 | 67.69 | 78.55 | 7.75 | 38.04 |
| 10 | 96.49 | 99.11 | 95.93 | 96.51 | 101.72 | 89.87 | 96.61 | 4.10 | 69.68 |
| 15 | 97.56 | 98.68 | 96.12 | 95.27 | 101.53 | 98.55 | 97.95 | 2.25 | 85.87 |
| 20 | 97.45 | 98.84 | 95.73 | 96.13 | 101.68 | 98.54 | 98.06 | 2.21 | 94.36 |
| 30 | 97.60 | 98.59 | 95.98 | 96.21 | 101.17 | 98.29 | 97.97 | 1.93 | 96.93 |
| 45 | 97.33 | 98.16 | 96.29 | 95.58 | 101.39 | 98.35 | 97.85 | 2.08 | 97.42 |
Table 7 embodiment 3 compares with flupentixol dissolution in commercially available Flupentixol and Melitracen Tablets
| Time min | Sheet 1 | Sheet 2 | Sheet 3 | Sheet 4 | Sheet 5 | Sheet 6 | On average | RSD% | Commercially available product |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 5 | 76.69 | 73.04 | 83.48 | 86.41 | 70.14 | 82.42 | 78.70 | 8.15 | 38.04 |
| 10 | 95.47 | 96.33 | 93.89 | 99.04 | 102.04 | 97.05 | 97.30 | 2.96 | 69.68 |
| 15 | 95.14 | 96.81 | 94.34 | 99.73 | 101.69 | 97.06 | 97.46 | 2.86 | 85.87 |
| 20 | 95.37 | 96.74 | 94.06 | 99.52 | 101.86 | 96.46 | 97.34 | 2.94 | 94.36 |
| 30 | 95.48 | 96.35 | 94.52 | 99.64 | 101.71 | 96.97 | 97.45 | 2.79 | 96.93 |
| 45 | 95.68 | 96.58 | 94.20 | 99.69 | 101.65 | 96.58 | 97.40 | 2.82 | 97.42 |
Table 8 comparative example 3 compares with flupentixol dissolution in commercially available Flupentixol and Melitracen Tablets
| Time min | Sheet 1 | Sheet 2 | Sheet 3 | Sheet 4 | Sheet 5 | Sheet 6 | On average | RSD% | Commercially available product |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| 5 | 52.14 | 48.69 | 63.91 | 65.48 | 46.36 | 58.41 | 55.83 | 14.31 | 38.04 |
| 10 | 86.00 | 87.05 | 76.47 | 78.15 | 68.69 | 82.24 | 79.77 | 8.58 | 69.68 |
| 15 | 92.45 | 90.38 | 83.59 | 88.85 | 81.39 | 96.79 | 88.91 | 6.40 | 85.87 |
| 20 | 92.73 | 92.41 | 92.45 | 92.46 | 94.01 | 99.40 | 93.91 | 2.94 | 94.36 |
| 30 | 93.15 | 95.29 | 94.63 | 93.15 | 93.76 | 100.69 | 95.11 | 3.01 | 96.93 |
| 45 | 93.40 | 95.10 | 94.16 | 92.66 | 93.51 | 100.46 | 94.88 | 3.01 | 97.42 |
Be can be seen that by the result of table 1-8 and Fig. 1-8, Flupentixol and Melitracen Tablets provided by the invention is compared with the Flupentixol and Melitracen Tablets that comparative example 3 (adopting method described in CN104288153A) obtains, and between the former flupentixol and the dissolution sheet of melitracen, difference is little, dissolution is rapider. Compared with commercially available flupentixol and melitracen sheet, its dissolution is also rapider. To sum up, the inventive method can effectively improve the uniformity of products material medicine and adjuvant, increases the dissolution efficiency of medicine, obtains rapid-action, effective, the reliable Flupentixol and Melitracen Tablets of steady quality.
Claims (10)
1. the preparation method of a flupentixol and melitracen pharmaceutical composition, the step that gained compound carries out mixing again is mixed with the filler being optionally present and/or disintegrating agent including flupentixol and melitracen, it is characterized in that described flupentixol and melitracen mix as follows: under the comminution by gas stream that liquidates, melitracen is joined in flupentixol equably in batches and mixes.
2. method according to claim 1, wherein, divides melitracen 2-5 batch to join in flupentixol equably and mixes.
3. method according to claim 1 and 2, wherein, 40-100 mesh sieve crossed before mixing respectively by described flupentixol, melitracen, filler and disintegrating agent, it is preferable that cross 60-100 mesh sieve.
4. the method according to any one of claim 1-3, wherein, flupentixol is 1-3 weight portion, and melitracen is 7-75 weight portion, and filler is 150-300 weight portion, and disintegrating agent is 8-20 weight portion.
5. the method according to any one of claim 1-4, wherein, the amount ratio of flupentixol and melitracen is 1:10-25, it is preferred to 1:18-25.
6. the method according to any one of claim 1-5, wherein, described filler is selected from one or more in microcrystalline Cellulose, lactose, starch, calcium hydrogen phosphate, calcium sulfate, calcium carbonate, magnesium carbonate, mannitol and sorbitol, and described disintegrating agent is selected from one or more in carboxymethyl starch sodium, sodium carboxymethyl cellulose, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose.
7. the flupentixol and melitracen pharmaceutical composition that method according to any one of a claim 1-6 prepares.
8. a Flupentixol and Melitracen Tablets, it is characterised in that containing the flupentixol and melitracen pharmaceutical composition described in claim 7 and the following adjuvant being optionally present: binding agent, disintegrating agent or lubricant; Preferably, calculate by weight, in described Flupentixol and Melitracen Tablets, flupentixol and melitracen pharmaceutical composition 8-78 part, binding agent 1-10 part, disintegrating agent 8-20 part, lubricant 1-10 part.
9. Flupentixol and Melitracen Tablets according to claim 8, wherein,
Described binding agent is selected from one or more in polyvinylpyrrolidone, hydroxypropylcellulose, starch, hypromellose, sodium carboxymethyl cellulose and gelatin;
Described disintegrating agent is selected from one or more in carboxymethyl starch sodium, sodium carboxymethyl cellulose, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose;
Described lubricant selects one or more in Pulvis Talci, magnesium stearate, calcium stearate, sodium stearyl fumarate, silicon dioxide and stearic acid.
10. the preparation method of the Flupentixol and Melitracen Tablets described in claim 8 or 9, the method comprises the following steps:
(1) described binding agent is configured to binder solution, then carries out mixing soft material processed with described flupentixol and melitracen pharmaceutical composition;
(2) soft material step (1) obtained adopts 24-18 mesh sieve to granulate, then the dry 0.5-3h when 40-70 DEG C;
(3) dry granule step (2) obtained adopts 20-14 mesh sieve to carry out dry granulate; Then by the dry granule obtained and disintegrating agent and mix lubricant uniformly rear tabletting.
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| CN111991397A (en) * | 2020-10-13 | 2020-11-27 | 深圳善康医疗健康产业有限公司 | Flupentixol melitracen microsphere 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 |
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| CN108498470A (en) * | 2017-02-24 | 2018-09-07 | 重庆圣华曦药业股份有限公司 | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof |
| 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 |
| 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 |
| GB2595140A (en) * | 2019-01-10 | 2021-11-17 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol/melitracen pharmaceutical composition and preparation thereof |
| GB2595140B (en) * | 2019-01-10 | 2023-06-14 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol/melitracen pharmaceutical composition and preparation 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 |
| 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 |
| CN111991397A (en) * | 2020-10-13 | 2020-11-27 | 深圳善康医疗健康产业有限公司 | Flupentixol melitracen microsphere and preparation method thereof |
| CN111991397B (en) * | 2020-10-13 | 2021-09-10 | 深圳善康医疗健康产业有限公司 | Flupentixol melitracen microsphere and preparation method thereof |
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