CN105663062B - 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
- Publication number
- CN105663062B CN105663062B CN201610089571.6A CN201610089571A CN105663062B CN 105663062 B CN105663062 B CN 105663062B CN 201610089571 A CN201610089571 A CN 201610089571A CN 105663062 B CN105663062 B CN 105663062B
- Authority
- CN
- China
- Prior art keywords
- flupentixol
- melitracen
- pharmaceutical composition
- parts
- disintegrating agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960004794 melitracen Drugs 0.000 title claims abstract description 136
- 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 135
- 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 130
- 229960002419 flupentixol Drugs 0.000 title claims abstract description 130
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 42
- 239000003795 chemical substances by application Substances 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 22
- 239000011122 softwood Substances 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 20
- 239000000853 adhesive Substances 0.000 claims description 17
- 230000001070 adhesive effect Effects 0.000 claims description 17
- 239000000945 filler Substances 0.000 claims description 17
- 239000000314 lubricant Substances 0.000 claims description 16
- 235000020985 whole grains Nutrition 0.000 claims description 15
- 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
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 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 8
- 239000011230 binding agent Substances 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 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
- 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
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 230000003796 beauty Effects 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 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
- AUZMDLDJTGPIEA-UHFFFAOYSA-N litracen Chemical compound C1=CC=C2C(=CCCNC)C3=CC=CC=C3C(C)(C)C2=C1 AUZMDLDJTGPIEA-UHFFFAOYSA-N 0.000 claims description 5
- 229950008498 litracen Drugs 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 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
- 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
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 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
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 235000009508 confectionery Nutrition 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 24
- 238000011017 operating method Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000013558 reference substance Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- -1 2- ethoxy Chemical group 0.000 description 6
- 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
- 238000000227 grinding Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- MCGSCYPIQDUAQD-UHFFFAOYSA-N C1=CC=CC=2SC3=CC=CC=C3CC12.N1CCNCC1 Chemical compound C1=CC=CC=2SC3=CC=CC=C3CC12.N1CCNCC1 MCGSCYPIQDUAQD-UHFFFAOYSA-N 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 229960001681 croscarmellose sodium Drugs 0.000 description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000012085 test 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
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 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
- 229930195725 Mannitol Natural products 0.000 description 2
- SNIXRMIHFOIVBB-UHFFFAOYSA-N N-Hydroxyl-tryptamine Chemical compound C1=CC=C2C(CCNO)=CNC2=C1 SNIXRMIHFOIVBB-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
- ITTKZVYGKKKWIY-UHFFFAOYSA-N [F].N1CCNCC1 Chemical compound [F].N1CCNCC1 ITTKZVYGKKKWIY-UHFFFAOYSA-N 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 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
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000033001 locomotion Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000005259 measurement 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
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-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
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- BCOMNMYMUMEKIW-UHFFFAOYSA-N N1CCNCC1.S1C=CC=C1.[F] Chemical compound N1CCNCC1.S1C=CC=C1.[F] BCOMNMYMUMEKIW-UHFFFAOYSA-N 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 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
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007865 diluting Methods 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
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 150000005075 thioxanthenes Chemical class 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000002604 ultrasonography Methods 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 present invention provides a kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof, and the Flupentixol and Melitracen Tablets made of the composition.In the flupentixol and melitracen pharmaceutical composition, Flupentixol and melitracen are mixed as follows: under the air-flow crushing that liquidates, melitracen being equably added in Flupentixol in batches and is mixed.Operating method of the invention is simple, at low cost, and can significantly improve the uniformity of flupentixol and melitracen pharmaceutical composition, and Flupentixol and melitracen dissolution rate are remarkably improved.
Description
Technical field
The invention belongs to technical field of medicine, and in particular, to a kind of flupentixol and melitracen pharmaceutical composition
And preparation method thereof, and the Flupentixol and Melitracen Tablets made of the composition.
Background technique
Flupentixol (flupentixol) belongs to thioxanthene class atypical antipsychotic, by blocking midbrain-edge system
System and midbrain-cortex system dopamine receptor work, chemical name are as follows: α-trifluoromethyl -9- { 3- [4- (2- ethoxy) -1-
Diethylene diamines]-propane }-thioxanthene, structure is as shown in formula I:
Melitracen (melitracen) belongs to tricyclic (heterocycle) class antidepressant, by inhibiting norepinephrine and 5-
The reuptake of hydroxytryptamine increases the concentration of both mediators of synaptic cleft and plays antidepressant effect, chemical name are as follows: 3- [10,
10- dimethyl -9 (10H)-anthracene subunit]-N, N- dimethyl -1- propylamine, structure is as shown in formula II:
Since there may be the side effects of extrapyramidal system for Flupentixol, and melitracen has the side effect of cholinolytic, because
On the one hand synaptic cleft dopamine, norepinephrine and 5- can be improved in Flupentixol and melitracen use in conjunction by this
The concentration of the neurotransmitters such as hydroxytryptamine generates synergistic effect, enhances its antidepression, antianxiety and firing properties；On the other hand, fluorine
Piperazine thioxanthene can weaken melitracen cholinolytic effect, and melitracen can fight the issuable extrapyramidal system of Flupentixol
Side effect.So both Flupentixol, melitracen are combined, collaboration, synergy, attenuation are haved the function that.
Have more documents at present and discloses flupentixol and melitracen compound preparation and preparation method thereof.
CN1732940A discloses a kind of compound melitracen Flupentixol capsule and preparation method thereof: by hydrochloric acid U.S. benefit
Qu Xin, diluent, disintegrating agent mix well, and powder is made；After the Flupenthixol Hydrochloride solvent dissolution pharmacologically allowed,
It is uniformly added in above-mentioned powder, it is dry；Again with adhesive wet granulation, drying, whole grain, addition lubricant total mix, dress after drying
Enter capsule to obtain the final product；The weight ratio range of melitracen and Flupentixol is 40~8: 1；Diluent, disintegrating agent and Flupentixol
Weight ratio is 850~60: 150~5: 1.
CN101125131A discloses a kind of preparation method of flupentixol and melitracen capsule, it is characterised in that takes ball
The Flupentixol of recipe quantity/U.S. benefit Qu Xin and diluent are carried out the mode of mixed grinding by grinding machine, and preparation method includes weighing, ball
Grinding machine ball milling mixing 22-26 hours, River Bank Stability, granulation, drying, total mix, capsule charge.
CN104288153A discloses a kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof, open to make
The pharmaceutical composition is prepared with the method for equal increments, specifically, the equal increments hybrid mode is as follows: taking recipe quantity fluorine
Piperazine thioxanthene is added the melitracen of equivalent, sieving, stirring or movement mixing, then takes and continue with the melitracen of mixture equivalent
Mixing, continuously adds after mixing and mixes with the melitracen of mixture equivalent, until by the melitracen of whole recipe quantities
It mixes and finishes with Flupentixol.Although this method improves the stability of product, but equal increments method preparation contains fluorine
The uniformity of the capsule of piperazine thioxanthene melitracen pharmaceutical composition is very low, the dosage phase of Flupentixol and melitracen in prescription
Difference is very big, brings difficulty to the mixing of supplementary material, so that the uniformity of product is very low, affects the curative effect of the drug.
To solve the above-mentioned problems, be badly in need of developing it is a kind of it is at low cost, operating method is simple and can effectively improve fluorine piperazine thiophene
The preparation method of the ton melitracen pharmaceutical composition uniformity.
Summary of the invention
It is an object of that present invention to provide a kind of preparation methods of flupentixol and melitracen pharmaceutical composition, mainly solve existing
There is the uniform of the flupentixol and melitracen pharmaceutical composition of the preparation method preparation of flupentixol and melitracen pharmaceutical composition
Spend the problem of difference.
The first aspect of the present invention provides a kind of preparation method of flupentixol and melitracen pharmaceutical composition, including fluorine
Piperazine thioxanthene and melitracen mix the step of gained mixture is mixed with the filler and/or disintegrating agent being optionally present again,
Wherein the Flupentixol and melitracen are mixed as follows: under the air-flow crushing that liquidates, melitracen is equal
It is added in Flupentixol and is mixed in batches evenly.
Preferably, it melitracen is evenly divided into 2-5 batch is added in Flupentixol and mix.
In order to further increase the uniformity of flupentixol and melitracen pharmaceutical composition, the preferably described Flupentixol and beauty
Litracen, filler and disintegrating agent cross 40-100 mesh before mixing, preferably cross 60-100 mesh.
Preferably, Flupentixol is 1-3 parts by weight, and melitracen is 7-75 parts by weight, and filler is 150-300 weight
Part, disintegrating agent is 8-20 parts by weight.
Preferably, the amount ratio of the Flupentixol and the melitracen is 1:10-25；Further preferably 1:18-
25。
In the present invention, the selection of the filler is not particularly limited, the preferably described filler is selected from crystallite
One of cellulose, lactose, starch, calcium monohydrogen phosphate, calcium sulfate, calcium carbonate, magnesium carbonate, mannitol and sorbierite are a variety of.
In addition, to the selection of the disintegrating agent, also there is no particular limitation, and the preferably described disintegrating agent is selected from sodium carboxymethyl starch, carboxymethyl
One of sodium cellulosate, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose are a variety of.
The second aspect of the present invention provides a kind of flupentixol and melitracen pharmaceutical composition prepared by the above method
Object.
The third aspect of the present invention provides a kind of Flupentixol and Melitracen Tablets, which contains
Above-mentioned flupentixol and melitracen pharmaceutical composition and the following auxiliary material being optionally present: adhesive, disintegrating agent or lubricant.
Preferably, it calculates by weight, in the Flupentixol and Melitracen Tablets, flupentixol and melitracen medicine group
Close object 8-78 parts, 1-10 parts of adhesive, 8-20 parts of disintegrating agent, 1-10 parts of lubricant.
Described adhesive is preferably selected from polyvinylpyrrolidone, hydroxypropylcellulose, starch, hydroxypropyl methylcellulose, carboxymethyl
One of sodium cellulosate and gelatin are a variety of；
The disintegrating agent is preferably selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, crosslinked polyethylene pyrrole network alkanone and hydroxyl
One of third cellulose is a variety of；
The lubricant is preferably selected from talcum powder, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica and hard
One of resin acid is a variety of.
The fourth aspect of the present invention provides a kind of preparation method of above-mentioned Flupentixol and Melitracen Tablets, this method packet
Include following steps:
(1) described adhesive is configured to binder solution, then with the flupentixol and melitracen pharmaceutical composition
Carry out mixing softwood processed；
(2) softwood that step (1) obtains is pelletized using 24-18 mesh, it is then dry under conditions of 40-70 DEG C
0.5-3h；
(3) dry particl that step (2) obtains is subjected to dry whole grain using 20-14 mesh；Then by obtained dry particl with
Disintegrating agent and mix lubricant uniformly rear tabletting.
According to the fourth aspect of the invention, in step (1), prepare adhesive used in solvent be preferably selected from water, ethyl alcohol,
At least one of isopropanol；It is further preferred that the weight of the flupentixol and melitracen pharmaceutical composition and adhesive
Amount ratio is 20:1-5:1.
In step (3), the disintegrating agent is preferably selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, crosslinked polyethylene
One of pyrrole network alkanone and hydroxypropylcellulose are a variety of, and the lubricant is preferably selected from talcum powder, magnesium stearate, stearic rich horse
One of sour sodium, silica and stearic acid are a variety of.
The present inventor has found by in-depth study, and melitracen bulk pharmaceutical chemicals equably (are preferably divided in batches
Be 2-5 crowd) be added in Flupentixol bulk pharmaceutical chemicals, and the mode for the air-flow crushing that liquidates is combined to be mixed, using this kind of spy
Fixed preparation method can obtain the uniformity more tablet, ensure that drug effect.And disclosed in patent of invention CN104288153A
Equal increments mode be mainly a small amount of component raw material and a large amount of component raw materials and auxiliary material according to prescription weight from as little as more sequences by
A equal increments mixing, operating process is complicated, cumbersome, and compared with the above method of the application, prepares resulting fluorine piperazine
The uniformity of thioxanthene melitracen pharmaceutical composition is lower, influences the curative effect of medication.
Detailed description of the invention
Fig. 1 is the Dissolution profiles figure of melitracen in embodiment 1 and commercially available Flupentixol and Melitracen Tablets.
Fig. 2 is the Dissolution profiles figure of melitracen in embodiment 2 and commercially available Flupentixol and Melitracen Tablets.
Fig. 3 is the Dissolution profiles figure of melitracen in embodiment 3 and commercially available Flupentixol and Melitracen Tablets.
Fig. 4 is the Dissolution profiles figure of melitracen in comparative example 3 and commercially available Flupentixol and Melitracen Tablets.
Fig. 5 is the Dissolution profiles figure of Flupentixol in embodiment 1 and commercially available Flupentixol and Melitracen Tablets.
Fig. 6 is the Dissolution profiles figure of Flupentixol in embodiment 2 and commercially available Flupentixol and Melitracen Tablets.
Fig. 7 is the Dissolution profiles figure of Flupentixol in embodiment 3 and commercially available Flupentixol and Melitracen Tablets.
Fig. 8 is the Dissolution profiles figure of Flupentixol in comparative example 3 and commercially available Flupentixol and Melitracen Tablets.
Specific embodiment
The present invention is described in detail by the following examples.It should be understood that embodiments herein is given for example only
The present invention will be described for property, is not used to limit the invention.
Embodiment 1
Prescription:
| Title | Dosage |
| Flupenthixol Hydrochloride | 0.1168g |
| Melitracen hydrochloride | 2.25g |
| Lactose | 195.71g |
| Starch | 5.68g |
| Croscarmellose sodium | 1.48g |
| Hydroxypropyl methylcellulose | 0.1800g |
| Talcum powder | 0.3455g |
| Magnesium stearate | 0.1745g |
| It amounts to | 205.94g |
Preparation method:
(1) premixing prepares flupentixol and melitracen pharmaceutical composition: by the Flupentixol and melitracen of recipe quantity
80 meshes are crossed, then under the air-flow crushing that liquidates, the melitracen of recipe quantity is uniformly divided into 5 parts, Flupentixol is added portionwise
In mixed, obtained mixture is uniformly mixed with filler, the disintegrating agent of 80 mesh of mistake of recipe quantity then, obtains fluorine
Piperazine thioxanthene melitracen pharmaceutical composition.
(2) softwood processed: being configured to binder solution for the solvent of the adhesive of recipe quantity and 29 parts by weight, then with it is above-mentioned
Flupentixol and melitracen pharmaceutical composition carries out mixing softwood processed；
(3) it pelletizes, is dry: the softwood that step (2) obtains is crossed into the granulation of 24 meshes, dry 1h in baking oven；
(4) whole grain: the dry particl that step (3) obtains is crossed into 18 meshes and carries out dry whole grain；
(5) total mix, tabletting: the dry particl and disintegrating agent, mix lubricant that step (4) is obtained uniformly rear tabletting.
Embodiment 2
Prescription:
| Title | Dosage |
| Flupenthixol Hydrochloride | 0.1168g |
| Melitracen hydrochloride | 2.25g |
| Lactose | 115.14g |
| Starch | 25.87g |
| Croscarmellose sodium | 0.95g |
| Hydroxypropyl methylcellulose | 0.1254g |
| Talcum powder | 0.2641g |
| Silica | 0.0897g |
| It amounts to | 144.81g |
Preparation method:
(1) premixing prepares flupentixol and melitracen pharmaceutical composition: by the Flupentixol and melitracen of recipe quantity
60 meshes are crossed, then under the air-flow crushing that liquidates, the melitracen of recipe quantity is uniformly divided into 2 parts, Flupentixol is added portionwise
In, obtained mixture is uniformly mixed with filler, the disintegrating agent of 80 mesh of mistake of recipe quantity then, obtains Flupentixol beauty
Litracen pharmaceutical composition.
(2) softwood processed: being configured to binder solution for the solvent of the adhesive of recipe quantity and 36 parts by weight, then with it is above-mentioned
Flupentixol and melitracen pharmaceutical composition carries out mixing softwood processed；
(3) it pelletizes, is dry: the softwood that step (2) obtains is crossed into the granulation of 20 meshes, dry 1h in baking oven；
(4) whole grain: the dry particl that step (3) obtains is crossed into 18 meshes and carries out dry whole grain；
(5) total mix, tabletting: the dry particl and disintegrating agent, mix lubricant that step (4) is obtained uniformly rear tabletting.
Embodiment 3
Prescription:
| Title | Dosage |
| Flupenthixol Hydrochloride | 0.2554g |
| Melitracen hydrochloride | 1.7541g |
| Microcrystalline cellulose | 200g |
| Mannitol | 43.4g |
| Sodium carboxymethyl starch | 0.8669g |
| Polyvinylpyrrolidone | 0.2354g |
| Talcum powder | 0.3061g |
| Magnesium stearate | 0.1497g |
| It amounts to | 246.97g |
Preparation method:
(1) premixing prepares flupentixol and melitracen pharmaceutical composition: by the Flupentixol and melitracen of recipe quantity
It is sieved with 100 mesh sieve in prescription ratio, then under the air-flow crushing that liquidates, the melitracen of recipe quantity is uniformly divided into 3 parts in batches
It is added in Flupentixol, then mixes obtained mixture with the filler sieved with 100 mesh sieve, the disintegrating agent of recipe quantity
It is even, obtain flupentixol and melitracen pharmaceutical composition.
(2) softwood processed: being configured to binder solution for the solvent of the adhesive of recipe quantity and 50 parts by weight, then with it is above-mentioned
Flupentixol and melitracen pharmaceutical composition carries out mixing softwood processed；
(3) it pelletizes, is dry: the softwood that step (2) obtains is crossed into the granulation of 24 meshes, dry 1h in baking oven；
(4) whole grain: the dry particl that step (3) obtains is crossed into 20 meshes and carries out dry whole grain；
(5) total mix, tabletting: the dry particl and disintegrating agent, mix lubricant that step (4) is obtained uniformly rear tabletting.
Comparative example 1
Prescription:
Preparation method:
(1) premixing prepares flupentixol and melitracen pharmaceutical composition: by the Flupentixol and melitracen of recipe quantity
80 meshes are crossed, then under the grinding of ball mill, the melitracen of recipe quantity is uniformly divided into 5 parts, fluorine piperazine is added portionwise
It is mixed in thioxanthene, obtained mixture is uniformly mixed with filler, the disintegrating agent of 80 mesh of mistake of recipe quantity then, is obtained
To flupentixol and melitracen pharmaceutical composition.
(2) softwood processed: being configured to binder solution for the solvent of the adhesive of recipe quantity and 29 parts by weight, then with it is above-mentioned
Flupentixol and melitracen pharmaceutical composition carries out mixing softwood processed；
(3) it pelletizes, is dry: the softwood that step (2) obtains is crossed into the granulation of 24 meshes, dry 1h in baking oven；
(4) whole grain: the dry particl that step (3) obtains is crossed into 18 meshes and carries out dry whole grain；
(5) total mix, tabletting: the dry particl and disintegrating agent, mix lubricant that step (4) is obtained uniformly rear tabletting.
Comparative example 2
Prescription:
Preparation method:
(1) premixing prepares flupentixol and melitracen pharmaceutical composition: by the Flupentixol of recipe quantity and recipe quantity beauty
Litracen crosses 80 meshes, is then mixed under the air-flow crushing that liquidates, then by the mistake 80 of obtained mixture and recipe quantity
Filler, the disintegrating agent of mesh are uniformly mixed, and obtain flupentixol and melitracen pharmaceutical composition.
(2) softwood processed: being configured to binder solution for the solvent of the adhesive of recipe quantity and 29 parts by weight, then with it is above-mentioned
Flupentixol and melitracen pharmaceutical composition carries out mixing softwood processed；
(3) it pelletizes, is dry: the softwood that step (2) obtains is crossed into the granulation of 24 meshes, dry 1h in baking oven；
(4) whole grain: the dry particl that step (3) obtains is crossed into 18 meshes and carries out dry whole grain；
(5) total mix, tabletting: the dry particl and disintegrating agent, mix lubricant that step (4) is obtained uniformly rear tabletting.
Comparative example 3
Prescription:
Preparation method:
(1) Flupentixol of recipe quantity and croscarmellose sodium are carried out four equivalent to progressively increase mixing, 80 mesh of mistake
1. sieve, obtains mixture；
(2) 1. with the secondary equivalent of melitracen hydrochloride progress and is mixed, crossed 80 meshes, obtain mixture 2.；
(3) 2. with the secondary equivalent of starch progress and is mixed, crossed 80 meshes, obtain mixture 3.；
(4) 3. with the secondary equivalent of lactose progress and is mixed, crossed 80 meshes, obtain mixture 4.；
(5) 4. mixture is put into three-dimensional motion mixer with remaining lactose, crosses 40 meshes, obtains mixture 5.；
(6) softwood processed: being configured to binder solution for the solvent of the adhesive of recipe quantity and 29 parts by weight, then with mix
5. object carries out mixing softwood processed；
(7) it pelletizes, is dry: the softwood that step (6) obtains is crossed into the granulation of 24 meshes, dry 1h in baking oven；
(8) whole grain: the dry particl that step (7) obtains is crossed into 18 meshes and carries out dry whole grain；
(9) total mix, tabletting: the dry particl and disintegrating agent, mix lubricant that step (8) is obtained uniformly rear tabletting.
The test of 1 uniformity of dosage units of test example
Method: prepare each 1, tablet of Example 1-3 and comparative example 1 and 2 sets in 25mL measuring bottle respectively, adds water suitable
Amount adds methanol to make to dissolve in right amount after shaking makes disintegration of tablet, and ultrasound 40 minutes with methanol dilution to scale, shakes up, and filters, and shines
High performance liquid chromatography (four chromatographies 0512 of Chinese Pharmacopoeia version in 2015) measurement.It is filler with phenyl silane bonded silica gel
(chromatographic column of phenyl, 4.6 × 150mm, 5 μm of XBridge TM or same efficiency)；With 0.04mol/L Ammonium formate buffer
(ammonium formate 2.52g is taken, appropriate amount of water is added to make to dissolve, adds triethylamine 10mL, mixes, adds water to 1000mL, extremely with formic acid tune pH
7.5)-methanol (20: 80) is mobile phase, and column temperature is 35 DEG C, Detection wavelength 270nm, flow velocity 1.0mL/min.Take hydrochloric acid U.S. benefit
Bent pungent reference substance adds methanol to dissolve and quantifies the solution for diluting and being made in every 1mL containing about 0.6mg, takes 10 μ L, inject liquid chromatogram
Instrument records chromatogram, and theoretical cam curve is calculated by melitracen peak is not less than 2000, and tailing factor meets the requirements.Precision measures
10 μ L of test solution injects liquid chromatograph, records chromatogram；Separately take melitracen hydrochloride reference substance and Flupenthixol Hydrochloride
Appropriate reference substance, it is accurately weighed, add methanol to dissolve and dilute and is made in every 1mL containing about melitracen 0.6mg and Flupentixol
The solution of 0.03mg, is measured in the same method, by external standard method with calculated by peak area to get.
1 air blending method of table (embodiment 1,2,3) and equal increments method (comparative example 3) product uniformity effect
2 Comparative Examples 1 and 2 product uniformity effect of table
Remarks: S: standard deviation, A: every with relative amount that labelled amount is 100 for x, mean value X, A=| 100-X |,
" Chinese Pharmacopoeia " (version in 2015) regulation:
If A+2.2S≤L, the uniformity of dosage units of test sample meets regulation；
It is against regulation if A+S > L；
If A+2.2S > L, and A+S < L then should separately take 20 retrials of test sample.
L is specified value in above-mentioned formula.Unless otherwise specified, L=15.0.
From the results shown in Table 1, melitracen bulk pharmaceutical chemicals equably (are preferably divided into 2 batches, 3 batches, 5 batches) in batches
Ground is added in Flupentixol bulk pharmaceutical chemicals, and the mode for the air-flow crushing that liquidates is combined to be mixed, Flupentixol beauty obtained
The uniformity of litracen tablet is superior to the fluorine that equal increments mixing method is prepared described in patent of invention CN104288153A
The uniformity of piperazine thioxanthene melitracen tablet.Under the air-flow that liquidates, melitracen bulk pharmaceutical chemicals are added to equably dividing 5 batches
In Flupentixol bulk pharmaceutical chemicals, the uniformity effect of the Flupentixol and Melitracen Tablets agent of acquisition has more apparent raising.In addition, grinding
Mixing method and disposable mixture content uniformity effect are unable to reach pharmacopoeial requirements.
2 dissolution rate of test example is investigated
Method: prepare each 1, tablet of Example 1-3 and comparative example 3, according to high performance liquid chromatography (middle traditional Chinese medicines
Four chromatographies 0512 of allusion quotation version in 2015) measurement.According to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015 0931 second
Method) using 1.2 hydrochloric acid solution 900mL of pH as solvent, revolving speed is 50 turns per minute, is operated according to methods, and takes solution suitable when through 30 minutes
Amount, filtration, takes subsequent filtrate as test solution；With phenyl silane bonded silica gel be filler (XBridge TM phenyl,
4.6 × 150mm, the chromatographic column of 5 μm or same efficiency)；With 0.04mol/L Ammonium formate buffer (ammonium formate 2.52g is taken, water is added
Make to dissolve in right amount, add triethylamine 10mL, mix, add water to 1000mL, is flowing with formic acid tune pH to 7.5)-methanol (20: 80)
Phase, column temperature are 35 DEG C, Detection wavelength 270nm, flow velocity 1.0mL/min.Melitracen hydrochloride reference substance is taken, adds methanol dissolution simultaneously
The solution in every 1mL containing about 0.6mg is made in quantitative dilution, takes 10 μ L, injects liquid chromatograph, records chromatogram, theoretical tray
Number is calculated by melitracen peak is not less than 2000, and tailing factor meets the requirements.Precision measures 10 μ L of test solution and injects liquid phase
Chromatograph records chromatogram；Separately take melitracen hydrochloride (conversion factor of melitracen and melitracen hydrochloride is 0.8887)
Reference substance about 11.3mg, it is accurately weighed, it sets in 25mL volumetric flask, precision measures 5mL, sets in 10mL volumetric flask, adds methanol dilution
It to scale, shakes up, as melitracen hydrochloride reference substance mother liquor；Take Flupenthixol Hydrochloride (Flupentixol and Flupenthixol Hydrochloride
Conversion factor be 0.8562) reference substance about 11.8mg, it is accurately weighed, set in 25mL measuring bottle, add methanol to dissolve and be diluted to quarter
Degree, shakes up, and precision measures 5mL, sets in 200mL volumetric flask, adds methanol dilution to scale, shake up, as Flupenthixol Hydrochloride pair
According to product mother liquor solution；It is accurate respectively to measure melitracen hydrochloride reference substance mother liquor and each 1mL of Flupenthixol Hydrochloride reference substance mother liquor,
It sets in 20mL volumetric flask, solubilization goes out medium to scale, shakes up, as reference substance solution.It is measured in the same method, calculates every middle fluorine
The amount of dissolution of piperazine thioxanthene and melitracen.Limit is the 80% of labelled amount, should meet regulation.
1 embodiment 1 of table is compared with the dissolution rate of melitracen in commercially available Flupentixol and Melitracen Tablets
2 embodiment 2 of table is compared with the dissolution rate of melitracen in commercially available Flupentixol and Melitracen Tablets
3 embodiment 3 of table is compared with the dissolution rate of melitracen in commercially available Flupentixol and Melitracen Tablets
4 comparative example 3 of table is compared with the dissolution rate of melitracen in commercially available Flupentixol and Melitracen Tablets
| Time min | Piece 1 | Piece 2 | Piece 3 | Piece 4 | Piece 5 | Piece 6 | It is 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 |
5 embodiment 1 of table is compared with Flupentixol dissolution rate in commercially available Flupentixol and Melitracen Tablets
6 embodiment 2 of table is compared with Flupentixol dissolution rate in commercially available Flupentixol and Melitracen Tablets
| Time min | Piece 1 | Piece 2 | Piece 3 | Piece 4 | Piece 5 | Piece 6 | It is 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 |
7 embodiment 3 of table is compared with Flupentixol dissolution rate in commercially available Flupentixol and Melitracen Tablets
| Time min | Piece 1 | Piece 2 | Piece 3 | Piece 4 | Piece 5 | Piece 6 | It is 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 |
8 comparative example 3 of table is compared with Flupentixol dissolution rate in commercially available Flupentixol and Melitracen Tablets
| Time min | Piece 1 | Piece 2 | Piece 3 | Piece 4 | Piece 5 | Piece 6 | It is 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 |
Flupentixol and Melitracen Tablets and comparative example provided by the invention it can be seen from the result of table 1-8 and Fig. 1-8
The Flupentixol and Melitracen Tablets that 3 (using CN104288153A the method) obtain are compared, the former Flupentixol and Mei Li
Difference is small between the dissolution rate piece of Qu Xin, it is rapider to dissolve out.Compared with commercially available Flupentixol and melitracen piece, dissolution rate
More rapidly.To sum up, the method for the present invention can effectively improve the uniformity of products material medicine and auxiliary material, increase the dissolution effect of drug
Rate, obtains that rapid-action, effect is good, stable and reliable quality Flupentixol and Melitracen Tablets.
Claims (8)
1. a kind of preparation method of flupentixol and melitracen pharmaceutical composition, including Flupentixol and melitracen mix gained
The step of mixture is mixed with the filler and/or disintegrating agent being optionally present again, it is characterised in that the Flupentixol
It is mixed with melitracen: under the air-flow crushing that liquidates, being added to while melitracen is equably divided to 2-5 batches as follows
It is mixed in Flupentixol；
Wherein Flupentixol, melitracen, filler and the disintegrating agent cross 40-100 mesh respectively before mixing；
Wherein Flupentixol is 1-3 parts by weight, and melitracen is 7-75 parts by weight, and filler is 150-300 parts by weight, disintegrating agent
For 8-20 parts by weight；
Wherein the amount ratio of Flupentixol and melitracen is 1:(10-25)；
Wherein the filler is selected from microcrystalline cellulose, lactose, starch, calcium monohydrogen phosphate, calcium sulfate, calcium carbonate, magnesium carbonate, sweet dew
One of pure and mild sorbierite is a variety of, and the disintegrating agent is selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, crosslinked polyethylene
One of pyrrole network alkanone and hydroxypropylcellulose are a variety of.
2. preparation method according to claim 1, it is characterized in that, it the Flupentixol, melitracen, filler and collapses
It solves agent and crosses 60-100 mesh respectively before mixing.
3. preparation method according to claim 1, it is characterized in that, the amount ratio of the Flupentixol and melitracen is 1:
(18-25)。
4. the flupentixol and melitracen pharmaceutical composition that a kind of method described in claim 1 is prepared.
5. a kind of Flupentixol and Melitracen Tablets, it is characterised in that contain flupentixol and melitracen medicine as claimed in claim 4
Compositions and the following auxiliary material being optionally present: adhesive, disintegrating agent or lubricant.
6. Flupentixol and Melitracen Tablets according to claim 5, it is characterized in that, it calculates by weight, Flupentixol beauty
8-78 parts of litracen pharmaceutical composition, 1-10 parts of adhesive, 8-20 parts of disintegrating agent, 1-10 parts of lubricant.
7. Flupentixol and Melitracen Tablets according to claim 5, wherein
Described adhesive is selected from polyvinylpyrrolidone, hydroxypropylcellulose, starch, hydroxypropyl methylcellulose, sodium carboxymethylcellulose
With one of gelatin or a variety of；
The disintegrating agent is selected from sodium carboxymethyl starch, sodium carboxymethylcellulose, crosslinked polyethylene pyrrole network alkanone and hydroxypropylcellulose
One of or it is a variety of；
The lubricant selects one in talcum powder, magnesium stearate, calcium stearate, sodium stearyl fumarate, silica and stearic acid
Kind is a variety of.
8. the preparation method of any Flupentixol and Melitracen Tablets in claim 5-7, method includes the following steps:
(1) described adhesive is configured to binder solution, is then carried out with the flupentixol and melitracen pharmaceutical composition
Mix softwood processed；
(2) softwood that step (1) obtains is pelletized using 24-18 mesh, then dry 0.5- under conditions of 40-70 DEG C
3h；
(3) dry particl that step (2) obtains is subjected to dry whole grain using 20-14 mesh；Then by obtained dry particl and disintegration
Agent and mix lubricant uniformly rear tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610089571.6A CN105663062B (en) | 2016-02-17 | 2016-02-17 | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610089571.6A CN105663062B (en) | 2016-02-17 | 2016-02-17 | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105663062A CN105663062A (en) | 2016-06-15 |
| CN105663062B true CN105663062B (en) | 2019-01-29 |
Family
ID=56305733
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610089571.6A Active CN105663062B (en) | 2016-02-17 | 2016-02-17 | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105663062B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732940A (en) * | 2005-07-01 | 2006-02-15 | 赵洪光 | Compound flupentixol and melitracen capsule and preparation process thereof |
| CN101125131A (en) * | 2007-09-04 | 2008-02-20 | 上海慈瑞医药科技有限公司 | Method for preparing flupentixol and melitracen capsule |
| EP2374450A1 (en) * | 2010-04-06 | 2011-10-12 | H. Lundbeck A/S | Flupentixol compositions |
| CN104288153A (en) * | 2014-09-19 | 2015-01-21 | 四川海思科制药有限公司 | Flupentixol and melitracen pharmaceutical composition and preparation method thereof |
| CN105267150A (en) * | 2015-09-11 | 2016-01-27 | 江苏嘉逸医药有限公司 | Method for preparing rivaroxaban solid composition |
-
2016
- 2016-02-17 CN CN201610089571.6A patent/CN105663062B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732940A (en) * | 2005-07-01 | 2006-02-15 | 赵洪光 | Compound flupentixol and melitracen capsule and preparation process thereof |
| CN101125131A (en) * | 2007-09-04 | 2008-02-20 | 上海慈瑞医药科技有限公司 | Method for preparing flupentixol and melitracen capsule |
| EP2374450A1 (en) * | 2010-04-06 | 2011-10-12 | H. Lundbeck A/S | Flupentixol compositions |
| CN104288153A (en) * | 2014-09-19 | 2015-01-21 | 四川海思科制药有限公司 | Flupentixol and melitracen pharmaceutical composition and preparation method thereof |
| CN105267150A (en) * | 2015-09-11 | 2016-01-27 | 江苏嘉逸医药有限公司 | Method for preparing rivaroxaban solid composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105663062A (en) | 2016-06-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105125515B (en) | A kind of levo-oxiracetam tablet and preparation method thereof | |
| CN105663062B (en) | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof | |
| CN106667952A (en) | Palbociclib pharmaceutical composition and preparation method thereof | |
| CN101695480A (en) | Olopatadine hydrochloride dispersible tablets, preparation method thereof and quality control method thereof | |
| CN104800175A (en) | Gefitinib tablet preparation method | |
| CN101273973A (en) | Pharmaceutical combination containing Mosapride citrate and method of preparing the same | |
| CN105412026B (en) | Acotiamide hydrochloride hydrate piece and preparation method thereof | |
| CN103919747A (en) | Ambrisentan tablet composition and preparation method thereof | |
| CN104586804A (en) | Preparation method for letrozole tablets with good stability | |
| CN107167401A (en) | Levetiracetam sustained-release tablets pharmaceutical composition and its Quality Control and preparation method | |
| CN106176738A (en) | A kind of Febustat pharmaceutical composition and tablet producing technology thereof | |
| CN108553433A (en) | A kind of Azilsartan piece and preparation method thereof | |
| CN106344531B (en) | A kind of Nifedipine controlled-release tablet composition and preparation method thereof | |
| CN108498470A (en) | A kind of flupentixol and melitracen pharmaceutical composition and preparation method thereof | |
| CN105853386A (en) | Dapagliflozin propanediol hydrate-contained tablet and method of manufacturing the same | |
| CN110420188A (en) | A method of improving Entecavir tablet uniformity of dosage units | |
| CN110037991A (en) | Stable China advanced in years is for Buddhist nun's pharmaceutical composition and preparation method thereof | |
| CN111000812B (en) | Preparation method of lacosamide tablets | |
| CN106265557A (en) | Pharmaceutical composition containing ticagrelor | |
| CN105030717A (en) | Moxifloxacin hydrochloride film-coated tablet and preparation method thereof | |
| CN107496369A (en) | A kind of Citicoline sodium tablets and its direct powder compression preparation method | |
| CN112023056B (en) | Fluconazole pharmaceutical composition and preparation method thereof | |
| CN109953966A (en) | A kind of pharmaceutical composition and preparation method thereof containing Rui Boxini | |
| CN104352465B (en) | Prucalopride succinate pharmaceutical composition free of silicon dioxide and preparation method of prucalopride succinate pharmaceutical composition | |
| CN103463082A (en) | Telmisartan-amlodipine double-layer tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20171208 Address after: 210009, five building, Jiangsu Drug Institute, 26 Ma Jia street, Gulou District, Nanjing, Jiangsu Applicant after: NANJING CHOIPHARM TECHNOLOGY Co.,Ltd. Address before: 210009, Ma Jia street, Gulou District, Jiangsu, 26, Nanjing Applicant before: NANJING ZHUOTAI PHARMACEUTICAL Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A drug combination of flupentixol and melitracin and its preparation method Effective date of registration: 20231212 Granted publication date: 20190129 Pledgee: Nanjing Branch of Jiangsu Bank Co.,Ltd. Pledgor: NANJING CHOIPHARM TECHNOLOGY Co.,Ltd. Registration number: Y2023980069904 |