CN106074415B - A kind of aripirazole tablets and preparation method thereof - Google Patents
A kind of aripirazole tablets and preparation method thereof Download PDFInfo
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- CN106074415B CN106074415B CN201610583953.4A CN201610583953A CN106074415B CN 106074415 B CN106074415 B CN 106074415B CN 201610583953 A CN201610583953 A CN 201610583953A CN 106074415 B CN106074415 B CN 106074415B
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- Prior art keywords
- aripiprazole
- polyethylene glycol
- adhesive
- disintegrant
- silicon dioxide
- Prior art date
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- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title abstract description 23
- 229960004372 aripiprazole Drugs 0.000 claims abstract description 41
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000013078 crystal Substances 0.000 claims abstract description 31
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 26
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 26
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 25
- 239000000945 filler Substances 0.000 claims abstract description 13
- 239000007884 disintegrant Substances 0.000 claims abstract description 12
- 239000000314 lubricant Substances 0.000 claims abstract description 12
- 229920002472 Starch Polymers 0.000 claims abstract description 10
- 239000011734 sodium Substances 0.000 claims abstract description 10
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 10
- 239000008107 starch Substances 0.000 claims abstract description 10
- 235000019698 starch Nutrition 0.000 claims abstract description 10
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 9
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims abstract description 8
- 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 abstract description 7
- 229930195725 Mannitol Natural products 0.000 claims abstract description 7
- 239000000594 mannitol Substances 0.000 claims abstract description 7
- 235000010355 mannitol Nutrition 0.000 claims abstract description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 7
- 229960000913 crospovidone Drugs 0.000 claims abstract description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000008101 lactose Substances 0.000 claims abstract description 4
- 229920002261 Corn starch Polymers 0.000 claims abstract description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 3
- 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 abstract description 3
- 239000008120 corn starch Substances 0.000 claims abstract description 3
- 229940099112 cornstarch Drugs 0.000 claims abstract description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 3
- 229960001855 mannitol Drugs 0.000 claims abstract description 3
- 238000005469 granulation Methods 0.000 claims description 20
- 230000003179 granulation Effects 0.000 claims description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000002075 main ingredient Substances 0.000 claims description 14
- 239000000853 adhesive Substances 0.000 claims description 13
- 230000001070 adhesive effect Effects 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000011122 softwood Substances 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 239000012467 final product Substances 0.000 claims description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 238000005303 weighing Methods 0.000 claims description 9
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 229960003943 hypromellose Drugs 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 229940069328 povidone Drugs 0.000 claims description 4
- -1 hydroxy-propyl Chemical group 0.000 claims description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 2
- 229960003511 macrogol Drugs 0.000 claims description 2
- 239000000835 fiber Substances 0.000 claims 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical group [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 abstract description 14
- 235000019359 magnesium stearate Nutrition 0.000 abstract description 7
- 238000003860 storage Methods 0.000 abstract description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 abstract description 3
- 238000012546 transfer Methods 0.000 abstract description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 abstract description 2
- 239000000470 constituent Substances 0.000 abstract description 2
- 229960001375 lactose Drugs 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 229940032147 starch Drugs 0.000 abstract 1
- 239000000126 substance Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 14
- 239000003814 drug Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 230000008859 change Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000005453 pelletization Methods 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 201000000980 schizophrenia Diseases 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- KVMLCRQYXDYXDX-UHFFFAOYSA-M potassium;chloride;hydrochloride Chemical compound Cl.[Cl-].[K+] KVMLCRQYXDYXDX-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 206010026749 Mania Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910003978 SiClx Inorganic materials 0.000 description 1
- CBWUNQZJGJFJLZ-UHFFFAOYSA-N [Cl].Cl Chemical compound [Cl].Cl CBWUNQZJGJFJLZ-UHFFFAOYSA-N 0.000 description 1
- 229940056213 abilify Drugs 0.000 description 1
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940124604 anti-psychotic medication Drugs 0.000 description 1
- 229940029131 aripiprazole 10 mg Drugs 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method 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
- 230000000694 effects Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 235000020985 whole grains Nutrition 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of aripirazole tablets and preparation method thereof.The aripirazole tablets are by the Aripiprazole of active constituent I crystal, colloidal silicon dioxide, polyethylene glycol, the filler selected from cornstarch, microcrystalline cellulose, mannitol, lactose, disintegrant selected from sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, the lubricant composition selected from magnesium stearate, talcum powder, sodium stearyl fumarate.The aripirazole tablets stability of the present invention improves, and crystal transfer will not occur during preparation process and storage, can improve preparation dissolution rate and bioavilability.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, more particularly to a kind of aripirazole tablets and preparation method thereof.
Background technology
Schizophrenia is a kind of common mental disorder, is estimated according to the World Health Organization, and the whole world is schizoid
Lifetime prevalence is about 3.8%~8.4%.The schizophrenia cause of disease is complicated, and still end illustrates completely.A lot of diseases in person between twenty and fifty,
Many-sided obstacle such as perception, thinking, emotion, act of will is shown as, cerebration and ambient enviroment and inner experience are uncoordinated,
It is divorced from reality.Principle of reatment is early discovery, early treatment, and antipsychotic medications should be used as preferred remedy measures, and control
The important component for the treatment of.
Aripiprazole (Aripiprazole) is a kind of tool developed and released by Japanese great Zhong chemical industry Co., Ltd.
There are the dihydro quinoline ketone atypical antipsychotic agents of completely new mechanism of action, is dopamine system stabilizer.Entitled 7- [the 4- of chemistry
[4- (2,3- dichlorophenyls) -1- piperazinyls]-butoxy] -3,4- dihydro-quinolinones.U.S. FDA and European Union respectively at 2002,
Great Zhong chemical industry Co., Ltd. of approval Japan Aripiprazole piece listing in 2004, trade name " ABILIFY " are used for schizophrenia
The treatment of disease.U.S. FDA ratified it in 2004 and is used to treat acute bipolar mania, including bipolar disorder correlation is hot-tempered
The breaking-out of mad and Combination.
Aripiprazole belongs to insoluble drug, and the dissolution rate of conventional tablet is influenced by raw material crystal form and grain size, preparation
In the raw material of Suitable forms must be micronized, can just reach preferable dissolution, and then improve bioavilability.Aripiprazole
There are many crystal form, for example, WO 2003026659 disclose hydration Aripiprazole A crystal forms, B, C of anhydrous form Aripiprazole, D,
E, the crystal forms such as F, G；WO 2005058835 discloses crystal form I, II, IV, VIII, X, XI, XII, XIV, XIX, XX；EP
2082735 disclose unformed Aripiprazole.The big tomb pharmacy of Yuan Yan companies is using I crystal, powder X-ray diffraction collection of illustrative plates
(sources cuKa, a=1.54056A) has characteristic peak in following values or so：11.1,14.4,16.6,19.5,20.4 and 22.1, it is poor
Show that heating scan about has endothermic peak (heating rate at 140.2 DEG C：10℃/min).
It is well known that the different crystal habits of drug have larger impact to its quality, the dissolving of drug can be especially influenced
Degree and fusing point, it is also possible to influence medicine stability.And crystal form change caused by changes in solubility to normally result in vitro Drug molten
Go out the change with vivo biodistribution availability, especially for the drug that this kind of solubility of Aripiprazole is poor, this change causes
Dissolution and bioavilability variation can be more obvious.Therefore, product produce and store during keep stable crystal form be to
It closes important.
I crystal form of Aripiprazole is metastable-state crystal, and relative to stable type crystal form, I crystal form has higher solubility and life
Object availability, so Yuan Yan producers use crystal form of the I crystal as bulk pharmaceutical chemicals, but I crystal is easy during storage to stabilization
Type crystal transfer.Japanese PMDA is evaluated to be pointed out in file public information, and the unpackaged bare die of Aripiprazole piece of big tomb pharmacy is wet
Under heat condition (such as 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%), dissolution rate can be remarkably decreased.Supposition is and high temperature
The transformation of main ingredient crystal form is related under super-humid conditions.
Invention content
The technical problem to be solved by the present invention is to overcome the defect of the prior art, provide a kind of stabilization, dissolution rate it is high
Aripirazole tablets.
The aripirazole tablets of the present invention are by Aripiprazole, colloidal silicon dioxide and polyethylene glycol, and pharmaceutically may be used
The additive of receiving forms；
Wherein Aripiprazole is Aripiprazole I crystal；Polyethylene glycol is selected from Macrogol 6000, PEG 8000；Glue
The weight ratio of state silica and polyethylene glycol is 1：5~10.The total amount and Aripiprazole of colloidal silicon dioxide and polyethylene glycol
Ratio be 1：0.5~3.
Wherein pharmaceutically acceptable additive is filler, disintegrant, adhesive and lubricant.The filler choosing
From the one or more of cornstarch, microcrystalline cellulose, mannitol, lactose, preferably mannitol；Disintegrant is selected from carboxymethyl starch
Sodium, croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, preferably sodium carboxymethyl starch；Adhesive selects
From hypromellose, hydroxypropyl cellulose, povidone, preferably hydroxypropyl cellulose；Lubricant is selected from magnesium stearate, talcum
Powder, sodium stearyl fumarate, preferably sodium stearyl fumarate.
Wherein active constituent Aripiprazole accounts for the 5~15% of the tablet, colloidal silicon dioxide, polyethylene glycol total amount account for
The 5~10% of the tablet weight.The filler is the 55~80% of the tablet weight, and disintegrant is 2~10%, bonding
Agent is 2~13%, and lubricant is 1~2%.
The present invention also provides the preparation methods of the aripirazole tablets, by the Aripiprazole of recipe quantity, colloidal state dioxy
SiClx, polyethylene glycol after mixing, add filler, disintegrant mixing, then pelletize with the aqueous solution of adhesive；So
It is always mixed with the lubricant of recipe quantity afterwards, tabletting to obtain the final product.
Specifically, the preparation method includes the following steps：Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is standby
With；Weigh the colloidal silicon dioxide of recipe quantity, granulation pot is added with main ingredient and is uniformly mixed together for polyethylene glycol；Add filling
Agent, disintegrant mixing；The aqueous solution softwood of adhesive is added；The sieve granulation of 20 mesh, 65 DEG C of dryings 1 hour, 20 mesh sieves；Claim
Take the lubricant of recipe quantity always to mix, tabletting to obtain the final product.
The aqueous solution of described adhesive its a concentration of 5~13%, preferably 10%.
The present inventor has found that the bulk pharmaceutical chemicals of I crystal have the phenomenon that crystal transfer during storage in R&D process.
Aripiprazole I crystal bulk pharmaceutical chemicals are placed on testing chamber for medicine stability (40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%)
After interior 3 months, its X-ray powder diffraction data is measured, as a result sees Fig. 2, illustrates that there are small parts to turn under the conditions of high temperature and humidity
Brilliant phenomenon.
The present inventor is during optimizing preparation prescription, surprisingly it has been found that the silica of special ratios is added
And polyethylene glycol can there is a phenomenon where dissolution rates to be remarkably decreased under high temperature and humidity condition of storage to avoid Aripiprazole piece.According to
The prescription of the following table 1 prepares Aripiprazole piece.
1 prescription screening of table
| Component | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 |
| Aripiprazole | 10mg | 10mg | 10mg | 10mg | 10mg | 10mg |
| Lactose | 75mg | 75mg | 75mg | 75mg | 75mg | 75mg |
| Sodium carboxymethyl starch | 6mg | 6mg | 6mg | 6mg | 6mg | 6mg |
| Colloidal silicon dioxide | / | 8mg | / | 1mg | 4mg | 7mg |
| PEG 8000 | / | / | 8mg | 7mg | 4mg | 1mg |
| Hydroxypropyl cellulose | 7mg | 7mg | 7mg | 7mg | 7mg | 7mg |
| Magnesium stearate | 2mg | 2mg | 2mg | 2mg | 2mg | 2mg |
Unpackaged original is ground into tablet and is placed in open cillin bottle according to aripirazole tablets made from above-mentioned prescription 1-6
In, be put in testing chamber for medicine stability (40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%) 3 months, measure 60rpm,
The dissolution rate of 30min, as a result as follows in hydrochloric acid-potassium chloride buffer solution：
It is above-mentioned the experimental results showed that：Original grinds tablet, prescription 1, and that 3 months dissolution rates are placed under the conditions of high temperature and humidity is notable
Decline, prescription 2, prescription 3 have been separately added into a certain amount of colloidal silicon dioxide, polyethylene glycol, and dissolution rate increases, prescription 4
It is 1 to add weight ratio：7 colloidal silicon dioxide and polyethylene glycol, high temperature and humidity condition on its dissolution rate without influence, prescription 5,
The weight ratio of colloidal silicon dioxide and polyethylene glycol is respectively 1 in prescription 6：1,7：1, dissolution rate is more former to have ground piece and prescription 1
It improves, but dissolution rate when with 0 day is more still decreased significantly.Illustrate the colloidal silicon dioxide and polyethylene glycol energy of special ratios
The stability for increasing drug, dissolution rate caused by avoiding high temperature and humidity condition decline.
The present inventor has also investigated influence of the wet heat condition to bulk pharmaceutical chemicals crystal form in preparation.Because of main ingredient X-ray powder in preparation
Last diffraction maximum (XPRD) is easily covered by auxiliary material diffraction maximum, this research uses following processing mode, prescription 4 is based on, in main ingredient, colloidal state
In the case that silica, polyethylene glycol dosage are constant, the dosage of other auxiliary materials is reduced to the 10 of former dosage respectively,
Simulation production process prepares aripirazole tablets.X-ray powder diffraction pattern is shown in that Fig. 3, the crystal form of bulk pharmaceutical chemicals do not change.Table
Bright, it is 1 that weight ratio, which is added,：7 colloidal silicon dioxide and polyethylene glycol can generate good protection to the crystal form of main ingredient in preparation
Effect.
Beneficial effects of the present invention：Aripirazole tablets stability prepared in accordance with the present invention is high, is preparing and was storing
Dissolution rate will not be caused to decline because of the influence of humidity and high temperature in journey.
Description of the drawings
Fig. 1 is the X-ray powder diffraction pattern of Aripiprazole I crystal bulk pharmaceutical chemicals
Fig. 2 is the X-ray powder diffraction figure after Aripiprazole I crystal bulk pharmaceutical chemicals are placed 3 months under the conditions of high temperature and humidity
Spectrum
Fig. 3 is to be reduced to former dosage based on other supplementary product consumptions in addition to colloidal silicon dioxide, polyethylene glycol prepared by prescription 4
10 tablet placed 3 months under the conditions of high temperature and humidity after X-ray powder diffraction pattern
Specific implementation mode
The technical solution further illustrated the present invention with reference to specific embodiment, but do not limit the present invention.
Aripiprazole I crystal：Company makes by oneself, and X-ray powder diffraction pattern is shown in Fig. 1.
Dissolution determination method：According to dissolution method (Chinese Pharmacopoeia 2015 editions the 4th 0931 dissolution rate and releases
Measuring method) with hydrochloric acid-potassium chloride buffer solution, (potassium chloride 14.91g is dissolved in water and is diluted to 1000ml, shakes up, and measures
250ml adds 0.2mol/L hydrochloric acid 425ml, is diluted with water to 1000ml) it is dissolution medium, rotating speed 60prm is operated in accordance with the law, is passed through
After 30min, dissolution rate is measured at 255nm with ultraviolet spectrophotometry.
Content and related substances determination method：According to high performance liquid chromatography (2015 editions four 0512 efficient liquid of Chinese Pharmacopoeia
Phase chromatography) it measures, using octadecylsilane chemically bonded silica as filler, with 60：40 methanol-acetic acid solution (adds tri- second of 1mL
Amine is to 1000mL water, with second acid for adjusting pH to 4.0) being mobile phase；Detection wavelength 255nm；Take sample appropriate, with flowing phased soln
Test solution is made, and prepares contrast solution.The measurement of content according to external standard method, the measurement in relation to substance according to principal component from
Body counter point.
Embodiment 1
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；It is added micro-
Crystalline cellulose, sodium carboxymethyl starch continue dry-mixed 5min in said mixture；It is water-soluble to be slowly added to 13% hydroxypropyl cellulose
Liquid softwood；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；The magnesium stearate for weighing recipe quantity always mixes, tabletting
To obtain the final product.
Embodiment 2
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；It is added sweet
Dew alcohol, crospovidone continue dry-mixed 5min in said mixture；It is slowly added to 10% hypromellose aqueous solution system
Softwood；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；The sodium stearyl fumarate for weighing recipe quantity always mixes, pressure
Piece to obtain the final product.
Embodiment 3
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；It is added beautiful
Rice starch, low-substituted hydroxypropyl cellulose continue dry-mixed 5min in said mixture；It is slowly added to 5% povidone aqueous solution system
Softwood；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；The talcum powder for weighing recipe quantity always mixes, and tabletting to obtain the final product.
The tablet that comparative example 1 is prepared using Macrogol 4000
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；It is added micro-
Crystalline cellulose, sodium carboxymethyl starch continue dry-mixed 5min in said mixture；It is slowly added to 8% hydroxypropyl cellulose aqueous solution
Softwood processed；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；The magnesium stearate for weighing recipe quantity always mixes, and tabletting is
?.
The tablet that comparative example 2 is prepared using polyethylene glycol 10000
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；It is added micro-
Crystalline cellulose, sodium carboxymethyl starch continue dry-mixed 5min in said mixture；It is slowly added to 8% hydroxypropyl cellulose aqueous solution
Softwood processed；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；The magnesium stearate for weighing recipe quantity always mixes, and tabletting is
?.
3 colloidal silicon dioxide of comparative example is with the amount ratio of polyethylene glycol total amount and Aripiprazole not in the range of invention
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；It is added micro-
Crystalline cellulose, sodium carboxymethyl starch continue dry-mixed 5min in said mixture；It is slowly added to 8% hydroxypropyl cellulose aqueous solution
Softwood processed；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；The magnesium stearate for weighing recipe quantity always mixes, and tabletting is
?.
Comparative example 4 uses different preparation methods
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the colloidal silicon dioxide of recipe quantity, poly- second
Glycol, mannitol, povidone and main ingredient are added granulation pot together, under low whipping speed 300r/min, granulation speed 800r/min
Dry-mixed 5min；5% hypromellose aqueous solution softwood is added；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour are crossed 20 mesh and are sieved
Whole grain；The sodium stearyl fumarate for weighing recipe quantity always mixes, and tabletting to obtain the final product.
Comparative example 5 uses different preparation methods
Prescription：
Preparation process：
Aripiprazole and all auxiliary materials are first crossed to 80 mesh sieve respectively, it is spare；Weigh the polyethylene glycol of recipe quantity, mannitol,
Crospovidone and main ingredient are added granulation pot together, dry-mixed 5min under low whipping speed 300r/min, speed of pelletizing 800r/min；
5% hypromellose aqueous solution softwood is added；The sieve granulation of 20 mesh, 65 DEG C of drying 1 hour, 20 mesh sieves of mistake；It weighs
Colloidal silicon dioxide, the sodium stearyl fumarate of recipe quantity always mix, and tabletting to obtain the final product.
4 Dissolution Rate Testing of embodiment
By the tablet of embodiment 1-3, comparative example 1-4, not pack bare die form, it is placed in open cillin bottle, in drug
It places 3 months, is measured in 60prm, hydrochloric acid-chlorine in stability test case (40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%)
Change the dissolution rate of 30min in potassium buffer solution, as a result such as following table：
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| 0 day dissolution rate (%) | 99.6 | 99.5 | 99.7 | 99.5 | 99.8 | 99.4 | 99.6 | 99.1 |
| Dissolution rate (%) after 1 month | 99.5 | 99.6 | 99.5 | 91.2 | 90.7 | 92.7 | 94.1 | 90.2 |
| Dissolution rate (%) after 3 months | 99.5 | 99.6 | 99.4 | 86.9 | 85.7 | 90.1 | 90.4 | 85.2 |
It is above-mentioned the experimental results showed that：It is placed 3 months under the conditions of high temperature and humidity, the Dissolution of Tablet of embodiment 1-3 is without change
Change, and the Dissolution of Tablet of comparative example 1-5 has different degrees of decline.Illustrate the piece prepared according to the technique and scheme of the present invention
Agent dissolution rate is excellent, is not influenced by high temperature and humidity condition.
5 stability test of embodiment
By embodiment 1-3, comparative example 1-4 tablet at 40 DEG C ± 2 DEG C, place 6 under conditions of relative humidity 75% ± 5%
A month, respectively at 1,2,3, the content of active ingredient is measured by sampling June and in relation to the content of substance, the results are shown in table below：
It is above-mentioned the experimental results showed that：It places 6 months, its content of the tablet of embodiment 1-3 and has under the conditions of high temperature and humidity
It closes substance and still conforms to provide that there is very high chemical stability, and its content of the tablet of comparative example 1-4 and related substance are bad
In the tablet that Examples 1 to 3 is prepared.
Claims (12)
1. a kind of aripirazole tablets, it is characterised in that by Aripiprazole and colloidal silicon dioxide, polyethylene glycol and pharmaceutically
Acceptable additive composition, wherein Aripiprazole are Aripiprazole I crystal；Polyethylene glycol is selected from Macrogol 6000, poly- second
Glycol 8000；The weight ratio of colloidal silicon dioxide and polyethylene glycol is 1：5~10；The total amount of colloidal silicon dioxide and polyethylene glycol
And the ratio of Aripiprazole is 1：0.5~3.
2. tablet according to claim 1, it is characterised in that additive is filler, disintegrant, adhesive and lubrication
Agent.
3. tablet according to claim 2, it is characterised in that filler be selected from cornstarch, microcrystalline cellulose, mannitol,
The one or more of lactose；Disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxy-propyl fiber
Element, crospovidone；Adhesive is selected from hypromellose, hydroxypropyl cellulose, povidone；Lubricant is selected from stearic acid
Magnesium, talcum powder, sodium stearyl fumarate.
4. tablet according to claim 3, which is characterized in that filler is mannitol.
5. tablet according to claim 3, which is characterized in that disintegrant is sodium carboxymethyl starch.
6. tablet according to claim 3, which is characterized in that adhesive is hydroxypropyl cellulose.
7. tablet according to claim 3, which is characterized in that lubricant is sodium stearyl fumarate.
8. tablet according to claim 3, it is characterised in that Aripiprazole accounts for the 5~15% of the tablet weight, colloidal state
Silica, polyethylene glycol total amount account for the 5~10% of the tablet weight, filler be the tablet weight 55~
80%, disintegrant is 2~10%, and adhesive is 2~13%, and lubricant is 1~2%.
9. the method for preparing any one of the claim 1-8 tablets, it is characterised in that by the Aripiprazole of recipe quantity, colloidal state two
Silica, polyethylene glycol after mixing, add filler, disintegrant mixing, then pelletize with the aqueous solution of adhesive；
Then it is always mixed with the lubricant of recipe quantity, tabletting to obtain the final product.
10. according to the method described in claim 9, it is characterized in that it is prepared by the following method：By Aripiprazole and
All auxiliary materials first cross 80 mesh sieve respectively, spare；System is added in the colloidal silicon dioxide, polyethylene glycol and main ingredient for weighing recipe quantity together
Grain pot is uniformly mixed；Add filler, disintegrant mixing；The aqueous solution softwood of adhesive is added；The sieve granulation of 20 mesh, 65 DEG C
It is 1 hour dry, 20 mesh sieves；The lubricant for weighing recipe quantity always mixes, and tabletting to obtain the final product.
11. according to the method described in claim 10, it is characterized in that a concentration of the 5~13% of described adhesive aqueous solution.
12. according to the method for claim 11, it is characterised in that a concentration of the 10% of described adhesive aqueous solution.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102106826A (en) * | 2009-12-29 | 2011-06-29 | 上海中西制药有限公司 | Aripiprazole solid preparation and preparation method thereof |
| CN102106806A (en) * | 2009-12-29 | 2011-06-29 | 上海中西制药有限公司 | Method for preparing solid preparation and solid preparation |
| CN102850268A (en) * | 2011-06-27 | 2013-01-02 | 上海中西制药有限公司 | Aripiprazole I-type crystallite, aripiprazole solid preparation and preparation methods thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106826A (en) * | 2009-12-29 | 2011-06-29 | 上海中西制药有限公司 | Aripiprazole solid preparation and preparation method thereof |
| CN102106806A (en) * | 2009-12-29 | 2011-06-29 | 上海中西制药有限公司 | Method for preparing solid preparation and solid preparation |
| CN102850268A (en) * | 2011-06-27 | 2013-01-02 | 上海中西制药有限公司 | Aripiprazole I-type crystallite, aripiprazole solid preparation and preparation methods thereof |
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