CN106943405A - A kind of aripiprazole formulations and preparation method thereof - Google Patents
A kind of aripiprazole formulations and preparation method thereof Download PDFInfo
- Publication number
- CN106943405A CN106943405A CN201610006713.8A CN201610006713A CN106943405A CN 106943405 A CN106943405 A CN 106943405A CN 201610006713 A CN201610006713 A CN 201610006713A CN 106943405 A CN106943405 A CN 106943405A
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- CN
- China
- Prior art keywords
- aripiprazole
- parts
- well mixed
- formulations
- preparation
- 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.)
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Links
- 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 141
- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 141
- 239000000203 mixture Substances 0.000 title claims abstract description 78
- 238000009472 formulation Methods 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000000463 material Substances 0.000 claims abstract description 20
- 239000000945 filler Substances 0.000 claims abstract description 13
- 239000002904 solvent 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
- 239000002994 raw material Substances 0.000 claims abstract description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 46
- 239000000843 powder Substances 0.000 claims description 31
- 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 29
- 239000008101 lactose Substances 0.000 claims description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 28
- 239000000741 silica gel Substances 0.000 claims description 28
- 229910002027 silica gel Inorganic materials 0.000 claims description 28
- 239000002775 capsule Substances 0.000 claims description 26
- 235000019359 magnesium stearate Nutrition 0.000 claims description 23
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 21
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 17
- 229960000502 poloxamer Drugs 0.000 claims description 17
- 229920001983 poloxamer Polymers 0.000 claims description 17
- 229920002472 Starch Polymers 0.000 claims description 14
- 239000008107 starch Substances 0.000 claims description 14
- 235000019698 starch Nutrition 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 8
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 7
- -1 lactose compound Chemical class 0.000 claims description 7
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 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 4
- 230000008859 change Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- 239000003292 glue Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003960 organic solvent Substances 0.000 abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 abstract description 2
- 239000000853 adhesive Substances 0.000 abstract description 2
- 230000001070 adhesive effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000007876 drug discovery Methods 0.000 abstract description 2
- 238000005469 granulation Methods 0.000 abstract description 2
- 230000003179 granulation Effects 0.000 abstract description 2
- 230000036571 hydration Effects 0.000 abstract description 2
- 238000006703 hydration reaction Methods 0.000 abstract description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 abstract description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 abstract description 2
- 230000009466 transformation Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 42
- 239000007787 solid Substances 0.000 description 42
- 238000005516 engineering process Methods 0.000 description 21
- 229940032147 starch Drugs 0.000 description 11
- 229920000881 Modified starch Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000004132 cross linking Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229940080313 sodium starch Drugs 0.000 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 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005434 MCC/mannitol excipient Substances 0.000 description 1
- AQLLBJAXUCIJSR-UHFFFAOYSA-N OC(=O)C[Na] Chemical compound OC(=O)C[Na] AQLLBJAXUCIJSR-UHFFFAOYSA-N 0.000 description 1
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 239000004703 cross-linked polyethylene Substances 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- QPUMEZIFDXYGPG-UHFFFAOYSA-N piperazine 1H-pyrrole Chemical class N1CCNCC1.N1C=CC=C1 QPUMEZIFDXYGPG-UHFFFAOYSA-N 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
- 238000005550 wet granulation Methods 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular 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)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to Field of Drug Discovery, and in particular to a kind of aripiprazole formulations and preparation method thereof.The aripiprazole formulations, its raw material contains the component of following parts by weight：2.0~15.0 parts of Aripiprazole；60.0~90.0 parts of filler；1.0~18.0 parts of solubilizer；1.0~7.0 parts of disintegrant；0.5~6.0 part of lubricant.Without granulation and dry but direct preparation in the aripiprazole formulations of the present invention, therefore do not contain the adhesive of water, ethanol, PVP, hydroxypropylcellulose and other organic solvents etc., greatly reduce the generation and then associated polymorphic transformation of Aripiprazole hydration compound, amount about material can be significantly reduced, dissolution characteristic and good stability, bioavilability is high, and individual difference is small.
Description
Technical field
The invention belongs to Field of Drug Discovery, and in particular to a kind of aripiprazole formulations and preparation method thereof.
Background technology
Aripiprazole chemical name 7- [4- [4- (2,3- dichlorophenyl) -1- piperazinyls] butoxy] -3,4- dihydros -2 (1 hydrogen)-quinoline
Ketone, belongs to qualone derivative, U.S. FDA approval listing is obtained in November, 2002, for treating schizophrenia.
When preparing Aripiprazole solid pharmaceutical preparation using insoluble drug Aripiprazole coarse-grain or crystallite, with traditional wet method system
The Aripiprazole solid pharmaceutical preparation of standby gained, such as Chinese patent CN103860494, CN101574348B；United States Patent (USP)
US20100004262A1, needs wet granular being dried, this process easily produces relevant material simultaneously in production process
The stability of solid pharmaceutical preparation is reduced, so as to cause relevant content of material higher, has been difficult to meet 2015 editions pharmacopeia to relevant
The requirement of material.
Therefore, for aripiprazole drug substance preparation, it would be highly desirable to which seeking one kind can both overcome existing preparation method stability not enough to manage
The defect thought, can guarantee that aripiprazole formulations of various function admirables and preparation method thereof again.
The content of the invention
In order to overcome the problems of in the prior art, it is an object of the invention to provide a kind of aripiprazole formulations and its
Preparation method.
To achieve these goals and other related purposes, the present invention is adopted the following technical scheme that：
Compared with prior art, the present invention has the advantages that：
The first aspect of the present invention provides a kind of aripiprazole formulations, and its raw material contains the component of following parts by weight：
| Component | Parts by weight |
| Aripiprazole | 2.0~15.0 parts； |
| Filler | 60.0~90.0 parts； |
| Solubilizer | 1.0~18.0 parts； |
| Disintegrant | 1.0~7.0 parts； |
| Lubricant | 0.5~6.0 part； |
Preferably, the aripiprazole formulations, its raw material contains the component of following parts by weight：
Described Aripiprazole can select the Aripiprazole of the conventional various particle diameters in this area, such as larger than 100 μm or less than 100 μm.
Preferably, the Aripiprazole is Aripiprazole of the particle diameter below 50 μm, and such as average grain diameter is 20~50um or is less than
20 μm of aripiprazole crystallite.It is more preferably the aripiprazole crystallite less than 20 μm.
Aripiprazole employed in the preferred embodiments of the present invention is less than 50 μm of aripiprazole crystallite.
Preferably, the filler is selected from microcrystalline cellulose, pregelatinized starch, lactose, starch, mannitol, lactose compound
Any of or a variety of combinations.
The lactose compound is prior art, for example：It can select the lactose composite product of Mei Jile groups of Germany80、100、
Or the lactose composite product of JRS pharmaceutic adjuvants company of GermanySMCC。
Preferably, the solubilizer is in dodecyl sodium sulfate, polyethylene glycol, poloxamer, s6
Any one or more combinations.It is highly preferred that the solubilizer is in lauryl sodium sulfate, poloxamer and polyethylene glycol
Any one or more combinations.
Preferably, the disintegrant is appointed in Ac-Di-Sol, carboxyrnethyl starch sodium, PVPP
One or more combinations.
Preferably, the lubricant is any or many in magnesium stearate, talcum powder, sodium stearyl fumarate and superfine silica gel powder
The combination planted.
Preferably, the aripiprazole formulations can also include colouring agent.
Further, can also be as needed in the aripiprazole formulations, including other drugs active component, other drugs activity
Composition can be selected according to this area conventional method, as long as it does not produce antagonism with Aripiprazole.
The second aspect of the present invention, there is provided a kind of method for preparing foregoing aripiprazole formulations, is the direct preparation method of powder, bag
Include step：The mixture of Aripiprazole and other auxiliary materials is directly carried out compressing tablet or filler capsule.
Preferably, methods described includes step：
Aripiprazole is sieved, add filler it is well mixed after, then solubilizer and disintegrant added and is well mixed, finally
Lubricant is added and is well mixed, compressing tablet or filling capsule are to obtain aripiprazole formulations.
Preferably, methods described comprises the following steps：
Aripiprazole is sieved, then filler equivalent is progressively increased and is well mixed, disintegrant and solubilizer is then added and mixes
Uniformly, finally lubricant is added and is well mixed, compressing tablet or filling capsule are to obtain aripiprazole formulations.
Preferably, when containing superfine silica gel powder in the aripiprazole formulations, methods described may include following steps：By A Li piperazines
Azoles and superfine silica gel powder are mixed and sieved, and then filler equivalent is progressively increased and is well mixed, and then add disintegrant and solubilizer simultaneously
It is well mixed, finally other lubricants are added and are well mixed, compressing tablet or filling capsule are to obtain aripiprazole formulations.
The third aspect of the present invention, additionally provides application of the foregoing aripiprazole formulations in treatment of schizophrenia medicine is prepared.
The fourth aspect of the present invention, additionally provides one kind and treats schizoid method, including step：By foregoing Aripiprazole
Preparation is applied to patient.
Specific consumption can be selected by physician in view situation.
Compared with prior art, the present invention has the advantages that：
(1) amount in aripiprazole formulations of the invention about material can be significantly reduced, and dissolution characteristic and good stability are raw
Thing availability is high, and individual difference is small.(according to Chinese Pharmacopoeia two Aripiprazoles of version in 2015 in one of which case study on implementation
Solid pharmaceutical preparation dissolution detection method) with the Aripiprazole dissolution rate that 85% is no less than after about 15 minutes；It is many after about 30 minutes
In 90% Aripiprazole dissolution rate.
(2) aripiprazole formulations of the invention use the direct preparation method of powder, make without granulation and drying but directly
Agent, therefore the adhesive of water, ethanol, PVP, hydroxypropylcellulose and other organic solvents etc. is not contained, greatly reduce
The generation and then associated polymorphic transformation of Aripiprazole hydration compound.
(3) preparation method of aripiprazole formulations of the present invention needs less unit operation, uses less equipment, smaller energy
Consumption, smaller space, less time and less manpower, with obvious economic advantages.Methods described also avoids preparing in preparation
Period uses organic solvent, it is to avoid organic solvent is possible poisonous or because environmental factor is difficult to handle.Technical staff can be easy
Grasp the equipment and condition needed for blending step in ground.The factor of blending step can be influenceed to include but is not limited to the thing of material quantity, raw material
Manage characteristic, equipment and mixing velocity.The preparation method of the present invention is easy to operate, using dry formulations technique, without drying, it is big
Reduce cost greatly, it is easy to industrialized production.
Embodiment
Before the specific embodiment of the invention is further described, it should be appreciated that protection scope of the present invention is not limited to following spies
Fixed specific embodiment；It is also understood that the term used in the embodiment of the present invention is to describe specific specific implementation
Scheme, the protection domain being not intended to be limiting of the invention.The test method of unreceipted actual conditions in the following example, leads to
Often according to normal condition, or according to the condition proposed by each manufacturer.
When embodiment provides number range, it should be appreciated that except non-invention is otherwise noted, two end points of each number range with
And any one numerical value can select between two end points.Unless otherwise defined, all technologies used in the present invention and section are academic
Language is identical with the meaning that those skilled in the art of the present technique are generally understood that.In addition to the specific method used in embodiment, equipment, material,
According to those skilled in the art to the grasp of prior art and the record of the present invention, it can also use and the embodiment of the present invention
Described in method, any method, equipment and the material of equipment, material similar or equivalent prior art realize the present invention.
Aripiprazole employed in embodiments of the invention is less than 50 μm of aripiprazole crystallite.
The Aripiprazole solid pharmaceutical preparation of embodiment 1
Formula：
| Component | Parts by weight |
| Aripiprazole | 2.0 |
| Microcrystalline cellulose | 21.3 |
| Pregelatinized starch | 64.0 |
| Cross-linked carboxymethyl cellulose sodium | 3.0 |
| Dodecyl sodium sulfate | 6.8 |
| Superfine silica gel powder | 2.0 |
| Magnesium stearate | 1.0 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, then microcrystalline cellulose, pregelatinized starch equivalent are progressively increased well mixed
Afterwards, Ac-Di-Sol and dodecyl sodium sulfate are added, after being well mixed, magnesium stearate is added in mixture and mixed
Close 3 minutes, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 2
Formula：
Preparation technology：
It is standby after Aripiprazole is sieved, then microcrystalline cellulose, lactose equivalent are progressively increased and is well mixed, carboxylic first is then added
Sodium starch and polyethylene glycol are simultaneously well mixed, finally will talcum powder add mixture in mix 5 minutes, compressing tablet or filling capsule with
Obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 3
Formula：
| Component | Parts by weight |
| Aripiprazole | 4.7 |
| Microcrystalline cellulose | 15.1 |
| Lactose | 60.3 |
| Poloxamer | 15.0 |
| Carboxyrnethyl starch sodium | 1.0 |
| Superfine silica gel powder | 2.0 |
| Sodium stearyl fumarate | 2.0 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, then microcrystalline cellulose, lactose equivalent are progressively increased after being well mixed, plus
Enter carboxyrnethyl starch sodium and poloxamer, after being well mixed, sodium stearyl fumarate is added in mixture and mixed 5 minutes, compressing tablet
Or load capsule to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 4
Formula：
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, then starch equivalent is progressively increased after being well mixed, adds crosslinked polyethylene
Base pyrrolidones and poloxamer, by mixture it is well mixed after, talcum powder is added in mixture and mixed 3 minutes, compressing tablet or
Capsule is loaded to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 5
Formula：
| Component | Parts by weight |
| Aripiprazole | 14.9 |
| Microcrystalline cellulose | 6.9 |
| Lactose | 62.4 |
| S6 | 9.9 |
| Ac-Di-Sol | 2.0 |
| Magnesium stearate | 1.0 |
Preparation technology：
It is standby after Aripiprazole is sieved, then microcrystalline cellulose and lactose equivalent are progressively increased after being well mixed, add crosslinking carboxylic first
Base sodium cellulosate and s6, after mixture is well mixed, 3 points of mixing in mixture is added by magnesium stearate
Clock, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 6
Formula：
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, then lactose equivalent is progressively increased after being well mixed, adds cross-linked carboxymethyl
Sodium cellulosate and dodecyl sodium sulfate, after mixture is well mixed, mixing 3 minutes in mixture are added by magnesium stearate,
Compressing tablet loads capsule to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 7
Formula：
| Component | Parts by weight |
| Aripiprazole | 4.8 |
| Microcrystalline cellulose | 23.0 |
| Lactose | 26.8 |
| Mannitol | 26.8 |
| Polyethylene glycol | 9.6 |
| Carboxyrnethyl starch sodium | 3.8 |
| Superfine silica gel powder | 3.8 |
| Magnesium stearate | 1.4 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, microcrystalline cellulose, lactose and mannitol equivalent are then progressively increased into mixing
After even, carboxyrnethyl starch sodium and polyethylene glycol are added, after mixture is well mixed, 3 will be mixed in magnesium stearate addition mixture
Minute, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 8
Formula：
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, after then microcrystalline cellulose and lactose are mixed in proportion, equivalent
Progressively increase into the mixture of Aripiprazole and superfine silica gel powder and be well mixed, afterwards by Ac-Di-Sol and poloxamer
It is added in mixture, after being well mixed, magnesium stearate is added in mixture and mixed 3 minutes, compressing tablet or filling capsule are to obtain
Obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 9
Formula：
| Component | Parts by weight |
| Aripiprazole | 4.7 |
| Microcrystalline cellulose | 16.9 |
| Lactose | 67.5 |
| Polyethylene glycol | 4.2 |
| Carboxyrnethyl starch sodium | 2.8 |
| Magnesium stearate | 1.1 |
Preparation technology：
Standby after Aripiprazole is sieved, after then mixing in proportion microcrystalline cellulose and lactose, equivalent is progressively increased to A Li
In the mixture of piperazine azoles and superfine silica gel powder and it is well mixed, carboxyrnethyl starch sodium and polyethylene glycol is added in mixture afterwards, mixes
Close it is uniform after, magnesium stearate is added in mixture and mixed 3 minutes, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 10
Formula：
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, subsequent equivalent, which is progressively increased, to be added microcrystalline cellulose and lactose and be well mixed,
Ac-Di-Sol and poloxamer are added in mixture afterwards, after being well mixed, by sodium stearyl fumarate plus
Enter in mixture and mix 3 minutes, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 11
Formula：
| Component | Parts by weight |
| Aripiprazole | 4.4 |
| Microcrystalline cellulose | 23.5 |
| Mannitol | 55.9 |
| PVPP | 7.0 |
| Poloxamer | 3.2 |
| Superfine silica gel powder | 5.0 |
| Magnesium stearate | 1.0 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, subsequent equivalent, which is progressively increased, to be added microcrystalline cellulose and mannitol and mix equal
It is even, PVPP and poloxamer are added in mixture afterwards, after being well mixed, magnesium stearate added
Mixed 3 minutes in mixture, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 12
Formula：
Preparation technology：
Standby after Aripiprazole is sieved, subsequent equivalent, which is progressively increased, to be added microcrystalline cellulose and lactose and is well mixed, afterwards will crosslinking
Polyvinylpyrrolidone and poloxamer are added in mixture, after being well mixed, and magnesium stearate is added in mixture and mixes 3
Minute, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 13
Formula：
| Component | Parts by weight |
| Aripiprazole | 9.1 |
| Lactose compound | 65.5 |
| Poloxamer | 18.0 |
| Ac-Di-Sol | 2.7 |
| Superfine silica gel powder | 3.7 |
| Magnesium stearate | 1.0 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, subsequent equivalent, which is progressively increased, lactose compound and to be well mixed, afterwards will crosslinking
Sodium carboxymethylcellulose and poloxamer are added in mixture, after being well mixed, and magnesium stearate is added in mixture and mixes 3
Minute, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 14
Formula：
Preparation technology：
Standby after Aripiprazole is sieved, subsequent equivalent, which is progressively increased, lactose and cellulose and to be well mixed, afterwards by carboxyrnethyl starch sodium and
Dodecyl sodium sulfate is added in mixture, after being well mixed, and magnesium stearate is added in mixture and mixed 3 minutes, compressing tablet
Or load capsule to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 15
Formula：
| Component | Parts by weight |
| Aripiprazole | 2.5 |
| Lactose | 63.0 |
| Microcrystalline cellulose | 22.5 |
| Poloxamer | 2.5 |
| Dodecyl sodium sulfate | 1.0 |
| Sodium carboxymethyl starch | 6.0 |
| Superfine silica gel powder | 2.0 |
| Magnesium stearate | 0.5 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, subsequent equivalent, which is progressively increased, lactose and cellulose and to be well mixed, afterwards by carboxylic
First sodium starch, poloxamer and dodecyl sodium sulfate are added in mixture, after being well mixed, and magnesium stearate is added and mixed
Mixed 3 minutes in thing, compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 16
Formula：
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, subsequent equivalent, which is progressively increased, lactose and cellulose and to be well mixed, afterwards by carboxylic
First sodium starch, PVPP and dodecyl sodium sulfate are added in mixture, after being well mixed, by stearic acid
Magnesium is added in mixture and mixed 3 minutes, and compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation of embodiment 17
Formula：
| Component | Parts by weight |
| Aripiprazole | 9.1 |
| Microcrystalline cellulose | 31.1 |
| Lactose | 46.1 |
| Poloxamer | 8.2 |
| Ac-Di-Sol | 1.0 |
| Superfine silica gel powder | 3.0 |
| Sodium stearyl fumarate | 1.0 |
| Magnesium stearate | 0.5 |
Preparation technology：
Aripiprazole and superfine silica gel powder are mixed and sieved, subsequent equivalent, which is progressively increased, to be added microcrystalline cellulose and lactose and be well mixed,
Ac-Di-Sol and poloxamer are added in mixture afterwards, after being well mixed, by sodium stearyl fumarate and
Magnesium stearate is added in mixture and mixed 3 minutes, and compressing tablet or filling capsule are to obtain Aripiprazole solid pharmaceutical preparation.
The Aripiprazole solid pharmaceutical preparation (wet granulation) of comparative example 18
Formula：
Preparation technology：
It is standby by initial aripiprazole through 80 mesh screens；Remaining auxiliary material crosses 60 mesh sieves, standby.By the Aripiprazole of recipe quantity
Raw material and interior plus auxiliary material (PVP, lactose, microcrystalline cellulose, Ac-Di-Sol) are well mixed.Add after water
Wet granular is prepared on wet granulator；Then wet granular is dried to moisture within 4% at 60 DEG C.After whole grain,
Add additional Ac-Di-Sol, magnesium stearate and superfine silica gel powder it is well mixed after, compressing tablet or filling capsule are to obtain
Aripiprazole solid pharmaceutical preparation.
Embodiment 19
Sample prepared by embodiment 1~18 is put after high-density polyethylene bottle packaging, in 40 DEG C ± 2 DEG C of temperature, relative humidity 75
Placed under conditions of % ± 5%, inspection content, dissolution rate and relevant material are carried out in sampling after accelerated test 6 months.
Content, dissolution rate, about material and containing equal assay method：According to two Aripiprazole contents of Chinese Pharmacopoeia version in 2015,
Dissolution rate, about material and containing equal detection method.
As a result it is as shown in table 1：
Table 1
From the acquired results of upper table 1, due to each auxiliary material added in the Aripiprazole solid pharmaceutical preparation of the embodiment of the present invention 1~17
And the mutual cooperation of dry formulations technique, the hydrophily of medicine obtained greatly improving, and drug dissolution is substantially 100%
Left and right.
Due to the present invention, take is dry formulations technique, after Acceleration study 6 months, the change of content within 0.08%, and
And relevant material is basically stable within 0.1% and (meets 2015 editions standards of pharmacopoeia：Relevant material≤0.2%).But contrast is implemented
Example 18 (wet method preparation, patent CN103860494), after accelerating 6 months, content waste is in 0.3-1.0% or so, relevant thing
Matter also increases to 0.33% (not met 2015 editions standards of pharmacopoeia).
Pass through each auxiliary material added in Aripiprazole solid pharmaceutical preparation of the present invention and the mutual cooperation of dry formulations technique, piece simultaneously
Containing also superior to comparative example 18, difference is small in batch.
The above, only presently preferred embodiments of the present invention, it is not any to the present invention in form and substantial limitation, should
Point out, for those skilled in the art, on the premise of the inventive method is not departed from, can also make some
Improve and supplement, these are improved and supplement also should be regarded as protection scope of the present invention.All those skilled in the art, not
In the case of departing from the spirit and scope of the present invention, when a little change made using disclosed above technology contents, repair
Decorations and the equivalent variations developed, are the Equivalent embodiments of the present invention；Meanwhile, all substantial technologicals according to the present invention are to above-mentioned reality
The variation, modification and evolution for any equivalent variations that example is made are applied, in the range of still falling within technical scheme.
Claims (14)
1. a kind of aripiprazole formulations, its raw material contains the component of following parts by weight：2.0~15.0 parts of Aripiprazole；Filler
60.0~90.0 parts；1.0~18.0 parts of solubilizer；1.0~7.0 parts of disintegrant；0.5~6.0 part of lubricant.
2. aripiprazole formulations according to claim 1, it is characterised in that its raw material contains the component of following parts by weight：
2.0~14.9 parts of Aripiprazole；62.8~90.0 parts of filler；1.0~18.0 parts of solubilizer；Disintegrant 1.0~7.0
Part；0.5~6.0 part of lubricant.
3. aripiprazole formulations according to claim 1, it is characterised in that the Aripiprazole is average grain diameter at 50 μm
Following Aripiprazole.
4. aripiprazole formulations according to claim 1, it is characterised in that the average grain diameter of the Aripiprazole is 20~
50um。
5. aripiprazole formulations according to claim 1, it is characterised in that the Aripiprazole is that average grain diameter is less than 20 μm
Aripiprazole crystallite.
6. aripiprazole formulations according to claim 1, it is characterised in that the filler is selected from microcrystalline cellulose, pre- glue
Change any of starch, lactose, starch, mannitol, lactose compound or a variety of combinations.
7. aripiprazole formulations according to claim 1, it is characterised in that the solubilizer be selected from dodecyl sodium sulfate,
Any one or more combination in polyethylene glycol, poloxamer, s6.
8. aripiprazole formulations according to claim 1, it is characterised in that the disintegrant is selected from cross-linked carboxymethyl cellulose
Any one or more combination in sodium, carboxyrnethyl starch sodium, PVPP.
9. aripiprazole formulations according to claim 1, it is characterised in that the lubricant be selected from magnesium stearate, talcum powder,
Any one or more combination in sodium stearyl fumarate, superfine silica gel powder.
10. a kind of method for preparing the aripiprazole formulations as described in claim 1~9 any claim, is the direct preparation method of powder,
Including step：The mixture of Aripiprazole and other auxiliary materials is directly carried out compressing tablet or filler capsule.
11. preparation method according to claim 10, comprises the following steps：Aripiprazole is sieved, filler mixing is added
After uniform, then solubilizer and disintegrant added and is well mixed, finally lubricant is added and is well mixed, compressing tablet or
Capsule is loaded to obtain aripiprazole formulations.
12. preparation method according to claim 10, comprises the following steps：It is standby after Aripiprazole is sieved, it will then fill out
Fill agent equivalent to progressively increase and be well mixed, then add disintegrant and solubilizer and be well mixed, finally add lubricant simultaneously
Well mixed, compressing tablet or filling capsule are to obtain aripiprazole formulations.
13. preparation method according to claim 10, when containing superfine silica gel powder in the aripiprazole formulations, methods described
It may include following steps：Aripiprazole and superfine silica gel powder are mixed and sieved, then filler equivalent is progressively increased and mixed
It is even, then add disintegrant and solubilizer and be well mixed, finally other lubricants are added and are well mixed, compressing tablet or
Capsule is loaded to obtain aripiprazole formulations.
14. application of the aripiprazole formulations in treatment of schizophrenia medicine is prepared as described in claim 1~9 any claim.
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|---|---|---|---|---|
| CN109984999A (en) * | 2019-04-28 | 2019-07-09 | 重庆仁泽医药科技有限公司 | A kind of pharmaceutical composition and its preparation method and application |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101351193A (en) * | 2006-01-05 | 2009-01-21 | 特瓦制药工业有限公司 | Dry formulations of aripiprazole |
| 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 |
-
2016
- 2016-01-06 CN CN201610006713.8A patent/CN106943405B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101351193A (en) * | 2006-01-05 | 2009-01-21 | 特瓦制药工业有限公司 | Dry formulations of aripiprazole |
| 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 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109984999A (en) * | 2019-04-28 | 2019-07-09 | 重庆仁泽医药科技有限公司 | A kind of pharmaceutical composition and its preparation method and application |
| CN109984999B (en) * | 2019-04-28 | 2021-12-24 | 重庆仁泽医药科技有限公司 | Pharmaceutical composition and preparation method and application thereof |
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