CN110025572A - Lauroyl Aripiprazole suspension and preparation method thereof - Google Patents
Lauroyl Aripiprazole suspension and preparation method thereof Download PDFInfo
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- CN110025572A CN110025572A CN201811624496.4A CN201811624496A CN110025572A CN 110025572 A CN110025572 A CN 110025572A CN 201811624496 A CN201811624496 A CN 201811624496A CN 110025572 A CN110025572 A CN 110025572A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
- A61K9/10—Dispersions; Emulsions
Abstract
The invention discloses a kind of lauroyl Aripiprazole suspension and preparation method thereof, the method is the following steps are included: obtain surfactant solution for surfactant mixed dissolution Yu Shuizhong；It is dissolved in the water salt and buffer salt to obtain salting liquid；Surfactant solution and salting liquid are mixed, lauroyl Aripiprazole is added, is dispersed using cutter, stirring at low speed or vacuumizing makes its defoaming；Suspension after defoaming carries out ball milling using ball mill, and the medical fluid after ball milling is diluted with water up to the lauroyl Aripiprazole suspension.The problem of present invention prepares drug microcrystalline suspension using media milling process, size tunable, narrow distribution, favorable reproducibility, the suspension having good stability is prepared, and do not use organic solvent in preparation process, therefore dissolvent residual is not present.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of lauroyl Aripiprazole suspension and preparation method thereof.
Background technique
Suspension refers to that solid drugs are scattered in the heterogeneous system formed in liquid medium, and drug is generally slightly solubility medicine
Object, containing stabilizers such as surfactant or high molecular polymers, medium is water (can also be oil).It is big according to the drug granule of dispersion
Small, suspension can be divided into nano suspension and micron suspension, can be administered by oral or muscle, subcutaneous, intravenous injection.It is micro-
Rice suspension is generally administered by modes such as intramuscular injection, after drug injection enters human body, forms a drug storage in injection site
Library, drug are slowly dissolved release and absorption, to play long-acting effect, are mainly used for needing controlling for the chronic disease of Long-term taking medicine
It treats.Have multiple microns of suspension listings at present, is mainly used for treating schizophrenia, a few weeks or months are administered once
Meet therapeutic effect, greatly improves the compliance of patient.
Lauroyl Aripiprazole is the N- laurel pivaloyloxymethyl prodrug forms of Aripiprazole.Due to water-soluble extremely low, system
Standby at aqueous suspension, there are partial sizes slowly to become larger, and is easy to happen reunion.
CN107106556A disclose it is a kind of lauroyl Aripiprazole micron suspension is prepared using solvent precipitation, should
Drug is dissolved in the first solvent by method first, and the second solvent is then added and forms mixed solution, mixed solution is cooled to mesh
Temperature range is marked, homogeneous mixed solution obtains drug crystallite mixed suspension preparation.The technique has the drawback that control condition and require
Higher, the drug microcrystalline suspension of formation is easy to reunite, and will cause organic solvent residual.
CN105012236A discloses a kind of long-acting nonaqueous carrier injection and preparation method thereof, using non-in the injection
For water carrier as decentralized medium, decentralized medium is selected from oil for injection, glycerol or solubilizer, mulser, the oil for injection choosing
From soybean oil, solubilizer or emulsifier are selected from lecithin or poloxamer, oleic acid, enuatrol or Emulsifier EL-60, preferably
Lecithin.Nonaqueous carrier has bigger human body irritation, it is easier to generate adverse reaction as decentralized medium；In addition, the Shen
Please disclosed preparation method need first to be crushed drug with airslide disintegrating mill, injection soybean oil, lecithin, glycerol is added；Point
After dissipating, then homogeneous obtains Fat Emulsion suspension.Not only increasing processing step using the operation crushed in advance reduces efficiency, and
The loss that will cause drug is directly crushed, there is also blocking cavity, turns the disadvantages of brilliant.
Therefore, in order to solve the problems, such as organic solvent residual and preparation stability, more controllable mixed of more safety, quality is obtained
Outstanding preparation, is the technical problem to be solved in the present invention.
Summary of the invention
A kind of the object of the present invention is to provide reaction conditions easily-controllable, preparation stabilization, organic solvent-free remaining lauroyl Ah
Vertical piperazine azoles suspension and preparation method thereof.
In order to reach above-mentioned technical effect, the present invention takes following technical scheme:
An aspect of of the present present invention provides a kind of preparation method of lauroyl Aripiprazole suspension, comprising the following steps:
1) surfactant mixed dissolution Yu Shuizhong is obtained into surfactant solution；
2) it is dissolved in the water salt and buffer salt to obtain salting liquid；
3) surfactant solution and salting liquid are mixed, lauroyl Aripiprazole is added, uses high cut disperse emulsification
Machine dispersion, stirring at low speed or vacuumizing makes its defoaming；
4) suspension after defoaming carries out ball milling using ball mill, and the medical fluid after ball milling is diluted with water up to the laurel
Acyl Aripiprazole suspension.
Further technical solution is that the surfactant is selected from polyoxyethylene sorbitan monoleate, span 20, span 40, sapn
60, sorbester p17, polyethylene glycol 1000 vitamin E succinic acid ester, Solutol HS 15, poloxamer, dodecane
Base sodium sulphate, mono fatty acid glyceride, lecithin, cyclodextrin, Emulsifier EL-60, sodium carboxymethylcellulose, in mannitol
It is any two or more, preferably polyoxyethylene sorbitan monoleate and span 20.
Further technical solution is that the salt is sodium chloride, and buffer salt is disodium hydrogen phosphate and sodium dihydrogen phosphate.
Further technical solution is that the shear velocity of the high-shearing dispersion emulsifying machine is 1000~10000rpm,
Preferably 2000~6000rpm；The time of shearing is 1~60min.
Further technical solution is that the design parameter of the ball milling is as follows: ball milling pearl is zirconium pearl, and the diameter of zirconium pearl is
0.5~2.5mm, the loading of ball milling pearl are 40~90%, and rotational speed of ball-mill is 4m/s~14m/s, and flow velocity is 100~3500ml/
Min, it is further preferred that the diameter of zirconium pearl is 0.5~2.2mm；Further, the diameter of zirconium pearl is 1~2.2mm.
Further technical solution is that the surfactant is two kinds, and the mass ratio of two kinds of surfactants is
0.01:1~10:1, preferably 0.1:1~1:1.
Further technical solution is that lauroyl Aripiprazole D10 is 10~20 μm in the medical fluid after the ball milling,
D50 is 20~35 μm, and D90 is 40~55 μm.
Further technical solution is that the stirring rate stirred at low speed is 100~800rpm, and the time of stirring is
10~60min.
Further technical solution is, the surfactant, salt, buffer salt, lauroyl Aripiprazole mass ratio
For 1~10:1~10:1~10:100~1000.
Another aspect of the present invention provide the preparation method preparation of the lauroyl Aripiprazole suspension lauroyl Ah
Vertical piperazine azoles suspension.
Compared with prior art, the present invention have it is below the utility model has the advantages that
The suspension particle diameter distribution that the present invention is prepared using media milling process is narrow, favorable reproducibility, and influence because
Under the conditions of element test and accelerated test, phenomena such as will not assembling, there is good stability；
Mixed suspension preparation prepared by the present invention may be implemented to be administered once for 4-8 weeks, be able to satisfy the demand of Different Individual, and be administered
It is preceding to be not necessarily to redisperse, it can be improved the convenience of clinical use.
Operating condition of the invention is easy to control, simple process, and organic solvent is not used in preparation process, is conducive to give birth to
The problem of producing safety, be also beneficial to reduce environmental pollution, while dissolvent residual being not present in finished dosage form.
The resulting lauroyl Aripiprazole suspension of the present invention clinically can be used directly, and is not necessarily to solvent, prevents secondary
Pollution.
Detailed description of the invention
1 sample particle diameter measure of spread map of Fig. 1 comparative example
2 sample particle diameter measure of spread map of Fig. 2 comparative example
3 sample particle diameter measure of spread map of Fig. 3 comparative example
7 sample particle diameter measure of spread map of Fig. 4 embodiment
Specific embodiment
The present invention is further explained below, it should be appreciated that the term is intended to describe purpose, rather than limits this hair
It is bright.
Lauroyl Aripiprazole, chemical name are dodecanoic acid (7- (4- (4- (2,3- dichlorophenyl) piperazine -1- base) fourth
Oxygroup) -1 (2H)-yl of -2- oxo -3,4- dihydroquinoline) methyl esters, structural formula is shown in formula I.
In this application, lauroyl Aripiprazole can be obtained by purchase.
In this application, surfactant is polyoxyethylene sorbitan monoleate (Tween 80), span 20, span 40, sorbester p18, sapn
80, polyethylene glycol 1000 vitamin E succinic acid ester (TPGS1000), -15 hydroxy stearic acid ester of polyethylene glycol (
HS15), poloxamer, lauryl sodium sulfate (SDS), mono fatty acid glyceride, lecithin, cyclodextrin, polyoxyethylene caster
Oil, sodium carboxymethylcellulose, in mannitol it is any two or more.Such as polyoxyethylene sorbitan monoleate and span 20, polyoxyethylene sorbitan monoleate
And span 40, polyoxyethylene sorbitan monoleate and polyethylene glycol 1000 vitamin E succinic acid ester, preferably polyoxyethylene sorbitan monoleate and span 20.
In this application, the mass ratio of two kinds of surfactants is 0.01:1~10:1, preferably 0.1:1~1:1.
In this application, surfactant is the polyoxyethylene sorbitan monoleate and span 20 that mass ratio is 0.01:1~10:1, preferably
For the polyoxyethylene sorbitan monoleate and span 20 of 0.1:1~1:1.
In this application, surfactant, salt, buffer salt, lauroyl Aripiprazole mass ratio be 1~10:1~10:1
~10:100~1000.Specifically, the matter of surfactant, salt, disodium hydrogen phosphate, sodium dihydrogen phosphate, lauroyl Aripiprazole
Amount is than being 1~8:1~8:1~8:100~800.Preferably, surfactant, salt, disodium hydrogen phosphate, sodium dihydrogen phosphate, laurel
The mass ratio of acyl Aripiprazole is 3~8:3~8:3~8:100~600.
In this application, the salt be sodium chloride, buffer salt be disodium hydrogen phosphate and sodium dihydrogen phosphate, preferably wherein
Sodium chloride concentration is selected from 1~10mg/ml, and disodium hydrogen phosphate concentration is selected from 0.8~8mg/ml, and phosphate dihydrogen sodium concentration is selected from 0.5
~5mg/ml, the mass ratio of sodium chloride, disodium hydrogen phosphate and sodium dihydrogen phosphate are 1~10:1~10:1~5.
In this application, high-shearing dispersion emulsifying machine be it is a kind of material can sufficiently be refined to uniform machine, oil can be promoted
Property substance (oily phase) machine of uniform emulsion is mutually mixed and formed with aqueous substance (water phase).One in the application is specific real
It applies in example, the shear velocity of high-shearing dispersion emulsifying machine is 1000~10000rpm, for example, 1000~9000rpm, 2000~
8000rpm, 2000~6000rpm, 3000~6000rpm；4000~6000rpm.The time of shearing is 1~60min.
In the specific embodiment of the application, ball mill be it is resistance to speed (Minicer, Neos,Discus,
Macro, RS, ) or Wall treasured (- MILL KD,- MILL ECM,- MILL NPM,- MILL MULTI LAB,-MILL
RESEARCH LAB)。
In the specific embodiment of the application, the design parameter of ball milling is as follows: ball milling pearl is zirconium pearl, the diameter of zirconium pearl
For 0.5~2.5mm, the loading of ball milling pearl is 40~90%, and rotational speed of ball-mill is 4m/s~14m/s, flow velocity is 100~
3500ml/min。
In one preferred embodiment of the application, the diameter of zirconium pearl is 0.5~2.5mm, it is preferred that the diameter of zirconium pearl is
0.5~2.2mm, it is furthermore preferred that the diameter of zirconium pearl is 1~2.2mm；
In one preferred embodiment of the application, the loading of ball milling pearl is 40~80%, it is preferred that the filling of ball milling pearl
Amount is 40~70%, it is furthermore preferred that the loading of ball milling pearl is 40~60%.
In the preferred embodiment of the application, rotational speed of ball-mill be 4~12m/s, it is preferred that rotational speed of ball-mill be 4~
10m/s, it is furthermore preferred that rotational speed of ball-mill is 6~10m/s.
In the preferred embodiment of the application, flow velocity be 200~3000ml/min, it is preferred that flow velocity be 400~
2800ml/min, it is furthermore preferred that flow velocity is 400~2600ml/min, it is furthermore preferred that flow velocity is 400~2400ml/min, it is more excellent
Choosing, flow velocity is 400~2000ml/min, it is furthermore preferred that flow velocity is 400~1800ml/min, it is furthermore preferred that flow velocity is 400
~1600ml/min, it is furthermore preferred that flow velocity is 400~1400ml/min, it is furthermore preferred that flow velocity is 400~1200ml/min, more
Preferably, flow velocity is 400~1000ml/min, it is furthermore preferred that flow velocity is 400~800ml/min.
In the specific embodiment of the application, cooled down in ball milling using tap water.
In this application, lauroyl Aripiprazole D10 is 10~20 μm in the medical fluid after ball milling, and D50 is 20~35 μm,
D90 is 40~55 μm；A specific embodiment according to the present invention, lauroyl Aripiprazole D10 is in the medical fluid after ball milling
14.5 μm, D50 is 26.0 μm, and D90 is 48.5 μm.
In this application, institute is right when the cumulative particle sizes distribution number of one sample of D10 (also known as D (0.1)) expression reaches 10%
The partial size answered, its physical significance are that partial size is less than its particle and accounts for 10%.
D50 (also known as D (0.5)) indicates that the cumulative particle sizes percentile of a sample reaches grain corresponding when 50%
Diameter, its physical significance are that partial size is greater than its particle and accounts for 50%, and the particle less than it also accounts for 50%.D50 also cry meso-position radius or
Median particle diameter, D50 are commonly used to indicate the average particle size of powder.
D90 (also known as D (0.9)) indicates that the cumulative particle sizes distribution number of a sample reaches partial size corresponding when 90%, it
Physical significance be that partial size is less than its particle and accounts for 90%.
In this application, defoaming can be used and stir at low speed or vacuumize, the rate stirred at low speed be stirring rate be 100~
800rpm, the time of stirring are 10~60min.
Embodiment
The present invention is further elaborated below by embodiment, purpose be only that more fully understand it is of the invention interior
Hold.
Characterizing method:
Particle diameter distribution: the particle diameter distribution of suspension is measured using laser particle analyzer Malvern Mastersizer 3000.
Blood concentration, using LC/MS, mass spectrum is the triple quadrupole rods tandem mass spectrometries of Applied Biosystem API4000
Instrument, liquid chromatogram are the supper-fast liquid chromatographic system of SHIMADZU LC-20AD.
Experimental example 1
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 6000rpm, and stirring at low speed 15min makes its defoaming；
(4) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm, ball milling
The loading of pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 2
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 3
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 2000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 4
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl is 60%, and rotational speed of ball-mill 10m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 5
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl be 60%, rotational speed of ball-mill 4m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 6
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is
1.3mm, the loading of ball milling pearl are 60%, rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water uses tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 7
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is
1.8mm, the loading of ball milling pearl are 60%, rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water uses tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 8
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl is 40%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 9
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 400ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 10
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm,
The loading of ball milling pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 800ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 11
(1) 0.4g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 6000rpm, and stirring at low speed 15min makes its defoaming；
(4) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm, ball milling
The loading of pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 12
(1) 1.2g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 6000rpm, and stirring at low speed 15min makes its defoaming；
(4) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm, ball milling
The loading of pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Experimental example 13
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 4000rpm, and stirring at low speed 15min makes its defoaming；
(4) the suspension sample after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is
2.2mm, the loading of ball milling pearl are 60%, and rotational speed of ball-mill 6m/s, flow velocity 800ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Comparative example 1:
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 6000rpm, and stirring at low speed 15min makes its defoaming；
(4) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 0.3mm, ball
Grind pearl loading be 60%, rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Comparative example 2:
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 6000rpm, and stirring at low speed 15min makes its defoaming；
(4) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm, ball milling
The loading of pearl is 30%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Comparative example 3:
(1) 0.75g Tween 80 and 1.9g span 20 are weighed, is stirred evenly, 100ml water is added, stirring makes it completely dissolved；
(2) 3.05g sodium chloride, 2.5g disodium hydrogen phosphate are weighed, 50ml water, stirring is added in 1.25g sodium dihydrogen phosphate-water
It makes it completely dissolved；
(3) solution (1) and solution (2) is mixed, 137.5g lauroyl Aripiprazole is added, stirs evenly, 47ml is added
Water shears solution at 6000rpm, and stirring at low speed 15min makes its defoaming；
(4) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm, ball milling
The loading of pearl is 60%, and rotational speed of ball-mill 16m/s, flow velocity 600ml/min, cooling water use tap water；
(5) after the completion of ball milling, medical fluid is taken out, is diluted with water to aimed concn, it is filling.
Comparative example 4:
(1) 0.75g Tween 80 is weighed, is stirred evenly, 150ml water is added, stirring makes it completely dissolved；
(2) 137.5g lauroyl Aripiprazole is weighed, solution in (1) is added, stirs evenly, is sheared at 6000rpm molten
Liquid, stirring at low speed 15min makes its defoaming；
(3) suspension after defoaming is added in ball mill and carries out ball milling.Ball milling condition are as follows: zirconium pearl diameter is 1mm, ball milling
The loading of pearl is 60%, and rotational speed of ball-mill 6m/s, flow velocity 600ml/min, cooling water use tap water, by medical fluid after ball milling
It takes out；
(4) 2g sodium carboxymethylcellulose is weighed, 10g mannitol, 1.25g Anhydrous Disodium Phosphate, 2.5g sodium dihydrogen phosphate,
30ml water is added, stirring makes it completely dissolved；
(5) by medical fluid after appropriate solution (4) addition ball milling, moisturizing to aimed concn is filling.
Experimental example 1: sample stability investigates test
Lauroyl Aripiprazole suspension sample prepared by embodiment 1 and comparative example 4 is subjected to influence factor test respectively
(60 DEG C of high temperature) and accelerated test (40 DEG C ± 2 DEG C), investigate variation tendency of the target particle size of sample compared with 0 day, using sharp
Light particle size analyzer (Malvern Mastersizer 3000) measures the particle diameter distribution of suspension, test result such as Tables 1 and 2 institute
Show.
Table 1: embodiment 1 and 4 sample effects factorial experiments result of comparative example
Particle changing ratio=(partial size (60 DEG C high temperature 10 days)-partial size (0 day))/partial size (0 day) * 100%
Table 2: embodiment 1 and 4 sample accelerated test result of comparative example
By Tables 1 and 2 result it is found that 1 sample of embodiment prepared by the present invention has more preferable compared to 4 sample of comparative example
Stability.In influence factor test and accelerated test, as sample standing time increases, the partial size of 1 sample of embodiment
It has almost no change, and the partial size of 4 sample of comparative example then significantly increases.
Experimental example 2: particle diameter distribution is investigated
Investigation object: embodiment 7；Comparative example 1-3；
Detecting instrument: laser particle analyzer Malvern Mastersizer 3000
Experimental result as shown in attached drawing 1 to 4, from experimental result as can be seen that product cut size made from embodiment 7 have compared with
Good normal distribution, and narrow distribution, D90 are 40~55 μm, and sample stability is preferable, quality controllable.And comparative example 1, comparison
Product cut size made from example 2, comparative example 3 shows acromion or bimodal distribution, and wider distribution, sample stability is bad, and quality is not
Controllably.
Experimental example 3: sample is in the intracorporal pharmacokinetic of rat
Animal experiment is carried out to the lauroyl Aripiprazole sample of embodiment 1, investigates rat after intramuscular injection sample, Ah
The blood concentration ongoing change process of vertical piperazine azoles.
Experimental method: by the lauroyl Aripiprazole sample to male rat intramuscular injection embodiment 1, sample is investigated
Pharmacokinetic characteristics.Intramuscular injection metering be 95mg/kg, acquire intramuscular injection after 2d, 4d, 7d, 10d, 14d, 17d, 20d,
The blood of 24d, 27d, 30d, 36d, 42d, 48d, 54d, 60d analyze the blood concentration ongoing change mistake of Aripiprazole in blood plasma
Journey.Blood concentration is detected using LC/MS.
Experimental result: the C of AripiprazolemaxAbout 42.1ng/ml, TmaxAbout 17day, AUC are about 975.2day*ng/
ml。
Claims (10)
1. a kind of preparation method of lauroyl Aripiprazole suspension, it is characterised in that the following steps are included:
1) surfactant mixed dissolution Yu Shuizhong is obtained into surfactant solution；
2) it is dissolved in the water salt and buffer salt to obtain salting liquid；
3) surfactant solution and salting liquid are mixed, lauroyl Aripiprazole is added, use high-shearing dispersion emulsifying machine point
It dissipates, stirring at low speed or vacuumizing makes its defoaming；
4) suspension after defoaming carries out ball milling using ball mill, and the medical fluid after ball milling is diluted with water up to the lauroyl Ah
Vertical piperazine azoles suspension.
2. the preparation method of lauroyl Aripiprazole suspension according to claim 1, it is characterised in that the surface
Activating agent be selected from polyoxyethylene sorbitan monoleate, span 20, span 40, sorbester p18, sorbester p17, polyethylene glycol 1000 vitamin E succinic acid ester,
Solutol HS 15, poloxamer, lauryl sodium sulfate, mono fatty acid glyceride, lecithin, cyclodextrin,
Emulsifier EL-60, sodium carboxymethylcellulose, in mannitol it is any two or more, preferably polyoxyethylene sorbitan monoleate and sapn
20。
3. the preparation method of lauroyl Aripiprazole suspension according to claim 1 or 2, it is characterised in that the salt
For sodium chloride, buffer salt is disodium hydrogen phosphate and sodium dihydrogen phosphate, and preferably wherein sodium chloride concentration is selected from 1~10mg/ml, phosphorus
Sour disodium hydrogen concentration be selected from 0.8~8mg/ml, phosphate dihydrogen sodium concentration be selected from 0.5~5mg/ml, sodium chloride, disodium hydrogen phosphate and
The mass ratio of sodium dihydrogen phosphate is 1~10:1~10:1~5.
4. the preparation method of lauroyl Aripiprazole suspension according to claim 1-3, it is characterised in that institute
The shear velocity for the high-shearing dispersion emulsifying machine stated is 1000~10000rpm, preferably 2000~6000rpm；The time of shearing
For 1~60min.
5. the preparation method of lauroyl Aripiprazole suspension according to claim 1-4, it is characterised in that institute
The design parameter for the ball milling stated is as follows: ball milling pearl is zirconium pearl, and the diameter of zirconium pearl is 0.5~2.5mm, and the loading of ball milling pearl is 40
~90%, rotational speed of ball-mill is 4m/s~14m/s, and flow velocity is 100~3500ml/min；Preferably, the diameter of zirconium pearl be 0.5~
2.2mm；It is highly preferred that the diameter of zirconium pearl is 1~2.2mm.
6. according to the preparation method of the described in any item lauroyl Aripiprazole suspensions of claim 2-5, it is characterised in that institute
The surfactant stated is two kinds, and the mass ratio of two kinds of surfactants is 0.01:1~10:1, preferably 0.1:1~1:1.
7. the preparation method of lauroyl Aripiprazole suspension according to claim 1-6, it is characterised in that institute
Lauroyl Aripiprazole D10 is 10~20 μm in medical fluid after the ball milling stated, and D50 is 20~35 μm, and D90 is 40~55 μm.
8. the preparation method of lauroyl Aripiprazole suspension according to claim 1-7, it is characterised in that institute
The stirring rate stirred at low speed stated is 100~800rpm, and the time of stirring is 10~60min.
9. the preparation method of lauroyl Aripiprazole suspension according to claim 1-8, it is characterised in that institute
The surfactant stated, salt, buffer salt, lauroyl Aripiprazole mass ratio be 1~10:1~10:1~10:100~1000.
10. the lauroyl of the preparation method preparation of -9 described in any item lauroyl Aripiprazole suspensions according to claim 1
Aripiprazole suspension.
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