CN104382859B - A kind of SLGT2 inhibitor particle and preparation method thereof - Google Patents
A kind of SLGT2 inhibitor particle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of SLGT2 inhibitor particle and preparation method thereof, the SLGT2 inhibitor particle is made up of SLGT2 inhibitor, crystallizing inhibitor, filler, and SLGT2 inhibitor, crystallizing inhibitor, the mass ratio of filler three are 10:0.5~10:0.5~20, preferably 10:1~5:1~15, SLGT2 inhibitor are any of net selected from canagliflozin, Dapagliflozin, Yi Palie.By formed inhibitor containing SLGT2, crystallizing inhibitor, filler three organic solution, be prepared particle under spray drying.The mobility of particle is good, and compressibility is strong, and dust is few, can be further prepared into the preparations such as tablet, capsule, granule, solves the problems, such as SLGT2 inhibitor poorly water-soluble and causes dissolution rate and bioavilability low.
Description
Technical field
The present invention relates to a kind of SLGT2 inhibitor particle and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
SLGT2 inhibitor (white 2 inhibitor of sodium glucose co-transporter 2, sodium-glucose co-
Transporter 2inhibitors) it is that one kind specific can suppress glomerulus proximal tubule, filtration glucose is inhaled again
Receive, excessive glucose is discharged from urine, directly reduce the medicine of blood glucose.Clinical research shows that SGLT2 inhibitor has
Good drug effect, security and tolerance, blood glucose can be effectively reduced, increase the discharge rate of glucose in urine, turn into one
Method (progress [J] medical science of Hu Li, Zhou Zhaoyuan .SGLT2 inhibitor medicaments of the new treatment diabetes B hyperglycaemia of kind
Summarize .2011,17 (24):3782-3785).The medicine clinically used has the canagliflozin of Johson ＆ Johnson
(Canagliflozin, trade name：) and Bristol-Myers Squibb Co. is (referred to as：BMS Dapagliflozin)
(Dapagliflozin, trade name：), in addition, Yi Palie net (Empagliflozin), Ipragliflozin,
The medicines such as Luseogliflozin are in clinical research.Canagliflozin, Dapagliflozin, Yi Palie net chemical constitution is seen below.
The aqueous solution of the SLGT2 inhibitor in pH 1~8 such as canagliflozin, Dapagliflozin, Yi Palie be net (are free of surface-active
Agent) in equal indissoluble, therefore, in order to meet the requirement of clinical biochemical availability, it is necessary to increase SLGT2 inhibitor in an aqueous medium
Dissolubility.Patent US6774112 discloses the method that SLGT2 inhibitor forms eutectic with l-amino acid or D- amino acid.
For canagliflozin, the method that different crystal forms can be used, canagliflozin anhydride is such as prepared into canagliflozin half
Hydrate improves dissolubility and crystallographic property, sees patent disclosed in Japanese Tanabe Mitsubishi Pharmaceutical Co
CN201180023380.5.In addition, Taiwan Shenlong Co., Ltd discloses canagliflozin point in patent WO2013064909
1 is not formed with L-PROLINE, D-PROLINE and L-phenylalanine:The method of 1 eutectic, also disclose canagliflozin formed it is amorphous
Method.These methods are advantageous to improve the crystalline structure of canagliflozin, dissolubility of the increase medicine in water.In addition, the U.S.
Johson ＆ Johnson discloses the method that canagliflozin semihydrate prepares piece agent in patent CN201180023642.8, in tablet
Non-active ingredient contains filler, disintegrant, adhesive, lubricant, and further discloses its proportion of composing.
For Dapagliflozin, on the one hand solubility improves by reducing the method for particle diameter in BMS companies, such as by canagliflozin
Size controlling is for 20 μm≤D90≤ 50 μm, see patent CN201080044077.9；On the other hand also use and propane diols list water
The method that compound forms eutectic improves solubility, sees patent CN200880016902.7.Canagliflozin can also be with ethanol, L- dried meat ammonia
Acid, L-phenylalanine form eutectic, see patent WO2008002824.In patent WO2013064909, Dapagliflozin is disclosed
Form unbodied method.In customary preparation methods, surfactant (such as Tween 80, dodecane are usually added in the formulation
Base sodium sulphate etc.) to improve the dissolubility of medicine, but for the medicine of method Surfactant sensitivity, it is understood that there may be stability
The problem of.
It is net for Yi Palie, its solubility also very little in an aqueous medium.Calculate to obtain according to ACD/Labs softwares, 25
At DEG C, in pH 1~10 aqueous solution, it is 41 μ g/ml that solubility, which only has,.
Research finds that SLGT2 inhibitor is before preparation is made, if raw material reduces particle diameter by being micronized, but due to medicine
Fusing point it is low (such as canagliflozin be 98~100 DEG C, Dapagliflozin be 75~80 DEG C), easily produce " tacky phenomenon ", rear continued powder
It is broken to be difficult to；If diameter of aspirin particle can be controlled in smaller range, such as D90≤ 50 μm, but because the specific surface area of medicine is big,
Drug density is small, easily it is unstable, using 4~8% hydroxypropylcelluloses the aqueous solution wet granulation when, be also easy to produce showing for incomplete mixing
As pelletizing for a long time, amount of heat can be produced, causing drug accumulation balling-up, particle diameter increase, cause the tablet dissolution rate prepared not
High or between piece and piece otherness is larger.
Experiment it has also been found that, SLGT2 inhibitor be prepared into it is amorphous after, the amorphous stability is bad, and fusing point is low (such as to be reached
Lattice row are 49.5~62.6 DEG C only), easily change into stability crystal formation, it is difficult to long-term storage.
Due to problem above in production be present, dissolubility can be improved by being badly in need of exploitation one kind, and and can is applied to big industrialization
Preparation is made in the technique of production, and the invention provides a kind of effective solution.
The content of the invention
It is an object of the invention to provide a kind of SLGT2 inhibitor particle and preparation method thereof, the particle can be prepared further
The formulations such as piece agent, capsule, granule.
To achieve the above object, the present invention is achieved through the following technical solutions：
A kind of SLGT2 inhibitor particle, is made up of SLGT2 inhibitor, crystallizing inhibitor, filler, and SLGT2 inhibitor, suppression are brilliant
Agent, the mass ratio of filler three are 10:(0.5~10):(0.5~20), preferably 10:(1~5):(1~15).
SLGT2 inhibitor is any of net selected from canagliflozin, Dapagliflozin, Yi Palie in the present invention.In no spy
Under different explanation, the present invention mentions the monomer that SLGT2 inhibitor is free from other materials.The anhydrous Ka Gelie used such as canagliflozin
Only, Dapagliflozin uses the Dapagliflozin without propane diols monohydrate.
Crystallizing inhibitor is selected from PVP, polyvinyl alcohol-polyethyleneglycol-graft copolymer, hydroxypropylcellulose, hydroxypropyl in the present invention
Any of methylcellulose, or the mixture of any two or more compositions.The effect of crystallizing inhibitor can be pressed down in spray drying
The formation of SLGT2 inhibitor crystallization processed.Because SLGT2 inhibitor and crystallizing inhibitor form eutectic compound, therefore, SLGT2 suppressions
Preparation exists in the form of the high degree of dispersion such as crystallite, amorphous in the composite, the result is that SLGT2 inhibitor can be significantly improved
Dissolubility in the composite.
The crystallizing inhibitor of the present invention selects the water miscible high polymer material of low-viscosity, as the U.S. can be selected in PVP
The production of Ashland companies(viscosity be 5.5~8.5mPas, 10% aqueous), or BASF Corp. of Germany's life
ProductionK30 (viscosity be 5.5~8.5mPas, 10% aqueous)；Polyvinyl alcohol-polyethyleneglycol-graft copolymer
(3:1) BASF Corp. of Germany's production can be selected(viscosity be 50~250mPas, 20% aqueous)；Hydroxypropyl
The production of Ashland companies of the U.S. can be selected in cellulose(viscosity be 300~600mPas, 10% aqueous) or
ELF (viscosity be 150~225mPas, 10% aqueous), or the production of Japanese Cao Da companies(viscosity is
3.0~5.9mPas, 2% aqueous)；The production of Dow companies of the U.S. can be selected in hydroxypropyl methylcellulose(viscosity
For 40~60mPas, 2% aqueous) or K100LV (viscosity be 80~120mPas, 2% aqueous).
The crystallizing inhibitor of the present invention also has a purpose, can be used as binder.By increasing SLGT2 inhibitor and filling
The cohesive of agent and play a role.According to the factor such as crystallizing inhibitor species and its viscosity, the species and its dosage of filler of selection
Considered, screen the dosage of crystallizing inhibitor.Under no specified otherwise, the model of the crystallizing inhibitor mentioned by the present invention and life
Producer is produced to be selected in above-mentioned provide.According to preliminary experiment, the mass ratio (w/w) of SLGT2 inhibitor and crystallizing inhibitor is
10:(0.5~10), it is preferably 10:(1~5).
Filler is selected from lactose, mannitol, any of xylitol in the present invention, or any two or more compositions is mixed
Compound.Contain multiple hydroxyls in three kinds of lactose, mannitol and xylitol filling agent molecules, be respectively provided with good water solubility.Such as
Lactose is about 19g/100g water (20 DEG C, similarly hereinafter), and mannitol is about 18g/100g water, and xylitol is about 62.5g/100g water.
Under usual conditions, the equal very little of hygroscopicity of three, below 0.1%.The critical relative moisture of lactose is about 90%, and xylitol is about
For 80%, mannitol is about 85%, as long as illustrating to control terms of packing, these fillers are almost non-hygroscopic.
The present invention from one kind of three kinds of fillers or its combination another object is that the weight of increase particle, such as to up to lattice
Row are net, and dosage is relatively low, only 5mg or 10mg, and after adding filler, the quality of SLGT2 inhibitor particles can substantially increase.In addition
On the one hand, it due to having used water miscible filler, can largely dissolve in water or dispersed, suppress adding containing SLGT2
It after the organic solution of agent, may be homogenously dispersed in around drug molecule, or drug molecule be diluted in water soluble adjuvant, isolate
Hydrophobic effect between drug molecule, the result is that in drug-eluting, because filler and crystallizing inhibitor first dissolve, makes drug containing
Multiple small molecule cavities are produced around particle, this capillary force accelerates contact of the medicine with hydrone, ultimately results in medicine
Release is obviously improved.Under no specified otherwise, lactose of the invention, mannitol, the auxiliary material that xylitol is common grade, in order to
Reach good releasing effect, the mass ratio (w/w) of SLGT2 inhibitor and filler is 10:(0.5~20), it is preferably 10:(1
~15).
The preparation method of above-mentioned SLGT2 inhibitor particle, comprises the following steps：
(1) SLGT2 inhibitor is dissolved in organic solvent, SLGT2 inhibitor：The mass ratio of organic solvent is 1:(5~20)；
(2) crystallizing inhibitor is dissolved in or is dispersed in substantial amounts of aqueous or in aqueous organic solvent with filler, solid
Mass ratio with liquid is 1:(5~20), the solid are crystallizing inhibitor and filler, and the liquid is in aqueous or aqueous had
Solvent；
(3) under stirring, the organic liquor of SLGT2 inhibitor in (1) is poured into (2), persistently stirs 10 minutes~1
Hour；
(4) above-mentioned aqueous organic slurry is spray-dried, the temperature for controlling spray drying is 100~120 DEG C；Collect spray
The dried material of mist, 60 mesh sieves are crossed, obtain SLGT2 inhibitor particles.
The organic solvent used in the present invention in step (1) and (2) is any of acetone, ethanol, isopropanol, or is appointed
Anticipate the mixtures of two or more compositions.
The aqueous organic solvent used in the present invention in step (2) can be a variety of ratios, such as 10% ethanol (V/V),
15% acetone (V/V), 20% isopropanol (V/V) etc..Due to hydrophilic crystallizing inhibitor and filler is employed herein, therefore
Purified water can be used when dissolving or being scattered as solvent.
Beneficial effect caused by the present invention：
The invention provides a kind of method for being spray-dried and preparing SLGT2 inhibitor, this method is to be dissolved in medicine to contain
In the solution for having crystallizing inhibitor and filler, in order that medicine fully mixes, stirring 10 minutes~1 hour should be continued, according to production
Amount size, control mixing time.In view of production cost problem, the drug containing slurries of preparation are preferably concentrated solution, but should not
Medicine, crystallizing inhibitor and filler crystallization is set to be advisable, ratio, crystallizing inhibitor and the filling of specific organic solvent and SLGT2 inhibitor
The ratio of agent and water-containing organic solvent or aqueous needs to be screened as the case may be.
By the way that canagliflozin, Dapagliflozin, Yi Palie be net etc., SLGT2 inhibitor combines crystallizing inhibitor and filling in the present invention
Agent, play the synergy for improving drug release rate.Crystallizing inhibitor can play a part of framework material in the particle of formation, prevent
Contact between drug molecule, the potential energy of drug molecule is reduced, drug molecule is existed with the formation of molecule or crystallite, due to
Dosage is less during SLGT2 inhibitor etc. is clinical, and crystallizing inhibitor is used alone, it is impossible to the good release for improving medicine, or ratio
It is improper produce particle adhesion or granule content it is uneven.The addition of filler in particle, it can further increase point of medicine
Bulk state, good spheric granules is easily formed in simultaneous spray drying.Therefore, the ratio of the invention by adjusting three, it is reachable
To the purpose of improvement SLGT2 inhibitor solubility, and prepare the particle for doing other formulations such as piece agent, granule, capsule.
Brief description of the drawings
Fig. 1 is the stripping curve figure of embodiment 10~12；
Fig. 2 is the stripping curve figure of embodiment 13~15；
Fig. 3 is the stripping curve figure of embodiment 16~18.
Embodiment
With reference to embodiment, the present invention is further illustrated, but the present invention is not limited to these embodiments.
Embodiment 1
The preparation of the canagliflozin particle of embodiment 1
Step (1)：Canagliflozin 100g is taken, adds ethanol 1500g, stirring makes it dissolve or be uniformly dispersed, as solution
A, it is standby.
Step (2)：PVP (K30) 25g and lactose 20g are taken, purified water 500g is added, stirring, makes its dissolving, as molten
Liquid B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is in spray dryer (model：SD-1500, mountain and sea irrigate the limited public affairs of enlightening automated arm share
Department, similarly hereinafter) in be spray-dried, control spray drying temperature be 100 DEG C；The material after spray drying is collected, 60 mesh sieves is crossed, obtains
Canagliflozin particle.
The preparation of the canagliflozin particle of embodiment 2
Step (1)：Taking canagliflozin 100g, add acetone 700g, stirring makes it dissolve or be uniformly dispersed, as solution A,
It is standby.
Step (2)：Polyvinyl alcohol-polyethyleneglycol-graft copolymer 80g and mannitol 180g are taken, adds 10% acetone aqueous
(w/w) 1500g, stirring, makes its dissolving, as solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 115 DEG C；Collect spray
The dried material of mist, 60 mesh sieves are crossed, obtain canagliflozin particle.
The preparation of the canagliflozin particle of embodiment 3
Step (1)：Canagliflozin 100g is taken, adds ethanol-aqueous isopropanol (2:8, w/w) 1500g, stirring make its dissolving
Or be uniformly dispersed, it is standby as solution A.
Step (2)：Hydroxypropylcellulose (ELF) 50g and xylitol 100g are taken, aqueous 800g is added, stirring, makes its dissolving,
As solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 105 DEG C；Collect spray
The dried material of mist, 60 mesh sieves are crossed, obtain canagliflozin particle.
The preparation of the Dapagliflozin particle of embodiment 4
Step (1)：Dapagliflozin 10g is taken, adds ethanol-acetone (3:7, w/w) 90g, stirring make it dissolve or disperse equal
It is even, it is standby as solution A.
Step (2)：Hydroxypropyl methylcellulose (E50) 5g and lactose 10g are taken, purified water 100g is added, stirring, makes its dissolving,
As solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 110 DEG C；Collect spray
The dried material of mist, 60 mesh sieves are crossed, obtain Dapagliflozin particle.
The preparation of the Dapagliflozin particle of embodiment 5
Step (1)：Taking Dapagliflozin 10g, add acetone 100g, stirring makes it dissolve or be uniformly dispersed, as solution A,
It is standby.
Step (2)：Polyvinyl alcohol-polyethyleneglycol-graft copolymer 2g and xylitol 18g are taken, adds 20% acetone aqueous
(w/w) 100g, stirring, makes its dissolving, as solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 100 DEG C；Collect spray
The dried material of mist, 60 mesh sieves are crossed, obtain Dapagliflozin particle.
The preparation of the Dapagliflozin particle of embodiment 6
Step (1)：Dapagliflozin 10g is taken, adds ethanol-aqueous isopropanol (6:4, w/w) 120g, stirring make its dissolve or
It is uniformly dispersed, it is standby as solution A.
Step (2)：Polyvinyl alcohol-polyethyleneglycol-graft copolymer 8g and mannitol 2g are taken, adds aqueous 100g, is stirred,
Make its dissolving, as solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 105~115 DEG C；Receive
Material after collection spray drying, crosses 60 mesh sieves, obtains Dapagliflozin particle.
The preparation of the net particles of the Yi Palie of embodiment 7
Step (1)：The net 10g of Yi Palie are taken, add ethanol-acetone (5:5, w/w) 100g, stirring make it dissolve or disperse equal
It is even, it is standby as solution A.
Step (2)：Hydroxypropyl methylcellulose (E50) 7g and lactose 18g are taken, purified water 150g is added, stirring, makes its dissolving,
As solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 110 DEG C；Collect spray
The dried material of mist, cross 60 mesh sieves, the net particles of get Yi Palie.
The preparation of the net particles of the Yi Palie of embodiment 8
Step (1)：Taking the net 10g of Yi Palie, add acetone 110g, stirring makes it dissolve or be uniformly dispersed, as solution A,
It is standby.
Step (2)：PVP (K30) 2g and xylitol 10g are taken, 20% acetone aqueous (w/w) 100g is added, stirring, makes
It dissolves, as solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 100 DEG C；Collect spray
The dried material of mist, cross 60 mesh sieves, the net particles of get Yi Palie.
The preparation of the net particles of the Yi Palie of embodiment 9
Step (1)：The net 10g of Yi Palie are taken, add ethanol-aqueous isopropanol (6:4, w/w) 120g, stirring make its dissolve or
It is uniformly dispersed, it is standby as solution A.
Step (2)：Polyvinyl alcohol-polyethyleneglycol-graft copolymer 8g and mannitol 4g are taken, adds ethanol-water solution (2:
8, w/w) 100g, stirring, makes its dissolving, as solution B.
Step (3)：Solution A is added into solution B, stirs, it is uniformly dispersed, as solution C.
Step (4)：Solution C is spray-dried in spray dryer, and the temperature for controlling spray drying is 115 DEG C；Collect spray
The dried material of mist, cross 60 mesh sieves, the net particles of get Yi Palie.
The preparation of the canagliflozin tablet of embodiment 10~12
Canagliflozin particle in Example 1,2,3, piece agent is prepared according to the prescription of table 1.
Preparation method (1000)：Dapagliflozin particle and other auxiliary materials are weighed by recipe quantity, is mixed (5~10 minutes),
In rotary pelleting machine (model：Tabletting, adjustment sheet weight and pressure on C＆C800, Beijing wound Bo Jiawei Science and Technology Ltd.s, similarly hereinafter),
It is 60~100N to control hardness.
The prescription of the canagliflozin tablet of table 1
Stripping curve determines：Canagliflozin piece in above-described embodiment 10~12 is taken, each 6, is used《Chinese Pharmacopoeia》(2010
Year version two) annex XC dissolution methods determine in accordance with the law.
Dissolving device：Paddle method；Rotating speed：75rpm；Temperature：37±0.5℃；Dissolution medium：Water (contains 0.75% dodecyl
Sodium sulphate)；Medium volume：600ml；Analysis method：High performance liquid chromatography (HPLC)；Detection wavelength：240nm；Mobile phase：Second
Nitrile-water (pH 6.5, H containing 20mM3PO4)(50:50)；Chromatographic column：C18 chromatographic columns (5 μm, 4.6 × 150mm)；Column temperature：40℃；
Flow velocity：1ml/min；
Stripping curve result is as shown in Figure 1.As a result show, medicine dissolution rate in 5min reaches in canagliflozin particle
Dissolution rate is more than 70% when more than 50%, 10min, and dissolution rate illustrates that medicine is providing in particle more than 80% during 15min
Aqueous in can rapid dissolution.
The preparation of the Dapagliflozin tablet of embodiment 13~15
Dapagliflozin particle in Example 4,5,6, piece agent is prepared according to the prescription of table 2.
Preparation method (1000)：Dapagliflozin particle and other auxiliary materials are weighed by recipe quantity, is mixed (5~10 minutes),
The tabletting on rotary pelleting machine, adjustment sheet weight and pressure, it is 60~100N to control hardness.
The prescription of the Dapagliflozin tablet of table 2
Stripping curve determines：Dapagliflozin piece in above-described embodiment 13~15 is taken, each 6, is used《Chinese Pharmacopoeia》(2010
Year version two) annex XC dissolution methods determine in accordance with the law.
Dissolving device：Paddle method；Rotating speed：75rpm；Temperature：37±0.5℃；Dissolution medium：Water (contains 0.5% dodecyl sulphur
Sour sodium)；Medium volume：900ml；Analysis method：High performance liquid chromatography (HPLC)；Detection wavelength：220nm；Mobile phase：Second
Nitrile-water (pH 6.5, H containing 20mM3PO4)(45:55)；Chromatographic column：C18 chromatographic columns (5 μm, 4.6 × 150mm)；Column temperature：40℃；
Flow velocity：1ml/min；Stripping curve result is as shown in Figure 2.As a result show, medicine dissolution rate in 5min in Dapagliflozin particle
Dissolution rate is more than 70% when reaching more than 50%, 10min, and dissolution rate is more than 80% during 15min.Illustrate that medicine exists in particle
Can rapid dissolution in defined aqueous.
The preparation of the net tablets of the Yi Palie of embodiment 16~18
The net particles of Yi Palie in Example 7,8,9, piece agent is prepared according to the prescription of table 3.
Preparation method (1000)：The net particles of Yi Palie and other auxiliary materials are weighed by recipe quantity, is mixed (5~10 minutes),
The tabletting on rotary pelleting machine, adjustment sheet weight and pressure, it is 60~100N to control hardness.
The prescription of the net tablets of the Yi Palie of table 3
Stripping curve determines：The net pieces of Yi Palie in above-described embodiment 13~15 are taken, each 6, are used《Chinese Pharmacopoeia》(2010
Year version two) annex XC dissolution methods determine in accordance with the law.
Dissolving device：Paddle method；Rotating speed：75rpm；Temperature：37±0.5℃；Dissolution medium：Water (contains 0.5% dodecyl sulphur
Sour sodium)；Medium volume：900ml；Analysis method：High performance liquid chromatography (HPLC)；Detection wavelength：220nm；Mobile phase：Second
Nitrile-water (pH 6.5, H containing 20mM3PO4)(45:55)；Chromatographic column：C18 chromatographic columns (5 μm, 4.6 × 150mm)；Column temperature：40℃；
Flow velocity：1ml/min；Stripping curve result is as shown in Figure 3.As a result show, medicine dissolution rate in 5min in the net particles of Yi Palie
Dissolution rate is more than 70% when reaching more than 50%, 10min, and dissolution rate is more than 80% during 15min.Illustrate that medicine exists in particle
Can rapid dissolution in defined aqueous.
Although the above-mentioned embodiment to the present invention is described, not to the limit of the scope of the present invention
System, one of ordinary skill in the art should be understood that on the basis of technical scheme those skilled in the art need not pay
Go out various modifications or deformation that creative work can make still within protection scope of the present invention.
Claims (2)
1. a kind of SLGT2 inhibitor particle, it is characterised in that be made up of SLGT2 inhibitor, crystallizing inhibitor, filler, SLGT2 suppressions
Preparation, crystallizing inhibitor, the mass ratio of filler three are 10:0.5~10:0.5~20；
The SLGT2 inhibitor is that canagliflozin, Dapagliflozin or Yi Palie are net；
The SLGT2 inhibitor is monomer；
The crystallizing inhibitor is selected from PVP, polyvinyl alcohol-polyethyleneglycol-graft copolymer, hydroxypropylcellulose, hydroxypropyl methylcellulose
Any of, or any two or more mixture；
The filler is selected from any of lactose, mannitol, xylitol, or any two or more mixture；
The preparation method of described SLGT2 inhibitor particles, comprises the following steps：
(1) SLGT2 inhibitor is dissolved in organic solvent, and the mass ratio of SLGT2 inhibitor and organic solvent is 1:5~20；
(2) crystallizing inhibitor is dissolved in or is dispersed in water or in aqueous organic solvent with filler, the quality of solid and liquid
Than for 1:(5~20), the solid are crystallizing inhibitor and filler, and the liquid is in water or aqueous organic solvent；
(3) under stirring, the liquid obtained by step (1) is poured into the liquid obtained by step (2), persistently stirred 10 minutes
~1 hour；
(4) organic slurry made from step (3) is spray-dried, the temperature for controlling spray drying is 100~120 DEG C, collects spray
The dried material of mist, 60 mesh sieves are crossed, obtain SLGT2 inhibitor particles；
The organic solvent used in the step (1) and (2) is any of acetone, ethanol, isopropanol, or any two kinds with
On mixture；
The aqueous organic solvent used in the step (2) be volume fraction be 10% ethanol, volume fraction be 15%
Acetone or the isopropanol that volume fraction is 20%.
2. particle as claimed in claim 1, it is characterised in that the SLGT2 inhibitor, crystallizing inhibitor, the matter of filler three
Amount is than being 10:1~5:1~15.
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| WO2016155578A1 (en) * | 2015-03-27 | 2016-10-06 | 苏州晶云药物科技有限公司 | New crystal form of dapagliflozin and preparation method therefor |
| CN110141555A (en) * | 2019-06-21 | 2019-08-20 | 江苏豪森药业集团有限公司 | A kind of net piece of En Gelie and preparation method thereof |
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| WO2010045656A2 (en) * | 2008-10-17 | 2010-04-22 | Nectid, Inc. | Novel sglt2 inhibitor dosage forms |
| CN103655539B (en) * | 2013-12-13 | 2019-09-13 | 重庆医药工业研究院有限责任公司 | A kind of oral solid formulation of canagliflozin and preparation method thereof |
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