CN104382859A - SLGT2 inhibitor granule and preparation method thereof - Google Patents
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Abstract
The invention discloses an SLGT2 inhibitor granule and a preparation method thereof. The SLGT2 inhibitor granule comprises an SLGT2 inhibitor, a crystal inhibitor and a filler, of which the mass ratio is 10: (0.5-10): (0.5-20), preferably 10:(1-5):(1-15). The SLGT2 inhibitor is any one component selected from the group consisting of Invokana, Dapagliflozin and Empagliflozin. An organic solution containing the SLGT2 inhibitor, the crystal inhibitor and the filler is formed and is spray-dried to be prepared into the granule. The granule has good mobility, strong compressibility and less dust, and can be further prepared into preparations such as tablets, capsules and granules, and the problems that the dissolution and the bioavailability are low due to the poor water solubility of the SLGT2 inhibitor are solved.
Description
Technical field
The present invention relates to a kind of SLGT2 inhibitor granule and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
SLGT2 inhibitor (the white inhibitor 2 of sodium glucose co-transporter 2, sodium-glucose co-transporter 2inhibitors) be that one can suppress glomerule proximal tubule by specificity, to filtration glucose reabsorption, excessive glucose is discharged from urine, directly falls hypoglycemic medicine.Clinical research shows, SGLT2 inhibitor has good drug effect, safety and toleration, effectively can reduce blood glucose, increase the output of glucose in urine, become a kind of method (Hu Li for the treatment of type 2 diabetes mellitus hyperglycemia newly, the progress [J] of Zhou Zhaoyuan .SGLT2 inhibitor medicaments. Medical review .2011,17 (24): 3782-3785).The medicine used clinically have the Ka Gelie of Johson & Johnson clean (Canagliflozin, trade name:
) and Bristol-Myers Squibb Co. (be called for short: Da Gelie BMS) clean (Dapagliflozin, trade name:
), in addition, the clean medicine such as (Empagliflozin), Ipragliflozin, Luseogliflozin of Yi Palie is in clinical research.Under the chemical constitution that Ka Gelie is clean, Da Gelie is clean, Yi Palie is clean is shown in.
The SLGT2 inhibitor such as Ka Gelie is clean, Da Gelie is clean, Yi Palie is clean are equal indissoluble in the aqueous solution (not containing surfactant) of pH 1 ~ 8, therefore, in order to meet the requirement of clinical biochemical availability, need to increase SLGT2 inhibitor dissolubility in an aqueous medium.Patent US6774112 discloses the method that SLGT2 inhibitor and L-aminoacid or D-aminoacid form eutectic.
Clean for Ka Gelie, the method for different crystal forms can be adopted, as clean for Ka Gelie anhydride is prepared into the clean semihydrate of Ka Gelie to improve dissolubility and crystallographic property, see patent CN201180023380.5 disclosed in Japanese Tanabe Mitsubishi Pharmaceutical Co.In addition, Taiwan Shenlong Co., Ltd discloses Ka Gelie at patent WO2013064909 and only forms the method for 1:1 eutectic with L-PROLINE, D-PROLINE and L-Phe respectively, also discloses Ka Gelie and only forms unbodied method.These methods are conducive to improving the clean crystalline structure of Ka Gelie, increase the dissolubility of medicine in water.In addition, Johnson Co. discloses the method that the clean semihydrate of Ka Gelie is prepared into tablet in patent CN201180023642.8, and in tablet, non-active ingredient contains filler, disintegrating agent, binding agent, lubricant, and further discloses its proportion of composing.
Clean for Da Gelie, dissolubility improves, as clean for Ka Gelie size controlling is being 20 μm≤D by the method reducing particle diameter on the one hand in BMS company
90≤ 50 μm, see patent CN201080044077.9; Also adopt the method forming eutectic with propylene glycol monohydrate to improve dissolubility on the other hand, see patent CN200880016902.7.Ka Gelie also can form eutectic with ethanol, L-PROLINE, L-Phe only, sees patent WO2008002824.In patent WO2013064909, disclose Da Gelie and only form unbodied method.In customary preparation methods, usually add surfactant (as Tween 80, sodium lauryl sulphate etc.) in the formulation to improve the dissolubility of medicine, but the medicine of this method Surfactant sensitivity, the problem of possible existence and stability.
Clean for Yi Palie, dissolubility is also very little in an aqueous medium for it.Obtain according to the measuring and calculating of ACD/Labs software, at 25 DEG C, in the aqueous solution of pH 1 ~ 10, it is 41 μ g/ml that dissolubility only has.
Research finds, SLGT2 inhibitor is before making preparation, if raw material reduces particle diameter by micronization, but because the fusing point of medicine is low (as Ka Gelie is 98 ~ 100 DEG C only, Da Gelie is 75 ~ 80 DEG C only), easily produce " be clamminess phenomenon ", follow-up pulverizing is difficult to carry out; If diameter of aspirin particle can be controlled in more among a small circle, as D
90≤ 50 μm, but because the specific surface area of medicine is large, drug density is little, easily unstable, when adopting the aqueous solution wet granulation of 4 ~ 8% hyprolose, the phenomenon of easy generation incomplete mixing, long-time granulation, can produce amount of heat, causes drug accumulation balling-up, particle diameter increases, and causes not high or between sheet and sheet the diversity of the tablet dissolution of preparation larger.
Experiment also find, SLGT2 inhibitor be prepared into amorphous after, this amorphous stability is bad, and fusing point low (as Da Gelie is 49.5 ~ 62.6 DEG C only), easily changes into stability crystal formation, be difficult to long-term storage.
In producing, there is above problem, being badly in need of exploitation one can improve dissolubility, and the technique that can be applicable to again large suitability for industrialized production, to make preparation, the invention provides a kind of effective solution.
Summary of the invention
The object of this invention is to provide a kind of SLGT2 inhibitor granule and preparation method thereof, this granule can be prepared into the dosage forms such as tablet, capsule, granule further.
For achieving the above object, the present invention is achieved through the following technical solutions:
A kind of SLGT2 inhibitor granule, be made up of SLGT2 inhibitor, crystallizing inhibitor, filler, the mass ratio of SLGT2 inhibitor, crystallizing inhibitor, filler three is 10:(0.5 ~ 10): (0.5 ~ 20), is preferably 10:(1 ~ 5): (1 ~ 15).
In the present invention SLGT2 inhibitor be selected from that Ka Gelie is clean, Da Gelie is clean, Yi Palie clean in any one.Do not having under specified otherwise, it is not containing the monomer of other materials that the present invention mentions SLGT2 inhibitor.Only the anhydrous Ka Gelie used as Ka Gelie is clean, and Da Gelie uses the Da Gelie not containing propylene glycol monohydrate clean only.
In the present invention, crystallizing inhibitor is selected from any one in polyvidone, polyvinyl alcohol-polyethyleneglycol-graft copolymer, hyprolose, hypromellose, or the mixture of any two or more composition.The effect of crystallizing inhibitor is the formation that can suppress the crystallization of SLGT2 inhibitor when spraying dry.Because SLGT2 inhibitor and crystallizing inhibitor define eutectic complex, therefore, SLGT2 inhibitor exists with the form of crystallite, the dispersion of amorphous equal altitudes in the composite, consequently can significantly improve SLGT2 inhibitor dissolubility in the composite.
Crystallizing inhibitor of the present invention selects the water miscible macromolecular material of low-viscosity, as polyvidone can select Ashland company of the U.S. to produce
(viscosity is 5.5 ~ 8.5mPas, 10% water liquid), or BASF Corp. of Germany's production
k30 (viscosity is 5.5 ~ 8.5mPas, 10% water liquid); Polyvinyl alcohol-polyethyleneglycol-graft copolymer (3:1) can select BASF Corp. of Germany to produce
(viscosity is 50 ~ 250mPas, 20% water liquid); Hyprolose can select Ashland company of the U.S. to produce
(viscosity is 300 ~ 600mPas, 10% water liquid) or ELF (viscosity is 150 ~ 225mPas, 10% water liquid), or the production of Japanese Cao Da company
(viscosity is 3.0 ~ 5.9mPas, 2% water liquid); Hypromellose can select Dow company of the U.S. to produce
(viscosity is 40 ~ 60mPas, 2% water liquid) or K100LV (viscosity is 80 ~ 120mPas, 2% water liquid).
Crystallizing inhibitor of the present invention also has an object, can be used as adhesive and uses.Play a role by increasing the cohesive of SLGT2 inhibitor and filler.According to the crystallizing inhibitor kind selected and viscosity thereof, the factors such as the kind of filler and consumption thereof consider, the consumption of screening crystallizing inhibitor.Do not having under specified otherwise, the model of the crystallizing inhibitor mentioned by the present invention and manufacturer are to select in above-mentioned providing.According to preliminary experiment, the mass ratio (w/w) of SLGT2 inhibitor and crystallizing inhibitor is 10:(0.5 ~ 10), be preferably 10:(1 ~ 5).
In the present invention, filler is selected from any one in lactose, mannitol, xylitol, or the mixture of any two or more composition.All containing multiple hydroxyl in lactose, mannitol and xylitol three kinds of filler molecules, all there is good water solublity.As lactose is about 19g/100g water (20 DEG C, lower same), mannitol is about 18g/100g water, and xylitol is about 62.5g/100g water.At typical condition, the hygroscopicity of three is all very little, below 0.1%.The critical relative humidity of lactose is about 90%, and xylitol is about 80%, and mannitol is about 85%, controls terms of packing well, the moisture absorption hardly of these filleies as long as illustrate.
The present invention selects another object of a kind of of three kinds of filleies or its combination to be the weight increasing granule, and as clean to Da Gelie, dosage is lower, only has 5mg or 10mg, and after adding filler, the quality of SLGT2 inhibitor granule can obviously increase.In addition on the one hand, owing to employing water miscible filler, can to dissolve in a large number in water or dispersed, after adding the organic solution containing SLGT2 inhibitor, can be dispersed in around drug molecule, or drug molecule is diluted in water soluble adjuvant, isolate the hydrophobic interaction between drug molecule, consequently when drug-eluting, because filler and crystallizing inhibitor first dissolve, make to produce multiple micromolecule cavity around medicine-containing particle, this capillary force accelerates the contact of medicine and hydrone, finally causes drug release obviously to promote.Do not having under specified otherwise, lactose of the present invention, mannitol, xylitol are the adjuvant of common grade, in order to reach good releasing effect, the mass ratio (w/w) of SLGT2 inhibitor and filler is 10:(0.5 ~ 20), be preferably 10:(1 ~ 15).
The preparation method of above-mentioned SLGT2 inhibitor granule, 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 and filler are dissolved in or are dispersed in organic solvent in a large amount of water liquid or moisture, the mass ratio of solid and liquid is 1:(5 ~ 20), described solid is crystallizing inhibitor and filler, and described liquid is organic solvent in water liquid or moisture;
(3) under stirring, the organic liquor of SLGT2 inhibitor in (1) is poured in (2), Keep agitation 10 minutes ~ 1 hour;
(4) by above-mentioned moisture organic slurry spraying dry, controlling spray-dired temperature is 100 ~ 120 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, obtain SLGT2 inhibitor granule.
In the present invention, step (1) and (2) middle organic solvent used are any one in acetone, ethanol, isopropyl alcohol, or the mixture of any two or more composition.
The moisture organic solvent used in step (2) in the present invention can be multiple ratio, as 10% ethanol (V/V), 15% acetone (V/V), 20% isopropyl alcohol (V/V) etc.Owing to being employed herein hydrophilic crystallizing inhibitor and filler, therefore purified water can be used as solvent when dissolving or disperse.
The beneficial effect that the present invention produces:
The invention provides a kind of method that spraying dry prepares SLGT2 inhibitor, the method makes medicine dissolution in the solution containing crystallizing inhibitor and filler, in order to make medicine fully mix, answers Keep agitation 10 minutes ~ 1 hour, according to the size of the amount of producing, control mixing time.Consider production cost problem, the pastille serosity of preparation is preferably concentrated solution, but medicine, crystallizing inhibitor and filler crystallize should do not made to be advisable, and the ratio of the ratio of concrete organic solvent and SLGT2 inhibitor, crystallizing inhibitor and filler and water-containing organic solvent or water liquid needs to screen as the case may be.
Pass through the SLGT2 inhibitor such as Ka Gelie is clean, Da Gelie is clean, Yi Palie is clean associating crystallizing inhibitor and filler in the present invention, play the synergism improving drug release rate.Crystallizing inhibitor can play the effect of framework material in the granule formed, stop the contact between drug molecule, reduce the potential energy of drug molecule, drug molecule is existed with the formation of molecule or crystallite, because the clinical middle dosages such as SLGT2 inhibitor are less, be used alone crystallizing inhibitor, well can not improve the release of medicine, or the adhesion of ratio improper generation granule or the uneven of granule content.The adding of filler in granule, the dispersity of medicine can be increased further, in simultaneous spray drying, easily form good spheroidal particle.Therefore, the present invention, by regulating the ratio of three, can reach the object improving SLGT2 inhibitor dissolubility, and prepare the granule making other dosage forms such as tablet, granule, capsule.
Accompanying drawing explanation
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.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated, but the present invention is not limited to these embodiments.
Embodiment 1
The preparation of the clean granule of embodiment 1 Ka Gelie
Step (1): card taking lattice arrange clean 100g, adds ethanol 1500g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get polyvidone (K30) 25g and lactose 20g, add purified water 500g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C spray dryer (model: SD-1500, mountain and sea Wo Di automated arm limited company, lower with) in spraying dry, controlling spray-dired temperature is 100 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Ka Gelie.
The preparation of the clean granule of embodiment 2 Ka Gelie
Step (1): card taking lattice arrange clean 100g, adds acetone 700g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get polyvinyl alcohol-polyethyleneglycol-graft copolymer 80g and mannitol 180g, adds 10% acetone water liquid (w/w) 1500g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 115 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Ka Gelie.
The preparation of the clean granule of embodiment 3 Ka Gelie
Step (1): card taking lattice arrange clean 100g, adds ethanol-aqueous isopropanol (2:8, w/w) 1500g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get hyprolose (ELF) 50g and xylitol 100g, adds water liquid 800g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 105 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Ka Gelie.
The preparation of the clean granule of embodiment 4 Da Gelie
Step (1): get the clean 10g of Da Gelie, add ethanol-acetone (3:7, w/w) 90g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get hypromellose (E50) 5g and lactose 10g, add purified water 100g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 110 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Da Gelie.
The preparation of the clean granule of embodiment 5 Da Gelie
Step (1): get the clean 10g of Da Gelie, add acetone 100g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get polyvinyl alcohol-polyethyleneglycol-graft copolymer 2g and xylitol 18g, adds 20% acetone water liquid (w/w) 100g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 100 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Da Gelie.
The preparation of the clean granule of embodiment 6 Da Gelie
Step (1): get the clean 10g of Da Gelie, adds ethanol-aqueous isopropanol (6:4, w/w) 120g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get polyvinyl alcohol-polyethyleneglycol-graft copolymer 8g and mannitol 2g, adds water liquid 100g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 105 ~ 115 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Da Gelie.
The preparation of the clean granule of embodiment 7 Yi Palie
Step (1): get the clean 10g of Yi Palie, add ethanol-acetone (5:5, w/w) 100g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get hypromellose (E50) 7g and lactose 18g, add purified water 150g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 110 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Yi Palie.
The preparation of the clean granule of embodiment 8 Yi Palie
Step (1): get the clean 10g of Yi Palie, add acetone 110g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get polyvidone (K30) 2g and xylitol 10g, adds 20% acetone water liquid (w/w) 100g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 100 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Yi Palie.
The preparation of the clean granule of embodiment 9 Yi Palie
Step (1): get the clean 10g of Yi Palie, adds ethanol-aqueous isopropanol (6:4, w/w) 120g, stirs and makes it dissolve or be uniformly dispersed, as solution A, for subsequent use.
Step (2): get polyvinyl alcohol-polyethyleneglycol-graft copolymer 8g and mannitol 4g, add ethanol-water solution (2:8, w/w) 100g, stirs, makes it dissolve, as solution B.
Step (3): add solution A in solution B, stirs, makes it be uniformly dispersed, as solution C.
Step (4): solution C is spraying dry in spray dryer, controlling spray-dired temperature is 115 DEG C; Collect the material after spraying dry, cross 60 mesh sieves, the clean granule of get Yi Palie.
The preparation of the clean tablet of embodiment 10 ~ 12 Ka Gelie
The clean granule of Ka Gelie in Example 1,2,3, becomes tablet according to the formula preparation of table 1.
Preparation method (1000): take the clean granule of Da Gelie and other adjuvants by recipe quantity, mixing (5 ~ 10 minutes), in rotary tablet machine (model: C & C800, Beijing wound Bo Jiawei Science and Technology Ltd., lower same) upper tabletting, adjustment sheet weighs and pressure, and control hardness is 60 ~ 100N.
The prescription of the clean tablet of table 1 Ka Gelie
Stripping curve measures: get the clean sheet of Ka Gelie in above-described embodiment 10 ~ 12, each 6, adopts " Chinese Pharmacopoeia " (version two in 2010) annex XC dissolution method to measure in accordance with the law.
Dissolving device: paddle method; Rotating speed: 75rpm; Temperature: 37 ± 0.5 DEG C; Dissolution medium: water (containing 0.75% sodium lauryl sulphate); Medium volume: 600ml; Analytical method: high performance liquid chromatography (HPLC); Determined wavelength: 240nm; Mobile phase: (pH 6.5, containing 20mM H for acetonitrile-water
3pO
4) (50:50); Chromatographic column: C18 chromatographic column (5 μm, 4.6 × 150mm); Column temperature: 40 DEG C; Flow velocity: 1ml/min;
Stripping curve result as shown in Figure 1.Result shows, when the clean granule Chinese medicine of Ka Gelie dissolution when 5min reaches more than 50%, 10min, dissolution is more than 70%, and during 15min, dissolution is more than 80%, illustrates that granule Chinese medicine can stripping rapidly in the water liquid of regulation.
The preparation of the clean tablet of embodiment 13 ~ 15 Da Gelie
The clean granule of Da Gelie in Example 4,5,6, becomes tablet according to the formula preparation of table 2.
Preparation method (1000): take the clean granule of Da Gelie and other adjuvants by recipe quantity, mixing (5 ~ 10 minutes), tabletting on rotary tablet machine, adjustment sheet weighs and pressure, and control hardness is 60 ~ 100N.
The prescription of the clean tablet of table 2 Da Gelie
Stripping curve measures: get the clean sheet of Da Gelie in above-described embodiment 13 ~ 15, each 6, adopts " Chinese Pharmacopoeia " (version two in 2010) annex XC dissolution method to measure in accordance with the law.
Dissolving device: paddle method; Rotating speed: 75rpm; Temperature: 37 ± 0.5 DEG C; Dissolution medium: water (containing 0.5% sodium lauryl sulphate); Medium volume: 900ml; Analytical method: high performance liquid chromatography (HPLC); Determined wavelength: 220nm; Mobile phase: (pH 6.5, containing 20mM H for acetonitrile-water
3pO
4) (45:55); Chromatographic column: C18 chromatographic column (5 μm, 4.6 × 150mm); Column temperature: 40 DEG C; Flow velocity: 1ml/min; Stripping curve result as shown in Figure 2.Result shows, when the clean granule Chinese medicine of Da Gelie dissolution when 5min reaches more than 50%, 10min, dissolution is more than 70%, and during 15min, dissolution is more than 80%.Illustrate that granule Chinese medicine can stripping rapidly in the water liquid of regulation.
The preparation of the clean tablet of embodiment 16 ~ 18 Yi Palie
The clean granule of Yi Palie in Example 7,8,9, becomes tablet according to the formula preparation of table 3.
Preparation method (1000): take the clean granule of Yi Palie and other adjuvants by recipe quantity, mixing (5 ~ 10 minutes), tabletting on rotary tablet machine, adjustment sheet weighs and pressure, and control hardness is 60 ~ 100N.
The prescription of the clean tablet of table 3 Yi Palie
Stripping curve measures: get the clean sheet of Yi Palie in above-described embodiment 13 ~ 15, each 6, adopts " Chinese Pharmacopoeia " (version two in 2010) annex XC dissolution method to measure in accordance with the law.
Dissolving device: paddle method; Rotating speed: 75rpm; Temperature: 37 ± 0.5 DEG C; Dissolution medium: water (containing 0.5% sodium lauryl sulphate); Medium volume: 900ml; Analytical method: high performance liquid chromatography (HPLC); Determined wavelength: 220nm; Mobile phase: (pH 6.5, containing 20mM H for acetonitrile-water
3pO
4) (45:55); Chromatographic column: C18 chromatographic column (5 μm, 4.6 × 150mm); Column temperature: 40 DEG C; Flow velocity: 1ml/min; Stripping curve result as shown in Figure 3.Result shows, when the clean granule Chinese medicine of Yi Palie dissolution when 5min reaches more than 50%, 10min, dissolution is more than 70%, and during 15min, dissolution is more than 80%.Illustrate that granule Chinese medicine can stripping rapidly in the water liquid of regulation.
Although above-mentioned, the specific embodiment of the present invention is described; but not limiting the scope of the invention; one of ordinary skill in the art should be understood that; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (8)
1. a SLGT2 inhibitor granule, is characterized in that, is made up of SLGT2 inhibitor, crystallizing inhibitor, filler, and the mass ratio of SLGT2 inhibitor, crystallizing inhibitor, filler three is 10:0.5 ~ 10:0.5 ~ 20.
2. granule as claimed in claim 1, it is characterized in that, the mass ratio of described SLGT2 inhibitor, crystallizing inhibitor, filler three is 10:1 ~ 5:1 ~ 15.
3. granule as claimed in claim 1, is characterized in that, described SLGT2 inhibitor is that Ka Gelie is clean, Da Gelie clean or Yi Palie is clean.
4. granule as claimed in claim 1, it is characterized in that, described SLGT2 inhibitor is monomer.
5. granule as claimed in claim 1, it is characterized in that, described crystallizing inhibitor is selected from any one in polyvidone, polyvinyl alcohol-polyethyleneglycol-graft copolymer, hyprolose, hypromellose, or mixture two or more arbitrarily.
6. granule as claimed in claim 1, it is characterized in that, described filler is selected from any one in lactose, mannitol, xylitol, or mixture two or more arbitrarily.
7. the preparation method of the granule as described in as arbitrary in claim 1-6, is characterized in that, comprise 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 and filler are dissolved in or are dispersed in organic solvent in water or moisture, and the mass ratio of solid and liquid is 1:(5 ~ 20), described solid is crystallizing inhibitor and filler, and described liquid is organic solvent in water or moisture;
(3) under stirring, the liquid of step (1) gained is poured in the liquid of step (2) gained, Keep agitation 10 minutes ~ 1 hour;
(4) by the organic slurry spraying dry that step (3) is obtained, controlling spray-dired temperature is 100 ~ 120 DEG C, collects the material after spraying dry, crosses 60 mesh sieves, obtains SLGT2 inhibitor granule;
Described step (1) and (2) middle organic solvent used are any one in acetone, ethanol, isopropyl alcohol, or mixture two or more arbitrarily.
8. preparation method as claimed in claim 7, is characterized in that, the moisture organic solvent used in described step (2) for ethanol, volume fraction that volume fraction is 10% be 15% acetone or volume fraction be the isopropyl alcohol of 20%.
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| 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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| 臧丽等: "钠－葡萄糖共转运蛋白2抑制剂的临床应用", 《中国实用内科杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| CN104382859B (en) | 2017-12-08 |
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