CN103463090A - Preparation method of sitagliptin metformin hydrochloride compound preparation - Google Patents
Preparation method of sitagliptin metformin hydrochloride compound preparation Download PDFInfo
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- CN103463090A CN103463090A CN201310412920XA CN201310412920A CN103463090A CN 103463090 A CN103463090 A CN 103463090A CN 201310412920X A CN201310412920X A CN 201310412920XA CN 201310412920 A CN201310412920 A CN 201310412920A CN 103463090 A CN103463090 A CN 103463090A
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Abstract
The invention relates to a preparation method of a sitagliptin metformin hydrochloride compound preparation. The preparation method comprises the following steps of (1) preparing a pelletization solution by using sitagliptin and an adhesive; (2) mixing metformin hydrochloride, a filler and a disintegrating agent; (3) spraying the pelletization solution in the step (1) onto the surface of the mixture in the step (2) for pelleting; (4) drying and granulating; and (5) adding a lubricating agent, and uniformly mixing, wherein the sum of the using percentages of the materials is 100 percentage by weight, and the adhesive can be mixed with the metformin hydrochloride, the filler and the disintegrating agent together in the step two instead of being added in the step (1). The preparation method can be used for preparing the sitagliptin metformin hydrochloride compound preparation with relatively good sitagliptin content uniformity, especially tablets.
Description
Technical field
The present invention relates to a kind of preparation method of sitagliptin metformin hydrochloride compound preparation.
Background technology
Sitagliptin is a kind of DPP-4(dipeptidyl peptidase-IV) inhibitor, it plays a role by the activation that delays the incretin in the type 2 diabetes mellitus patient body.Sitagliptin increases and extends action effect and time in the body of this hormone by the bulk concentration that increases this hormone.Incretin is the part of the endogenous system of glucose homeostasis physiological regulation, and it comprises glucagon-like-peptide-1 (GLP-1) and dependence on the glucose Xing Cu island element polypeptide (GIP), can be discharged by small intestinal in whole day, but increase to some extent in level after the meal.When blood sugar concentration is normal or raise, GLP-1 and GIP increase the synthetic of insulin and discharge by beta Cell of islet by signal pathway (comprising cyclic adenosine monophosphate) in cell.GLP-1 also can reduce alpha Cell of islet secretion glucagon, thereby reduces liver synthesizing glucose.Sitagliptin increases the release of insulin by the level that increases and extend active incretin, and reduces the level of glucose in the circulation of blood glucose dependency.Sitagliptin shows the selectivity retardance effect of DPP-4 and can not block DPP-8(dipeptidyl peptidase-VIII close to the external concentration level of therapeutic dose) or DPP-9(dipeptidyl peptidase-IX).
Metformin is a kind of biguanides, can improve type 2 diabetes mellitus patient's glycemic control, reduces basic blood sugar level and level of postprandial blood sugar.Metformin can reduce synthetic to glucose of liver, reduces small intestinal and increases insulin sensitivity to the absorption of glucose and by picked-up and the utilization that improves the periphery glucose.Metformin can not cause hypoglycemia in type 2 diabetes mellitus patient and healthy population under normal circumstances, can not cause hyperinsulinemia yet.During using Or Metformin In Treating, the secretion of insulin is unaffected, but the fasting insulin level and in the daytime insulin level really can decrease.
In July, 2012, state food and drug administration has ratified to be used for the treatment of the new oral tablet of type 2 diabetes mellitus
this medicine formally went on the market in Chinese market on January 24th, 2013.
be the complex of first orally-taken blood sugar reducing medicine DPP-4 inhibitor, it contains two kinds can provide lasting ingredient-sitagliptin and the metformin of effectively controlling blood glucose.
for the type 2 diabetes mellitus patient provides the excessively strong treatment selection of output of the large defect of direct attack disease three-beta Cell of islet insulin deficit, insulin resistant and hepatic glycogen.
Chinese patent CN101365432B discloses the pharmaceutical composition of the combination of dipeptidyl peptidase-4 inhibitors and metformin, has described tablet formulation of DPP-4 inhibitor and metformin combination and preparation method thereof.This pharmaceutical composition comprises by weight 3～20% DPP4-inhibitor or its pharmaceutically acceptable salt, 25～94% Metformin, 0.1～10% lubricant, 0～35% binding agent.Preparation method is, after DPP-4 inhibitor and metformin hydrochloride are put into to high speed shear wet granulator or fluid bed and mixed, first to add purified water to be granulated, and after drying, adds the aqueous solution of binding agent further to granulate, drying again.Then the dried particles made is ground, the fine grained that grinding is obtained is mixed homogeneously and is carried out tabletting, coating with filler, lubricant etc.Also can for example roll by pharmaceutical composition by direct pressing or dry granulation, be prepared.
Summary of the invention
In above-mentioned patent, the shared ratio great disparity of DPP-4 inhibitor and metformin hydrochloride-DPP-4 inhibitor: 3～20%, preferably 5～18%; Metformin hydrochloride: the particle size range of 25～94%, preferably 65～77%, and two kinds of crude drug may be inconsistent, so this technical scheme exists the DPP-4 inhibitor to mix inhomogeneous probability with metformin hydrochloride.
For solving this technical problem, the invention provides a kind of preparation method of sitagliptin metformin hydrochloride compound preparation, said method comprising the steps of:
1) by 1～18 % by weight, preferably the sitagliptin of 2～15 % by weight is dissolved in purified water, adds 0.5～8 % by weight, and preferably the binding agent of 1～3 % by weight is made granulation solution;
2) by 20～95 % by weight, the preferably metformin hydrochloride of 50～80 % by weight and 10～40 % by weight, the preferably filler of 10～20 % by weight, 1～10 % by weight, preferably the disintegrating agent of 1～3 % by weight is mixed;
3) granulated in the granulation spray solution of step 1 to the mixture surface of step 2;
4) drying, granulate;
5) add the mix lubricant of 0.5～3 % by weight even;
In said method, the usage ratio summation of each material is 100 % by weight.
In said method, can in step 1), not add binding agent, and in step 2 yet) in described binding agent is mixed together with metformin hydrochloride, filler, disintegrating agent.
The granule that method of the present invention makes can be directly granule, or granule is made to tablet or capsule etc.In one embodiment, the inventive method gained granule is made to tablet.
When being made into tablet, the granule of getting aforementioned preparation carries out tabletting.Preferably, can carry out coating after tabletting.
Use method of the present invention can make the better sitagliptin metformin hydrochloride of sitagliptin uniformity of dosage units compound preparation, especially tablet.
The specific embodiment
The invention provides a kind of preparation method of sitagliptin metformin hydrochloride compound preparation, said method comprising the steps of:
1) by 1～18 % by weight, preferably the sitagliptin of 2～15 % by weight is dissolved in purified water, adds 0.5～8 % by weight, and preferably the binding agent of 1～3 % by weight is made granulation solution;
2) by 20～95 % by weight, the preferably metformin hydrochloride of 50～80 % by weight and 10～40 % by weight, the preferably filler of 10～20 % by weight, 1～10 % by weight, preferably the disintegrating agent of 1～3 % by weight is mixed;
3) granulated in the granulation spray solution of step 1 to the mixture surface of step 2;
4) drying, granulate;
5) add the mix lubricant of 0.5～3 % by weight even;
In said method, the usage ratio summation of each material is 100 % by weight.
Described sitagliptin comprises sitagliptin and pharmaceutically acceptable salt thereof, such as sitagliptin phosphate, sitagliptin phosphate monohydrate, hydrochloric acid sitagliptin or sulphuric acid sitagliptin etc.
In step 1),
Described binding agent is the conventional any binding agent used in this area, for example polyvinylpyrrolidone (PVP), hydroxypropyl emthylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (CMC-Na) or its mixture.
Step 1) can be under magnetic agitation beaker or rustless steel container in carry out.
In step 2) in,
Described filler is the conventional any filler used in this area except lactose, for example microcrystalline Cellulose, starch, mannitol, sucrose or dextrin, preferably microcrystalline cellulose.
Described disintegrating agent is the conventional any disintegrating agent used in this area, for example cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or pregelatinized Starch.
Step 2) mixing can be carried out in pelletizer, such as wet-mixed fast granulating machine, multifunctional top spray fluid bed etc., and while wherein being mixed in the wet-mixed fast granulating machine, rotating speed of agitator is 1000rpm, the shredder bar rotating speed is 800rpm.
In step 3),
Described sprinkling can be used for example spray gun to realize.The atomizing pressure of spray gun is 0.5～2.0bar.
In step 4),
Drying is carried out in fluid bed, and when dry, temperature of charge is 30～50 ℃, and preferably 40 ℃, the air intake flow is 50～120m
3/ h, preferably 70m
3/ h, being dried to pellet moisture is 1～3%.
Step 5) lubricant used is the conventional any lubricant used in this area, such as magnesium stearate, Pulvis Talci, micropowder silica gel, fumaroyl sodium stearate etc.
In said method, can in step 1), not add binding agent, and in step 2 yet) in described binding agent is mixed together with metformin hydrochloride, filler, disintegrating agent.
Use method of the present invention can make the better sitagliptin metformin hydrochloride of sitagliptin uniformity of dosage units compound preparation, especially tablet.
Describe the present invention in detail referring to embodiment, should be understood that following embodiment is intended to explanation, is not construed as limiting the present invention.
Hereinafter listed the reagent and the medicine source that use in an embodiment:
Sitagliptin phosphate monohydrate: self-control (preparation method is referring to CN102516184A)
Metformin hydrochloride: Shandong Keyuan Pharmaceutical Co.,Ltd
Jie Nuoda: Mo Shadong pharmaceutical Co. Ltd
Microcrystalline Cellulose: German JRS company
Cross-linking sodium carboxymethyl cellulose: U.S. FMC Corp.
Magnesium stearate: Ahua Pharmaceutical Co., Ltd., Liaocheng, Shandong
Opadry, I Opadry II, HPMC (5cp): Shanghai Colorcon Coating Technology Co., Ltd
Polyvinylpyrrolidone: American I SP company
Low-substituted hydroxypropyl cellulose, fumaroyl sodium stearate: Anhui Shanhe Medical Accessary Material Co., Ltd.
Potassium dihydrogen phosphate: 1Guanghua Chemical Plant Co., Ltd., Guangdong
Acetonitrile: Sinence Company Inc
Methanol: Spain's Sa labor company limited
The preparation of embodiment 1. sitagliptin metformin hydrochloride Compound Tablets
(1) in beaker, 64.25g sitagliptin phosphate monohydrate is joined in the 600mL purified water, add 30g polyvinylpyrrolidone magnetic agitation to be prepared into the granulation solution of wet granulation;
(2) 500g metformin hydrochloride and 200g microcrystalline Cellulose, 10g cross-linking sodium carboxymethyl cellulose are put into to Mini-CG-2/10 wet-mixed fast granulating machine and mix, during mixing, rotating speed of agitator is 1000rpm, and the shredder bar rotating speed is 800rpm;
(3) use spray gun device that the granulation spray solution is carried out to wet granulation to the mixture surface of (2), the atomizing pressure of spray gun is 0.8bar;
(4) dry in fluid bed after granulation, granulate, when dry, temperature of charge is 40 ℃, the air intake flow is 70m
3/ h, being dried to pellet moisture is 1%;
(5) in the granule of (4), add the 5g magnesium stearate to mix, use C& C800 tablet machine tabletting, prepare 1000 altogether;
(6) use Opadry
the row coating, coating weightening finish 2%, obtain sitagliptin metformin hydrochloride Compound Tablet.
The preparation of embodiment 2. sitagliptin metformin hydrochloride Compound Tablets
(1) in rustless steel container, 64.25g sitagliptin phosphate monohydrate is joined in the 800mL purified water, add 10g hydroxypropyl emthylcellulose (5cp) magnetic agitation to be prepared into the granulation solution of wet granulation;
(2) 1000g metformin hydrochloride and 300g microcrystalline Cellulose, 20g cross-linking sodium carboxymethyl cellulose being put into to GPCG2 multifunctional top spray fluid bed mixes;
(3) use spray gun device that the granulation spray solution is carried out to wet granulation to the mixture surface of (2), the atomizing pressure of spray gun is 1.0bar;
(4) dry in fluid bed after granulation, granulate, when dry, temperature of charge is 35 ℃, the air intake flow is 100m
3/ h, being dried to pellet moisture is 1%;
(5) in the granule of (4), add the 10g micropowder silica gel to mix, use C& C800 tablet machine tabletting, prepare 1000 altogether;
(6) use Opadry
the row coating, coating weightening finish 3%, obtain sitagliptin metformin hydrochloride Compound Tablet.
The preparation of embodiment 3. sitagliptin metformin hydrochloride Compound Tablets
(1) in beaker, 124.06g sitagliptin phosphate monohydrate is joined in the 800mL purified water, add 20g polyvinylpyrrolidone magnetic agitation to be prepared into the granulation solution of wet granulation;
(2) the 1000g metformin hydrochloride is put into to the wet-mixed fast granulating machine with 200g microcrystalline Cellulose, 30g low-substituted hydroxypropyl cellulose and mix, during mixing, rotating speed of agitator is 1000rpm, and the shredder bar rotating speed is 800rpm;
(3) use spray gun device that the granulation spray solution is carried out to wet granulation to the mixture surface of (2), the atomizing pressure of spray gun is 1.2bar;
(4) dry after granulation, granulate, when dry, temperature of charge is 45 ℃, the air intake flow is 110m
3/ h, being dried to pellet moisture is 1%;
(5) in the granule of (4), add 15g fumaroyl sodium stearate to mix, use C& C800 tablet machine tabletting, prepare 1000 altogether;
(6) use the aqueous solution of 1%HPMC (5cp) to carry out coating, coating weightening finish 2%, obtain sitagliptin metformin hydrochloride Compound Tablet.
The preparation of embodiment 4. sitagliptin metformin hydrochloride Compound Tablets
(1) in beaker, 124.06g sitagliptin phosphate monohydrate is joined in the 800mL purified water, magnetic agitation is prepared into the granulation solution of wet granulation;
(2) the 1000g metformin hydrochloride is put into to the wet-mixed fast granulating machine with 200g microcrystalline Cellulose, 20g polyvinylpyrrolidone, 30g low-substituted hydroxypropyl cellulose and mix, during mixing, rotating speed of agitator is 1000rpm, and the shredder bar rotating speed is 800rpm;
(3) use spray gun device that the granulation spray solution is carried out to wet granulation to the mixture surface of (2), the atomizing pressure of spray gun is 1.2bar;
(4) dry after granulation, granulate, when dry, temperature of charge is 45 ℃, the air intake flow is 110m
3/ h, being dried to pellet moisture is 2%;
(5) in the granule of (4), add 15g fumaroyl sodium stearate to mix, use C& C800 tablet machine tabletting, prepare 1000 altogether;
(6) use the aqueous solution of 1%HPMC (5cp) to carry out coating, coating weightening finish 2%, obtain sitagliptin metformin hydrochloride Compound Tablet.
Embodiment 5. sitagliptin uniformity of dosage units detect
Use high performance liquid chromatography to detect the content of sitagliptin in preparation.The highly effective liquid phase chromatographic system used is Waters e2695-2489, mobile phase is 0.02mM potassium phosphate buffer (pH4.6)-acetonitrile-methanol (30:50:20), flow velocity is 1.0mL/min, the detection wavelength is 220nm, chromatographic column is Symmertry Waters C18 post (150 * 4.6mm, 5 μ m).1, tablet getting embodiment 1 is placed in the 100mL volumetric flask, add above-mentioned mobile phase to about 50mL, ultrasonic 3min, then add mobile phase and be diluted to scale, shakes up, filter, collect filtrate, precision measures in filtrate 5mL to 50mL volumetric flask, adds mobile phase and is diluted to scale, shake up, be mixed with containing the about sample solution a of 50 μ g/mL of sitagliptin.The tablet a slice of separately getting embodiment 4 is placed in the 100mL volumetric flask, add above-mentioned mobile phase to about 50mL, ultrasonic 3min, then add mobile phase and be diluted to scale, shakes up, filter, collect filtrate, precision measures in filtrate 5mL to 50mL volumetric flask, adds mobile phase and is diluted to scale, shake up, be mixed with containing the about sample solution b of 50 μ g/mL of sitagliptin.Get sitagliptin phosphate monohydrate reference substance 6.425mg, put in the 100mL volumetric flask, add mobile phase and dissolve and be diluted to scale, shake up, be mixed with the reference substance solution containing sitagliptin 50 μ g/mL.Get reference substance solution, each 25 μ L injection liquid chromatographies of sample solution, record chromatogram, calculate respectively the content of embodiment 1 and embodiment 2 every middle sitagliptins by external standard method.According to two appendix X E of Chinese Pharmacopoeia version in 2010, get the tablet of 10 embodiment 1 preparation, measure respectively every and take the sitagliptin relative amount X that labelled amount is 100, ask its meansigma methods
absolute value with the difference of standard deviation S and labelled amount and average
calculate the value of A+1.80S.Get again the tablet of 10 embodiment, 4 preparations, calculate the value of its A+1.80S according to identical method.
Get 10 of Jie Nuoda, measure respectively according to the method described above every and take the sitagliptin relative amount X that labelled amount is 100, ask its meansigma methods
absolute value with the difference of standard deviation S and labelled amount and average
calculate the value of A+1.80S.Tablet and the Jie Nuoda of embodiment 1 and embodiment 4 are compared, the results are shown in table 1.
Sitagliptin uniformity of dosage units contrast in table 1 Jie Nuoda and embodiment 1 tablet
By result, can be found out, the sitagliptin compound tablet made by embodiment 2 or embodiment 4, the A+1.80S value of its sitagliptin is significantly less than the A+1.80S value of Jie Nuoda, illustrates that the sitagliptin in the Compound Tablet that method of the present invention makes all has better uniformity of dosage units with respect to Jie Nuoda.
Claims (9)
1. the preparation method of a sitagliptin metformin hydrochloride compound preparation said method comprising the steps of:
1) by 1～18 % by weight, preferably the sitagliptin of 2～15 % by weight is dissolved in purified water, adds 0.5～8 % by weight, and preferably the binding agent of 1～3 % by weight is made granulation solution;
2) by 20～95 % by weight, the preferably metformin hydrochloride of 50～80 % by weight and 10～40 % by weight, the preferably filler of 10～20 % by weight, 1～10 % by weight, preferably the disintegrating agent of 1～3 % by weight is mixed;
3) granulated in the granulation spray solution of step 1 to the mixture surface of step 2;
4) drying, granulate;
5) add the mix lubricant of 0.5～3 % by weight even;
In said method, the usage ratio summation of each material is 100 % by weight.
2. preparation method according to claim 1, wherein sitagliptin is sitagliptin phosphate, sitagliptin phosphate monohydrate, hydrochloric acid sitagliptin or sulphuric acid sitagliptin.
3. preparation method according to claim 2, wherein binding agent is polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or its mixture.
4. preparation method according to claim 3, wherein said filler is microcrystalline Cellulose, starch, dew alcohol, sucrose or dextrin, preferably microcrystalline cellulose.
5. preparation method according to claim 4, wherein said disintegrating agent is cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or pregelatinized Starch.
6. preparation method according to claim 5, wherein said lubricant is magnesium stearate, Pulvis Talci, micropowder silica gel or fumaroyl sodium stearate.
7. preparation method according to claim 6, wherein step 2) be blended in pelletizer and carry out, described pelletizer is wet-mixed fast granulating machine or multifunctional top spray fluid bed.
8. preparation method according to claim 7, wherein said sprinkling is used spray gun to realize, and the atomizing pressure of spray gun is 0.5～2.0bar.
9. the preparation method of claim 1-7 any one does not wherein add binding agent in step 1), and in step 2) in described binding agent is mixed together with metformin hydrochloride, filler, disintegrating agent.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104771377A (en) * | 2015-04-15 | 2015-07-15 | 海南华益泰康药业有限公司 | Preparation method of immediate release oral preparation containing sitagliptin or sitagliptin pharmaceutical salt |
| CN110215437A (en) * | 2019-07-18 | 2019-09-10 | 北京中惠药业有限公司 | A kind of metformin hydrochloride tablet and preparation method thereof |
| CN115245495A (en) * | 2022-09-21 | 2022-10-28 | 北京惠之衡生物科技有限公司 | Sitagliptin and metformin tablet and preparation method thereof |
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| CN101932241A (en) * | 2008-02-05 | 2010-12-29 | 默沙东公司 | Combination pharmaceutical composition of metformin and dipeptidyl peptidase-IV inhibitor |
| CN101959406A (en) * | 2008-03-04 | 2011-01-26 | 默沙东公司 | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-IV inhibitor |
| CN102740839A (en) * | 2009-11-13 | 2012-10-17 | 百时美施贵宝公司 | Immediate release tablet formulations |
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- 2013-09-11 CN CN201310412920XA patent/CN103463090A/en active Pending
Patent Citations (4)
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| CN101365432A (en) * | 2005-12-16 | 2009-02-11 | 默克公司 | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin |
| CN101932241A (en) * | 2008-02-05 | 2010-12-29 | 默沙东公司 | Combination pharmaceutical composition of metformin and dipeptidyl peptidase-IV inhibitor |
| CN101959406A (en) * | 2008-03-04 | 2011-01-26 | 默沙东公司 | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-IV inhibitor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104771377A (en) * | 2015-04-15 | 2015-07-15 | 海南华益泰康药业有限公司 | Preparation method of immediate release oral preparation containing sitagliptin or sitagliptin pharmaceutical salt |
| CN104771377B (en) * | 2015-04-15 | 2017-06-09 | 海南华益泰康药业有限公司 | A kind of preparation method of the oral preparation of quick releasing containing sitagliptin or its pharmaceutical salts |
| CN110215437A (en) * | 2019-07-18 | 2019-09-10 | 北京中惠药业有限公司 | A kind of metformin hydrochloride tablet and preparation method thereof |
| CN110215437B (en) * | 2019-07-18 | 2021-10-08 | 北京中惠药业有限公司 | Metformin hydrochloride tablet and preparation method thereof |
| CN115245495A (en) * | 2022-09-21 | 2022-10-28 | 北京惠之衡生物科技有限公司 | Sitagliptin and metformin tablet and preparation method thereof |
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Application publication date: 20131225 |