CN105582008A - Composition containing vildagliptin and metformin and preparation method of composition - Google Patents
Composition containing vildagliptin and metformin and preparation method of composition Download PDFInfo
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- CN105582008A CN105582008A CN201410643205.1A CN201410643205A CN105582008A CN 105582008 A CN105582008 A CN 105582008A CN 201410643205 A CN201410643205 A CN 201410643205A CN 105582008 A CN105582008 A CN 105582008A
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Abstract
The invention discloses a composition containing vildagliptin and metformin and a preparation method of the composition. The composition contains more than 20% of a binding agent in terms of dry weight, wherein the metformin is prepared by virtue of a fluidized bed in a mode of hot-melting granulating. According to the composition provided by the invention, the compressibilities and the liquidities of the vildagliptin and the metformin are improved, and the method is simple and convenient to operate, low in production cost, environment-friendly and efficient. A prepared composite tablet is qualified in friability and rapid to dissolve out.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and system thereof that vildagliptin and melbine are active component that containPreparation Method.
Background technology
Diabetes are due to insufficient insulin or the caused glucose of insulin cell metabolism defect, albumenA kind of syndrome of matter and disorders of lipid metabolism. Along with the prolongation of ill time of diabetes, the metabolism in health is disorderlyDisorderly control as can not get, can cause a series of complication. Diabetes have become the cardiovascular and cerebrovascular that continues, malignant tumourThe third-largest disease of serious harm human health afterwards. According to Pathologic Characteristics, diabetes can be divided into I type sugarUrine disease and type ii diabetes. Type ii diabetes is Non-Insulin Dependent Diabetes Mellitus, how after 35-40 year, sends outDisease, accounts for diabetic more than 90%. Type ii diabetes, taking insulin resistance as feature, shows as pancreas islet β thinBorn of the same parents carry out sexual exhaustion, thereby cause hypoinsulinism after glucose load, and damage incretin is to sugarReaction.
Composition in the present invention, comprises two kinds of antidiabetic drugs that the mechanism of action is different, for diet control and motionThe IJ type treating diabetes that still can not suitably control, also for Metformin hydrochloride or vildagliptin can not be controlled separatelyThe type ii diabetes treatment of system.
Vildagliptin (vildagliptin), its chemical name is:: 1-[[(3-hydroxyl-1-adamantyl) ammoniaBase] acetyl group]-2-cyano group-(S)-tetrahydro pyrrolidine. Molecular formula is C17H15N3O2, relative molecular massBe 303.4, structural formula is as follows:
Vildagliptin is a kind ofly to have selective, competitive, reversible DPP IV (DPP-IV) and press downPreparation, it forms by being combined with DPP-IV the activity that DPP-IV compound suppresses dipeptidyl peptidase,Improve glucagon kind polypeptide-1 (GLP-1) concentration, when impelling beta Cell of islet to produce insulin,Reduce hyperglycemic factor concentration, thereby reduce blood sugar. Vildagliptin has no significant effect body weight, and its side effect onlyBe limited to hypoglycemia and edema, very nearly the same with the effectiveness of placebo.
Melbine (Metformin), conventional its hydrochloride clinically, i.e. Metformin hydrochloride, its chemical nameBe called 1,1-Dimethylbiguanide hydrochloride, relative molecular mass is 165.63, and molecular formula is C4Hi1N5·HCl，Structural formula is as follows:
Melbine is the hypoglycemic drug of biguanides, is that current World Developed Countries is widely used unique oralThe antihyperglycemic medicine of class, can improve type ii diabetes patient to sugared tolerance, reduction basis and after the meal blood plasma PortugalGrape sugar concentration. Melbine is with the mechanism of action difference of sulfonylurea drugs, normal person and type ii diabetes patientIn do not produce hypoglycemic reaction, do not produce hyperinsulinemia yet. The hypoglycemic mechanism of melbine comprises following severalPoint: (1) promotes the utilization of surrounding tissue cell to glucose; (2) suppress gluconeogenesis function of liver, therefore fallThe output of low glycogen; (3) suppress intestines parietal cell ingestion of glucose, different from insulin action, this product is without shortMake the effect of Fatty synthesis, normal person, without obvious hypoglycemic activity, therefore, is not generally caused to hypoglycemia. TwoFirst biguanides can be used for the unsatisfied Non-Insulin Dependent Diabetes Mellitus patient of diet-treated only, especially fatPerson, not only has hypoglycemic activity with this class medicine, also may slimming effect. But biguanidesBe not suitable for the patient that body weight is lighter and take, its topmost side effect is to cause lactic acidosis.
EMEA is in vildagliptin/hydrochloric acid diformazan of approval Novartis on November 14th, 2007 (Novartis)Biguanides Compound TabletListing, treatment type ii diabetes, is used for the treatment of and uses melbine maximum resistance toBe subject to dosage still can not effectively control the patient of blood sugar or combine at present and use vildagliptin (Galvus) and diformazanThe patient of biguanides. The dosage specification of this composite tablet be vildagliptin/Metformin hydrochloride 50mg/850mg or50mg/1000mg。
The patent CN101277688B of Novartis Co.,Ltd discloses one and has comprised DPP IV (DPP-IV)The formulation of inhibitor, preferably vildagliptin and Metformin hydrochloride, discloses the preparation method of compoundFor hot-melt extruded is granulated. In this patent, first melbine and adhesive are granulated by extruder hot melt, thenVertical compression or pelletizing press sheet after mixing with vildagliptin and other auxiliary materials. Metformin hydrochloride is crystal, poor compressibility,Dosage is large; Vildagliptin poor compressibility simultaneously, to damp and hot sensitivity, therefore the preparation of composite tablet exists a lot of difficult points.This patent provides a kind of method that improves melbine compressibility, expensive but the method need to be usedHot-melt extruded machine, industrial production cost is high, has increased patient's medication burden.
The patent 201410110433.2 of Jiangsu Olympic Competition health discloses the compound of a kind of vildagliptin and melbineComposition and method of making the same. Adopt organic solvent by melbine and adhesive wet granulation, then with Wei GelieCompressing tablet after spit of fland and other auxiliary materials mix, or vildagliptin is dissolved in to organic solvent, then with its to melbine with stickyMixture carries out wet granulation, finally adds all the other auxiliary materials to carry out compressing tablet.
It is the emerging a kind of granulation technique of Abroad in Recent Years that fluid bed heat is founded grain, is different from hot-melt extruded and granulates.This technology does not need to use the equipment such as special and expensive hot-melt extruded granulator, only needs fluid bed to get final product realExisting, and fluid bed is the conventional equipment generally using in modern pharmaceutical factory. The principle of this technology is first by be granulatedThe auxiliary material (as polyethylene glycol, poloxamer etc.) that material and fusing point are lower mixes, and material is at fluid mapper processIn be heated to gradually after the fusing point of this auxiliary material, storeroom move each other and mutually collision and bonding, temperature is reduced toAfter condensation point, material is solidified into granule, and this mobility of particle, compressibility are better. This technology is time saving and energy saving, quickEfficiently, be particularly useful for poor compressibility, the material of Brittle deformation easily occurs. Compared with hot-melt extruded technology, toolThere are energy-saving and emission-reduction, the advantage reducing production costs.
Summary of the invention
The invention discloses the composition that a kind of vildagliptin and Metformin hydrochloride are active component, its feature existsBe that fluid bed heat is founded the particle that grain obtains, the ratio of contained pharmaceutically acceptable adhesive in particle in Metformin hydrochlorideBe greater than 20% with dry weight basis.
The invention provides a kind of preparation method of vildagliptin melbine compound, for fluid bed heat is foundedGrain, comprises melbine and adhesive, after glidant mixes, carries out fluidized bed granulation, by the particle of systemEven with vildagliptin and mix lubricant, compressing tablet, dressing.
On the other hand, the invention discloses the combination that a kind of vildagliptin and Metformin hydrochloride are active componentThing, the adhesive that it is characterized in that said composition is polyethylene glycol, poloxamer, PVP or microcrystalline celluloseOne or more mixture, its consumption accounts for the more than 20% of particle.
On the other hand, the invention discloses the combination that a kind of vildagliptin and Metformin hydrochloride are active componentThing, is characterized in that the glidant of said composition is selected from silica, cataloid, a kind of in talcum powderOr several mixtures, its consumption accounts for the 0.1-2% of particle dry weight.
On the other hand, the invention discloses the combination that a kind of vildagliptin and Metformin hydrochloride are active componentThing, the lubricant that it is characterized in that said composition be selected from dolomol, stearic acid, calcium stearate, talcum powder,A kind of in lauryl sodium sulfate, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate, Compritol 888 ATOOr several mixtures, the 0.1-2% of composition quality in its weight, preferably 0.5-1.5%.
Pharmaceutical composition of the present invention is oral formulations, is preferably tablet.
Preparation method of the present invention be by hot melt granulation technique first by Metformin hydrochloride granulation, then pass throughAfter adding vildagliptin and lubricant, be prepared into tablet.
Concrete, preparation method of the present invention, comprises the following steps:
A) Metformin hydrochloride and vildagliptin are pulverized respectively, sieved;
B), by Metformin hydrochloride, polyethylene glycol and silica carry out hot melt after putting and mixing in fluid bedGranulate;
C) particle making is put to room temperature, mixes compressing tablet, dressing with vildagliptin and dolomol.
The molten granulating process of fluid bed heat adopting in the present invention does not need to be dried, and one is granulated, is mixed in to collection,When improving melbine with vildagliptin compressibility, avoid again vildagliptin to contact with damp and hot. Have simpleEasy to operate, reduce production costs, the advantage such as improve the quality of products. Compared with hot-melt extrusion process, there is equipmentAdvantage cheap and easy to get, easy and simple to handle; And compared with wet granulation, saved preparation adhesive, dry etc.Operational sequence, has saved the production costs such as equipment, material, man-hour, has reduced labour intensity.
Detailed description of the invention
Further illustrate by the following examples the present invention, but not as limitation of the present invention.
Embodiment 1-3
Pharmaceutical composition of the present invention, preferably fills a prescription composed as follows: prescription (1000 amounts, unit: g)
Preparation method of composition of the present invention, comprises the following steps:
A) Metformin hydrochloride was pulverized 60 mesh sieves, for subsequent use;
B) take recipe quantity Metformin hydrochloride and PEG6000, mix, put in fluid bed, wind is setUnit frequency 45Hz, 65 DEG C of temperature of charge, carry out hot melt granulation;
C) obtain particle and put to room temperature, the whole grain of 30 mesh sieves;
D) add vildagliptin and dolomol, mix compressing tablet.
Embodiment 4-6
Pharmaceutical composition of the present invention, preferably fills a prescription composed as follows: prescription (1000 amounts, unit: g)
Preparation method of composition of the present invention is with embodiment 1-3.
Embodiment 7-10
Pharmaceutical composition of the present invention, preferably fills a prescription composed as follows: prescription (1000 amounts, unit: g)
Preparation technology parameter is as follows:
| Parameter | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 |
| Blower fan frequency/Hz | 20 | 30 | 40 | 50 |
| Temperature of charge/DEG C | 55 | 60 | 65 | 70 |
Preparation method of composition of the present invention, comprises the following steps:
A) Metformin hydrochloride was pulverized 60 mesh sieves, for subsequent use;
B) take recipe quantity Metformin hydrochloride and PEG8000, mix, put in fluid bed, it is setParameter as shown above;
C) obtain particle and put to room temperature, the whole grain of 30 mesh sieves;
D) add vildagliptin and dolomol, mix compressing tablet.
The determination of physical appearance of experimental example 1, particle of the present invention and tablet
Get particle and the tablet of above-described embodiment 1-10, carry out mobility of particle, tablet hardness, friability surveyExamination
Mobility of particle (angle of repose), bulk density, make real density, tablet hardness, the measurement result of friabilitySee the following form:
Experimental example 2, particle size distribution of the present invention are measured
Get the particle of above-described embodiment 1-10, sieve method distributes and investigates particle diameter, and result is as follows:
Experimental example 3, stripping curve of the present invention are measured
Condition determination: slurry method, 0.01N hydrochloric acid solution, 1000ml, 50rpm, 37 DEG C.
5,10,15,30,45min sample time:.
In embodiment 1-10, vildagliptin stripping data are as follows:
In embodiment 1-10, melbine stripping data are as follows:
Claims (11)
1. the composition that vildagliptin and Metformin hydrochloride are active component, is characterized in thatMetformin hydrochloride is that fluid bed heat is founded the particle that grain obtains, contained pharmaceutically acceptable in particleThe ratio of adhesive is greater than 20% with dry weight basis.
2. pharmaceutical composition as claimed in claim 1, is characterized in that, in hot melt pelletizationIt is the pharmaceutically acceptable adhesive of 50～100 DEG C that adhesive therefor comprises fusing point.
3. the pharmaceutical composition as described in claim as arbitrary in claim 1～2, is characterized in that,In hot melt pelletization, adhesive therefor is polyethylene glycol, poloxamer, PVP or micro-The mixture of one or more of crystal fiber element.
4. pharmaceutical composition as claimed in claim 1, is characterized in that, thing when hot melt is granulatedMaterial temperature degree is 50～100 DEG C.
5. the pharmaceutical composition as described in claim 1～4, is characterized in that, when hot melt is granulatedTemperature of charge is 50～80 DEG C.
6. the pharmaceutical composition as described in claim 1～4, is characterized in that, when hot melt is granulatedTemperature of charge is 55～70 DEG C.
7. the pharmaceutical composition as described in claim 1～6, is characterized in that, in particle, comprises and helpsStream agent, glidant comprises silica, cataloid is a kind of or several in talcum powderThe mixture of planting.
8. pharmaceutical composition as claimed in claim 7, is characterized in that, glidant is preferably twoSilica, its consumption is 0.1%～2%.
9. pharmaceutical composition as claimed in claim 1, is characterized in that, described excipient comprisesLubricant, is selected from: dolomol, stearic acid, calcium stearate, talcum powder, dodecaneBase sodium sulphate, hydrogenated vegetable oil, polyethylene glycol, sodium stearyl fumarate, behenic acid glycerineThe mixture of one or more in ester.
10. composition claimed in claim 9, is characterized in that, lubricant is preferably dolomol,Its consumption is 0.1%～2%, is preferably 0.5%～1.5%.
The preparation method of the composition described in 11. claim 1-10 any one, is characterized in that,Preparation technology is as follows:
A) Metformin hydrochloride and vildagliptin are pulverized respectively, sieved;
B) by adding adhesive and glidant in Metformin hydrochloride, mix fluid bed heatFound grain;
C) after particle is cooling, add vildagliptin and lubricant, mix;
D) adopt suitable drift compressing tablet, film coating.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410643205.1A CN105582008A (en) | 2014-11-14 | 2014-11-14 | Composition containing vildagliptin and metformin and preparation method of composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410643205.1A CN105582008A (en) | 2014-11-14 | 2014-11-14 | Composition containing vildagliptin and metformin and preparation method of composition |
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| Publication Number | Publication Date |
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| CN105582008A true CN105582008A (en) | 2016-05-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410643205.1A Withdrawn CN105582008A (en) | 2014-11-14 | 2014-11-14 | Composition containing vildagliptin and metformin and preparation method of composition |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106265641A (en) * | 2016-08-12 | 2017-01-04 | 齐鲁制药有限公司 | A kind of pharmaceutical composition containing vildagliptin and metformin and preparation method thereof |
| CN106421794A (en) * | 2016-09-27 | 2017-02-22 | 黑龙江珍宝岛药业股份有限公司 | Drug compound for treating type II diabetes and preparation method thereof |
| CN106580962A (en) * | 2016-12-30 | 2017-04-26 | 江苏晶立信医药科技有限公司 | Compound metformin and vildagliptin tablet and preparation method thereof |
| CN106924237A (en) * | 2017-03-03 | 2017-07-07 | 杭州华东医药集团新药研究院有限公司 | A kind of pharmaceutical composition of and Metformin hydrochloride net containing En Gelie |
| CN107536831A (en) * | 2016-06-29 | 2018-01-05 | 深圳翰宇药业股份有限公司 | A kind of composition and preparation method containing vildagliptin and melbine |
| CN114306267A (en) * | 2020-09-30 | 2022-04-12 | 深圳翰宇药业股份有限公司 | Sitagliptin and metformin tablet preparation and preparation method thereof |
| EP4171532A4 (en) * | 2020-06-25 | 2024-07-24 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A stable combination of vildagliptin and metformin hci |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277688A (en) * | 2005-09-29 | 2008-10-01 | 诺瓦提斯公司 | Formulation comprising metformin and vildagli ptin |
| CN103070864A (en) * | 2012-12-06 | 2013-05-01 | 华润赛科药业有限责任公司 | Repaglinide and metformin hydrochloride medicinal composition and its preparation method |
| CN103083672A (en) * | 2008-04-03 | 2013-05-08 | 贝林格尔.英格海姆国际有限公司 | DPP-IV inhibitor combined with further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
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2014
- 2014-11-14 CN CN201410643205.1A patent/CN105582008A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277688A (en) * | 2005-09-29 | 2008-10-01 | 诺瓦提斯公司 | Formulation comprising metformin and vildagli ptin |
| CN103083672A (en) * | 2008-04-03 | 2013-05-08 | 贝林格尔.英格海姆国际有限公司 | DPP-IV inhibitor combined with further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
| CN103070864A (en) * | 2012-12-06 | 2013-05-01 | 华润赛科药业有限责任公司 | Repaglinide and metformin hydrochloride medicinal composition and its preparation method |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107536831A (en) * | 2016-06-29 | 2018-01-05 | 深圳翰宇药业股份有限公司 | A kind of composition and preparation method containing vildagliptin and melbine |
| CN106265641A (en) * | 2016-08-12 | 2017-01-04 | 齐鲁制药有限公司 | A kind of pharmaceutical composition containing vildagliptin and metformin and preparation method thereof |
| CN106265641B (en) * | 2016-08-12 | 2019-07-30 | 齐鲁制药有限公司 | A kind of pharmaceutical composition and preparation method thereof containing vildagliptin and melbine |
| CN106421794A (en) * | 2016-09-27 | 2017-02-22 | 黑龙江珍宝岛药业股份有限公司 | Drug compound for treating type II diabetes and preparation method thereof |
| CN106580962A (en) * | 2016-12-30 | 2017-04-26 | 江苏晶立信医药科技有限公司 | Compound metformin and vildagliptin tablet and preparation method thereof |
| CN106924237A (en) * | 2017-03-03 | 2017-07-07 | 杭州华东医药集团新药研究院有限公司 | A kind of pharmaceutical composition of and Metformin hydrochloride net containing En Gelie |
| CN106924237B (en) * | 2017-03-03 | 2019-12-03 | 杭州华东医药集团新药研究院有限公司 | It is a kind of containing En Gelie is net and the pharmaceutical composition of Metformin hydrochloride |
| EP4171532A4 (en) * | 2020-06-25 | 2024-07-24 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | A stable combination of vildagliptin and metformin hci |
| CN114306267A (en) * | 2020-09-30 | 2022-04-12 | 深圳翰宇药业股份有限公司 | Sitagliptin and metformin tablet preparation and preparation method thereof |
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