CN104840960A - Antidiabetic pharmaceutical composition and preparation method thereof - Google Patents
Antidiabetic pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN104840960A CN104840960A CN201410826967.5A CN201410826967A CN104840960A CN 104840960 A CN104840960 A CN 104840960A CN 201410826967 A CN201410826967 A CN 201410826967A CN 104840960 A CN104840960 A CN 104840960A
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Abstract
The invention relates to an antidiabetic pharmaceutical composition, more specifically to a pharmaceutical composition containing a DPP-4 inhibitor and metformin hydrochloride and a preparation method thereof. The composition contains DPP-4 inhibitor and metformin hydrochloride two active components, and meglumine as the stabilizer. The pharmaceutical composition has excellent storage stability and excellent dissolution characteristics. The invention also provides a preparation method of the composition, the auxiliary materials of the preparation technology are easily available and low in price, thus being suitable for industrial production.
Description
Technical field
The present invention relates to a kind of diabetes pharmaceutical composition, more specifically, relate to a kind ofly comprise pharmaceutical composition of DPP-4 inhibitor and metformin hydrochloride and preparation method thereof, belong to technical field of medicine.
Background technology
Diabetes are a kind of chronic diseases with multiple pathological manifestations, simultaneously with lipid metabolic disorder, circulatory disorder and carbohydrate metabolism disturbance.In many cases, diabetes easily develop into multiple complications to result.Therefore, be necessary to select for everyone state of an illness the medicine being applicable to prevailing disease stage.But this selection is normally more difficult when clinical implementation, this is because be used alone a kind of medicine can not produce enough curative effects when some morbid state, increase dosage or Long-term taking medicine can bring the various problems as side effect etc. simultaneously.
Dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride are treatment diabetic, and the pharmaceutical composition comprising these two kinds of active component has high clinical application.The present inventor finds when trial preparation comprises the pharmaceutical composition of these two kinds of active component, easily there is impurity with metformin hydrochloride or several formulations adjuvant (as lactose, microcrystalline Cellulose etc.) and react in DPP-4 inhibitor (especially Li Gelieting), and then has a strong impact on the stability of pharmaceutical composition.Therefore, be badly in need of providing a kind of and comprise DPP-4 inhibitor and the metformin hydrochloride stable pharmaceutical composition as active component.
Summary of the invention
Summary of the invention
The present invention is through deep research, have been surprisingly found that and add meglumine in the pharmaceutical composition comprising DPP-4 inhibitor and metformin hydrochloride, can significantly improve the stability of compositions, this may be that meglumine produces inhibitory action to the reaction of above-mentioned impurity.In addition, in preparation process, take the method that DPP-4 inhibitor and metformin hydrochloride are separately granulated separately, by physical isolation mode, reduce DPP-4 inhibitor and directly contact with metformin hydrochloride, can further improve compositions stability.
Therefore, one aspect of the present invention provides a kind of pharmaceutical composition comprising DPP-4 inhibitor and metformin hydrochloride, and said composition comprises DPP-4 inhibitor and metformin hydrochloride two kinds of active component.Described pharmaceutical composition has excellent storage stability and excellent dissolution characteristic.
The present invention on the other hand provides a kind of pharmaceutical composition comprising DPP-4 inhibitor and metformin hydrochloride, and it comprises containing DPP-4 inhibitor and first granule (hereafter claiming the first granule) of meglumine and the second granule (hereafter claiming the second granule) containing metformin hydrochloride.
The present invention also provides the method preparing pharmaceutical composition described in first aspect and second aspect, and this preparation technology's adjuvant is easy to get, cheap, is applicable to suitability for industrialized production.
Term definition
Term " optionally " or " optionally " refer to the event that describes subsequently or situation can but not necessarily occur, and this description comprises situation that wherein said event or situation occur and wherein its absent variable situation.
Detailed Description Of The Invention
First aspect, the present invention is through deep research, have been surprisingly found that and add meglumine in the pharmaceutical composition comprising DPP-4 inhibitor and metformin hydrochloride, the stability of compositions can be significantly improved, therefore the present invention relates to the pharmaceutical composition with high stability of a kind of DPP-4 of comprising inhibitor and metformin hydrochloride, said composition comprises DPP-4 inhibitor and metformin hydrochloride two kinds of active component, also comprises meglumine as stabilizing agent.
DPP-4 inhibitor of the present invention is the DPP-4 inhibitor with primary amino radical or secondary amino group, it includes but not limited to Li Gelieting, Egelieting, sitagliptin, BMS-477118, vildagliptin pharmaceutically acceptable salt, and the structural formula that these DPP-4 inhibitor are corresponding is as follows:
Unless otherwise stated, should understand according to the present invention pharmaceutically acceptable salt and hydrate, solvate and the polymorphic forms that above-named DPP-4 inhibitor also comprises them.
In some embodiments, in pharmaceutical composition of the present invention, the mass ratio of the relative metformin hydrochloride of quality of meglumine is 1:10 ~ 1:200; The mass ratio of the relative metformin hydrochloride of quality of DPP-4 inhibitor is 1:5 ~ 1:400.
In some embodiments, described pharmaceutical composition also optionally comprises pharmaceutically useful drug excipient, and described drug excipient is selected from filler, binding agent, disintegrating agent, lubricant, fluidizer, plasticizer, film coating materials, pigment or its combination.In some embodiments, described pharmaceutically useful drug excipient comprises filler, binding agent, lubricant, fluidizer.
Filler of the present invention is selected from microcrystalline Cellulose, pregelatinized Starch, corn starch, dextrin, lactose, sucrose, mannitol, calcium sulfate, calcium hydrogen phosphate or its combination; In some embodiments, described filler is selected from corn starch, mannitol, pregelatinized Starch, microcrystalline Cellulose or its combination.The percentage by weight of consumption in whole pharmaceutical composition of described filler is 2.00% ~ 30.00%.In some embodiments, the consumption of described filler is 2.00% ~ 10.00%.
Binding agent of the present invention is selected from polyvinylpyrrolidone, starch slurry, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its combination; In some embodiments, described filler is selected from polyvinylpyrrolidone.The percentage by weight of consumption in whole pharmaceutical composition of described binding agent is 3.00% ~ 10.00%.
Lubricant of the present invention is selected from stearic acid, magnesium stearate, calcium stearate, polyethylene glycol 6000, fumaric acid sodium, Glyceryl Behenate or its combination.In some embodiments, described lubricant is selected from magnesium stearate.The percentage by weight of consumption in whole pharmaceutical composition of described lubricant is 0.50% ~ 3.00%.
Fluidizer of the present invention is selected from micropowder silica gel, Pulvis Talci, magnesium stearate or its combination.In some embodiments, described fluidizer is selected from micropowder silica gel.The percentage by weight of consumption in whole pharmaceutical composition of described fluidizer is 0.50% ~ 3.00%.
In some embodiments, DPP-4 inhibitor of the present invention is Li Gelieting.
In some embodiments, in pharmaceutical composition of the present invention, the mass ratio of the relative metformin hydrochloride of quality of meglumine is 1:10 ~ 1:200; The mass ratio of the relative metformin hydrochloride of quality of Li Gelieting is 1:200 ~ 1:400.
In some embodiments, by unit dose gauge, pharmaceutical composition of the present invention comprises Li Gelieting 2.5mg, metformin hydrochloride 500mg ~ 1000mg and meglumine 5 ~ 50mg.
In some embodiments, pharmaceutical composition of the present invention, comprises Li Gelieting, metformin hydrochloride, meglumine and pharmaceutical excipient; Described excipient is filler, binding agent, lubricant, fluidizer or its combination.
In some embodiments, described pharmaceutical composition, by each component weight percentage, comprise Li Gelieting 0.10% ~ 0.50%, metformin hydrochloride 50.00% ~ 88.00%, meglumine 1.00% ~ 10.00%, filler 0% ~ 30.00%, binding agent 0% ~ 10.00%, lubricant 0% ~ 3.00% and fluidizer 0% ~ 3.00%.
In some embodiments, described pharmaceutical composition, by each component weight percentage, comprise Li Gelieting 0.20% ~ 0.50%, metformin hydrochloride 78.00% ~ 88.00%, meglumine 2.00% ~ 5.00%, filler 8.00% ~ 30.00%, binding agent 3% ~ 10.00%, lubricant 0.50% ~ 3.00% and fluidizer 0% ~ 3.00%.
In some embodiments, described pharmaceutical composition, by each component weight percentage, comprise Li Gelieting 0.20% ~ 0.45%, metformin hydrochloride 78.00% ~ 85.00%, meglumine 2.00% ~ 3.00%, filler 8.00% ~ 20.00%, binding agent 3% ~ 5.00%, lubricant 0.50% ~ 2.00% and fluidizer 0% ~ 2.00%.
In some embodiments, described pharmaceutical composition, by each components by weight percent percentage composition, comprise Li Gelieting 0.21%, metformin hydrochloride 83.33%, meglumine 2.00%, corn starch 2.00%, mannitol 7.86%, polyvinylpyrrolidone 3.60% and magnesium stearate 1.00%.
In some embodiments, the pharmaceutical composition related to, by each composition weight percentage composition, comprise Li Gelieting 0.23%, metformin hydrochloride 78.20%, meglumine 2.10%, pregelatinized Starch 5.60%, microcrystalline Cellulose 8.05%, polyvinylpyrrolidone 3.82%, magnesium stearate 1.50% and micropowder silica gel 0.5%.
In some embodiments, the pharmaceutical composition related to, by each composition weight percentage composition, comprise Li Gelieting 0.42%, metformin hydrochloride 84.00%, meglumine 2.30%, microcrystalline Cellulose 2.80%, mannitol 5.29%, polyvinylpyrrolidone 4.37% and magnesium stearate 0.82%.
Pharmaceutical composition described in first aspect present invention, adopts meglumine to DPP-4 inhibitor, especially Li Gelieting, can to react and produce inhibitory action, significantly improve the stability of compositions with the incident impurity of metformin hydrochloride as stabilizing agent.
Pharmaceutical composition described in first aspect present invention, finally can make oral solid formulation, and described oral solid formulation includes but not limited to granule, powder, tablet, capsule, suspensoid, slow releasing tablet, ordinary tablet, pill.In certain embodiments, described oral solid formulation is tablet.
The present invention is on the basis of first aspect research, also find in preparation process, take the method that DPP-4 inhibitor and metformin hydrochloride are separately granulated separately, by physical isolation mode, reduce DPP-4 inhibitor directly to contact with metformin hydrochloride, can further improve compositions stability.
Therefore, second aspect present invention provides a kind of pharmaceutical composition comprising DPP-4 inhibitor and metformin hydrochloride, its its comprise the first granule with the second granule.
First granule of the present invention, comprises DPP-4 inhibitor, meglumine, also can comprise pharmaceutically useful excipient.Described drug excipient is selected from filler, binding agent, disintegrating agent, lubricant, fluidizer, plasticizer, film coating materials, pigment or its combination.In some embodiments, described pharmaceutically useful drug excipient comprises filler, disintegrating agent, binding agent.
Second granule of the present invention, comprises metformin hydrochloride and pharmaceutically useful excipient.Described excipient is selected from filler, binding agent, disintegrating agent, lubricant, fluidizer, plasticizer, film coating materials, pigment or its combination.In some embodiments, described pharmaceutically useful drug excipient comprises binding agent.
Pharmaceutical composition described in first aspect present invention, final pharmaceutical dosage forms is oral solid formulation, and described oral solid formulation includes but not limited to granule, powder, tablet, capsule, suspensoid, slow releasing tablet, ordinary tablet, pill.In certain embodiments, described oral solid formulation is tablet.
The third aspect, the present invention also provides the method preparing pharmaceutical composition of the present invention, comprising:
1) the first granule is prepared: adopt fluidised bed granulator or high-shearing granulation machine by the DPP-4 inhibitor of recipe quantity, meglumine and other pharmaceutically useful mixed with excipients, prepare the first granule;
2) the second granule is prepared: adopt fluidised bed granulator by the metformin hydrochloride of recipe quantity and other pharmaceutically useful mixed with excipients, prepare the second granule;
3) granulate and mixing: the first granule and the second granule granulate mix homogeneously, obtains hybrid particles;
4) hybrid particles and other excipient alternatively make capsule, granule, powder, tablet, capsule, suspensoid etc.
Other excipient described comprise filler, binding agent, disintegrating agent, lubricant or its combination.Described filler is selected from microcrystalline Cellulose, pregelatinized Starch, corn starch, dextrin, lactose, sucrose, mannitol, calcium sulfate, calcium hydrogen phosphate or its combination; Described binding agent is selected from polyvinylpyrrolidone, starch slurry, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its combination; Described disintegrating agent is selected from carboxymethyl starch sodium, dried starch, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose or its combination; Described lubricant is selected from stearic acid, magnesium stearate, Pulvis Talci, polyethylene glycol 6000, fumaric acid sodium, Glyceryl Behenate or its combination.
In some embodiments, prepare the method for described pharmaceutical composition, comprising:
1) prepare the first granule: adopt fluidised bed granulator or high-shearing granulation machine by the Li Gelieting of recipe quantity, meglumine and other can medicine
Mixed with excipients, prepare the first granule;
2) the second granule is prepared: adopt fluidised bed granulator by the metformin hydrochloride of recipe quantity and other pharmaceutically useful mixed with excipients, prepare the second granule;
3) granulate and mixing: the first granule and the second granulate mix homogeneously;
4) hybrid particles makes capsule, granule, powder, tablet, capsule, suspensoid etc. with other excipient alternatively.
In some embodiments, pharmaceutical composition of the present invention can be tablet, and this tablet also carries out coating through thin film; Film coating comprises film coating materials, fluidizer, plasticizer, color element; Described film coating agent can be hydroxypropyl emthylcellulose/hydroxypropyl cellulose/ethyl cellulose, described fluidizer can be Pulvis Talci/micropowder silica gel, described plasticizer can be propylene glycol/Polyethylene Glycol/triethyl citrate/Polysorbate/Oleum Ricini, and described pigment can be iron oxide red/iron oxide yellow/titanium dioxide; In certain embodiments, this additional film coating can account for the 1-4% of described pharmaceutical composition gross weight.
In some embodiments, prepare the method for described pharmaceutical composition, comprising:
1) the first granule is prepared: recipe quantity Li Gelieting, meglumine and binding agent are added to the water the mixed solution made and comprise binding agent, pass through fluidised bed granulator, the mixed solution comprising binding agent is sprayed onto in the good filler of premixing, prepares the first granule;
2) prepare the second granule: by soluble in water for recipe quantity binding agent be mixed with solution after, by fluidised bed granulator, be sprayed onto in metformin hydrochloride, prepare the second granule;
3) granulate and mixing: the first granule and the second granulate mix homogeneously;
4) tabletting: by hybrid particles and recipe quantity mix lubricant, adopts tablet machine to carry out tabletting;
5) coating: configuration film coating solution, carries out coating in seed-coating machine.
The present invention also provides defined pharmaceutical composition preparing the purposes in medicine, and described medicine is used for the treatment of and/or preventing metabolic diseases, especially type Ⅱdiabetes mellitus and relative disease (such as diabetic complication).
Detailed description of the invention
In order to make those skilled in the art understand technical scheme of the present invention better, below disclose further some non-limiting embodiments the present invention is described in further detail.
Reagent used in the present invention all can be buied from the market or can be obtained by method described in the invention preparation.
In the present invention, min represents minute, and mg represents milligram, and LOD represents loss on drying.
Embodiment 1
Prescription forms
Preparation method:
1) the first granule is prepared: recipe quantity Li Gelieting, meglumine and polyvinylpyrrolidone are added water and obtains the mixed solution comprising binding agent, adopt fluidized bed granulation, setting inlet temperature 50 DEG C ~ 60 DEG C, temperature of charge 37 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the mannitol be pre-mixed and corn starch are added wherein and preheating 5 ~ 10min, start to spray binder solution, after hydrojet, the loss on drying (LOD) of dried particles is to 2.0% ~ 3%;
2) prepare the second granule: recipe quantity polyvinylpyrrolidone is added to the water obtained binder solution, adopt fluidized bed granulation, setting inlet temperature 45 DEG C ~ 55 DEG C, temperature of charge 34 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, metformin hydrochloride is added wherein and preheating 5 ~ 10min, start to spray binder solution, dry LOD to 1.0% ~ 1.5% after hydrojet;
3) granulate and mixing: by the first granule and the second granule granulate and mix homogeneously;
4) tabletting: hybrid particles mixes with recipe quantity magnesium stearate, adopts tablet machine to carry out tabletting;
5) coating: configuration film coating solution, carries out coating in seed-coating machine.
Embodiment 2
Prescription forms
Preparation method:
1) the first granule is prepared: recipe quantity Li Gelieting, meglumine and polyvinylpyrrolidone are added water and obtains the mixed solution comprising binding agent, adopt fluidized bed granulation, setting inlet temperature 50 DEG C ~ 60 DEG C, temperature of charge 37 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the pregelatinized Starch be pre-mixed and microcrystalline Cellulose are added wherein and preheating 5 ~ 10min, start to spray binder solution, after hydrojet, the loss on drying (LOD) of dried particles is to 2.0% ~ 3%;
2) prepare the second granule: recipe quantity polyvinylpyrrolidone is added to the water obtained binder solution, adopt fluidized bed granulation, setting inlet temperature 45 DEG C ~ 55 DEG C, temperature of charge 34 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the metformin hydrochloride be pre-mixed and pregelatinized Starch mixture are added wherein and preheating 5 ~ 10min, start to spray binder solution, dry LOD to 1.0% ~ 1.5% after hydrojet;
3) granulate and mixing: by the first granule and the second granule granulate and mix homogeneously;
4) tabletting: hybrid particles mixes with recipe quantity micropowder silica gel and magnesium stearate, adopts tablet machine to carry out tabletting;
5) coating: configuration film coating solution, carries out coating in seed-coating machine.
Embodiment 3
Prescription forms
Preparation method:
1) the first granule is prepared: recipe quantity Li Gelieting, meglumine and polyvinylpyrrolidone are added water and obtains the mixed solution comprising binding agent, adopt fluidized bed granulation, setting inlet temperature 50 DEG C ~ 60 DEG C, temperature of charge 37 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the microcrystalline Cellulose be pre-mixed and mannitol are added wherein and preheating 5 ~ 10min, start to spray binder solution, after hydrojet, the loss on drying (LOD) of dried particles is to 2.0% ~ 3%;
2) prepare the second granule: recipe quantity polyvinylpyrrolidone is added to the water obtained binder solution, adopt fluidized bed granulation, setting inlet temperature 45 DEG C ~ 55 DEG C, temperature of charge 34 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, metformin hydrochloride is added wherein and preheating 5 ~ 10min, start to spray binder solution, dry LOD to 1.0% ~ 1.5% after hydrojet;
3) granulate and mixing: by the first granule and the second granule granulate and mix homogeneously;
4) tabletting: hybrid particles mixes with recipe quantity magnesium stearate, adopts tablet machine to carry out tabletting;
5) coating: configuration film coating solution, carries out coating in seed-coating machine.
Embodiment 4 adds meglumine and does not separately granulate
Prescription forms
| Supplementary material | Weight (mg) |
| Li Gelieting | 2.50 |
| Meglumine | 24.00 |
| Corn starch | 24.00 |
| Mannitol | 118.30 |
| Polyvinylpyrrolidone | 43.20 |
| Metformin hydrochloride | 1000.00 |
| Magnesium stearate | 12.00 |
Preparation method
1) by recipe quantity Li Gelieting, metformin hydrochloride and meglumine mix homogeneously, add water again with polyvinylpyrrolidone and obtain the mixed solution comprising binding agent, adopt fluidized bed granulation, setting inlet temperature 50 DEG C ~ 60 DEG C, temperature of charge 37 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the mannitol be pre-mixed and corn starch are added wherein and preheating 5 ~ 10min, start to spray binder solution, after hydrojet, the loss on drying (LOD) of dried particles is to 2.0% ~ 3%;
2) Li Gelieting+metformin hydrochloride granule granulate is also dry;
3) granule mixes with recipe quantity magnesium stearate, adopts tablet machine to carry out tabletting;
4) configure film coating solution, in seed-coating machine, carry out coating.
Embodiment 5 comparative example: do not add meglumine and do not adopt and separately granulate
Prescription forms
| Supplementary material | Weight (mg) |
| Li Gelieting | 2.50 |
| Corn starch | 24.00 |
| Mannitol | 118.30 |
| Polyvinylpyrrolidone | 43.20 |
| Metformin hydrochloride | 1000.00 |
| Magnesium stearate | 12.00 |
Preparation method
1) by recipe quantity Li Gelieting and metformin hydrochloride mix homogeneously, add water again with polyvinylpyrrolidone and obtain the mixed solution comprising binding agent, adopt fluidized bed granulation, setting inlet temperature 50 DEG C ~ 60 DEG C, temperature of charge 37 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the mannitol be pre-mixed and corn starch are added wherein and preheating 5 ~ 10min, start to spray binder solution, after hydrojet, the loss on drying (LOD) of dried particles is to 2.0% ~ 3%;
2) Li Gelieting+metformin hydrochloride granule granulate is also dry;
3) granule mixes with recipe quantity magnesium stearate, adopts tablet machine to carry out tabletting;
4) configure film coating solution, in seed-coating machine, carry out coating.
Embodiment 6 comparative example: do not add meglumine and separately granulate
Prescription forms
Preparation method:
1) the first granule is prepared: recipe quantity Li Gelieting and polyvinylpyrrolidone are added water and obtains the mixed solution comprising binding agent, adopt fluidized bed granulation, setting inlet temperature 50 DEG C ~ 60 DEG C, temperature of charge 37 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, the mannitol be pre-mixed and corn starch are added wherein and preheating 5 ~ 10min, start to spray binder solution, after hydrojet, the loss on drying (LOD) of dried particles is to 2.0% ~ 3%;
2) prepare the second granule: recipe quantity polyvinylpyrrolidone is added to the water obtained binder solution, adopt fluidized bed granulation, setting inlet temperature 45 DEG C ~ 55 DEG C, temperature of charge 34 DEG C, fan delivery is according to goods fluid status adjustment; Reach after setting value until inlet temperature, metformin hydrochloride is added wherein and preheating 5 ~ 10min, start to spray binder solution, dry LOD to 1.0% ~ 1.5% after hydrojet;
3) granulate and mixing: by the first granule and the second granule granulate and mix homogeneously;
4) tabletting: hybrid particles mixes with recipe quantity magnesium stearate, adopts tablet machine to carry out tabletting;
5) coating: configuration film coating solution, carries out coating in seed-coating machine.
Embodiment 7 stability contrast test
Respectively the compositions (embodiment 1) containing meglumine and the compositions (embodiment 4) not containing meglumine are placed in the vial of 60 DEG C, stability data is measured respectively at when initial time 0 month, 1 month, 2 months, 3 months and 6 months, contrast its stability difference, the results are shown in Table 1.
Table 1. stability comparative test result
Stability test result shows, place 6 months in the vial of 60 DEG C, add Li Gelieting degraded content in the compositions of meglumine and be still less than 0.1%, and do not add meglumine and do not adopt separately method of granulating prepare the compositions (embodiment 5) of gained and do not add the compositions (embodiment 6) of meglumine, Nei Ligelieting degrades content respectively up to 35.7% and 29.6%.From embodiment 4, when adding meglumine in compositions, greatly can improve the stability of compositions, from embodiment 1, the separately method of granulating that the present invention adopts further on the basis adding meglumine can stable prod character further.Therefore, meglumine adds and separates granulation and can significantly suppress Li Gelieting to degrade, and improves the stability of compositions.
Method of the present invention is described by preferred embodiment, and related personnel obviously can change methods and applications as herein described or suitably change and combination in content of the present invention, spirit and scope, realizes and applies the technology of the present invention.Those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.
Claims (18)
1. a pharmaceutical composition, said composition comprises DPP-4 inhibitor and metformin hydrochloride two kinds of active component, also comprises meglumine as stabilizing agent.
2. pharmaceutical composition according to claim 1, the mass ratio of the relative metformin hydrochloride of quality of described meglumine is 1:10 ~ 1:200; The mass ratio of the relative metformin hydrochloride of quality of DPP-4 inhibitor is 1:5 ~ 1:400.
3. pharmaceutical composition according to claim 1 and 2, described DPP-4 inhibitor is Li Gelieting.
4. pharmaceutical composition according to claim 3, by unit dose gauge, comprises Li Gelieting 2.5mg, metformin hydrochloride 500 ~ 1000mg and meglumine 5 ~ 50mg.
5. pharmaceutical composition according to claim 3, described pharmaceutical composition also comprises pharmaceutically useful excipient, and wherein excipient is filler, binding agent, disintegrating agent, lubricant, fluidizer, plasticizer, film coating materials, pigment or its combination.
6. pharmaceutical composition according to claim 5, described filler is microcrystalline Cellulose, pregelatinized Starch, corn starch, dextrin, lactose, sucrose, mannitol, calcium sulfate, calcium hydrogen phosphate or its combination, and the percentage by weight of consumption in whole pharmaceutical composition of described filler is 2.00% ~ 30.00%.
7. pharmaceutical composition according to claim 5, described binding agent is polyvinylpyrrolidone, starch slurry, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose or its combination, and the consumption of the described binding agent percentage by weight in whole pharmaceutical composition is for being 3.00% ~ 10.00%.
8. pharmaceutical composition according to claim 5, described lubricant is stearic acid, magnesium stearate, calcium stearate, polyethylene glycol 6000, fumaric acid sodium, Glyceryl Behenate or its combination, and the percentage by weight of consumption in whole pharmaceutical composition of described lubricant is 0.50% ~ 3.00%.
9. pharmaceutical composition according to claim 5, described fluidizer is micropowder silica gel, Pulvis Talci, magnesium stearate or its combination, and the percentage by weight of consumption in whole pharmaceutical composition of described fluidizer is 0.50% ~ 3.00%.
10. pharmaceutical composition according to claim 5, weight percentage, comprises Li Gelieting 0.10% ~ 0.50%, metformin hydrochloride 50.00% ~ 88.00%, meglumine 1.00% ~ 10.00%, filler 2.00% ~ 30.00%, binding agent 3.00% ~ 10.00% and lubricant 0.50% ~ 3.00%.
11. pharmaceutical compositions according to claim 10, also comprise fluidizer 0.50% ~ 3.00%.
12. pharmaceutical compositions according to claim 5, by component percentages, comprise Li Gelieting 0.21%, metformin hydrochloride 83.33%, meglumine 2.00%, corn starch 2.00%, mannitol 7.86%, polyvinylpyrrolidone 3.60%, magnesium stearate 1.00%.
13. pharmaceutical compositions according to claim 5, by each components by weight percent percentage composition, comprise Li Gelieting 0.23%, metformin hydrochloride 78.20%, meglumine 2.10%, pregelatinized Starch 5.60%, microcrystalline Cellulose 8.05%, polyvinylpyrrolidone 3.82%, magnesium stearate 1.50%, micropowder silica gel 0.5%.
14. pharmaceutical compositions according to claim 5, by each components by weight percent percentage composition, comprise Li Gelieting 0.42%, metformin hydrochloride 84.00%, meglumine 2.30%, microcrystalline Cellulose 2.80%, mannitol 5.29%, polyvinylpyrrolidone 4.37%, magnesium stearate 0.82%.
15. 1 kinds of pharmaceutical compositions, its comprise the first granule with the second granule, wherein said first granule comprises DPP-4 inhibitor and meglumine; Described second granule comprises metformin hydrochloride and pharmaceutically useful excipient, and wherein excipient is filler, binding agent, disintegrating agent, lubricant, fluidizer, plasticizer, film coating materials, pigment or its combination.
16. 1 kinds of methods preparing pharmaceutical composition as claimed in claim 15, comprising:
1) the first granule is prepared: adopt fluidised bed granulator or high-shearing granulation machine by the DPP-4 inhibitor of recipe quantity, meglumine and other pharmaceutically useful mixed with excipients, obtain the first granule;
2) the second granule is prepared: adopt fluidised bed granulator by the metformin hydrochloride of recipe quantity and other pharmaceutically useful mixed with excipients, obtain the second granule;
3) granulate and mixing: the first granule and the second granule granulate mix homogeneously, obtains hybrid particles;
4) hybrid particles and other excipient make capsule, granule, powder, tablet, suspensoid.
17. pharmaceutical compositions according to claim 15 or 16, wherein DPP-4 inhibitor is Li Gelieting.
18. 1 kinds of methods prepared as pharmaceutical composition according to claim 17, comprising:
1) the first granule is prepared: recipe quantity Li Gelieting, meglumine and binding agent are added to the water the mixed solution made and comprise binding agent, pass through fluidised bed granulator, the mixed solution comprising binding agent is sprayed onto in the good filler of premixing, prepares the first granule;
2) prepare the second granule: by soluble in water for recipe quantity binding agent be mixed with solution after, by fluidised bed granulator, be sprayed onto in metformin hydrochloride, prepare the second granule;
3) granulate and mixing: the first granule and salt second granule granulate mix homogeneously, obtains hybrid particles;
4) tabletting: by hybrid particles and recipe quantity mix lubricant, adopts tablet machine to carry out tabletting;
5) coating: configuration film coating solution, carries out coating in seed-coating machine.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106137991A (en) * | 2016-08-01 | 2016-11-23 | 合肥远志医药科技开发有限公司 | A kind of Li Gelieting sheet method of granulating |
| CN106236754A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of compositions comprising Li Gelieting active component and preparation method thereof |
| CN106620715A (en) * | 2015-11-04 | 2017-05-10 | 江苏恒瑞医药股份有限公司 | Drug composition for treating diabetes and preparation method of drug composition |
| CN108524536A (en) * | 2018-06-27 | 2018-09-14 | 薛士军 | A kind of pharmaceutical composition and preparation method thereof for treating diabetes |
| WO2021160608A1 (en) | 2020-02-13 | 2021-08-19 | Zakłady Farmaceutyczne POLPHARMA S.A. | Pharmaceutical composition comprising linagliptin and metformin |
| WO2021246985A1 (en) * | 2020-06-03 | 2021-12-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | The process for the preparation of a film coated tablet comprising linagliptin and metformin |
| CN114159570A (en) * | 2018-05-31 | 2022-03-11 | 华领医药技术（上海）有限公司 | Pharmaceutical composition containing glucokinase activator and DPP-IV inhibitor and preparation method and application thereof |
| CN116211819A (en) * | 2023-04-12 | 2023-06-06 | 华润双鹤药业股份有限公司 | Liagliptin metformin hydrochloride multi-layer tablet and preparation method thereof |
| CN116919911A (en) * | 2023-07-20 | 2023-10-24 | 北京诺和德美医药技术有限公司 | Diabetes treatment medicine and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106620715A (en) * | 2015-11-04 | 2017-05-10 | 江苏恒瑞医药股份有限公司 | Drug composition for treating diabetes and preparation method of drug composition |
| CN106620715B (en) * | 2015-11-04 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | A Chinese medicinal composition for treating diabetes, and its preparation method |
| CN106236754A (en) * | 2016-07-31 | 2016-12-21 | 合肥远志医药科技开发有限公司 | A kind of compositions comprising Li Gelieting active component and preparation method thereof |
| CN106137991A (en) * | 2016-08-01 | 2016-11-23 | 合肥远志医药科技开发有限公司 | A kind of Li Gelieting sheet method of granulating |
| CN114159570A (en) * | 2018-05-31 | 2022-03-11 | 华领医药技术（上海）有限公司 | Pharmaceutical composition containing glucokinase activator and DPP-IV inhibitor and preparation method and application thereof |
| CN108524536A (en) * | 2018-06-27 | 2018-09-14 | 薛士军 | A kind of pharmaceutical composition and preparation method thereof for treating diabetes |
| WO2021160608A1 (en) | 2020-02-13 | 2021-08-19 | Zakłady Farmaceutyczne POLPHARMA S.A. | Pharmaceutical composition comprising linagliptin and metformin |
| WO2021246985A1 (en) * | 2020-06-03 | 2021-12-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | The process for the preparation of a film coated tablet comprising linagliptin and metformin |
| EP4161525A4 (en) * | 2020-06-03 | 2024-06-26 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | The process for the preparation of a film coated tablet comprising linagliptin and metformin |
| CN116211819A (en) * | 2023-04-12 | 2023-06-06 | 华润双鹤药业股份有限公司 | Liagliptin metformin hydrochloride multi-layer tablet and preparation method thereof |
| CN116919911A (en) * | 2023-07-20 | 2023-10-24 | 北京诺和德美医药技术有限公司 | Diabetes treatment medicine and preparation method thereof |
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