CN106176653A - A kind of pharmaceutical composition of sitagliptin - Google Patents
A kind of pharmaceutical composition of sitagliptin Download PDFInfo
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- CN106176653A CN106176653A CN201510215392.8A CN201510215392A CN106176653A CN 106176653 A CN106176653 A CN 106176653A CN 201510215392 A CN201510215392 A CN 201510215392A CN 106176653 A CN106176653 A CN 106176653A
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- sitagliptin
- pharmaceutical composition
- phosphoric acid
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Abstract
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of sitagliptin pharmaceutical composition and preparation method thereof.Sitagliptin Pharmaceutical composition prepared by the present invention, use and sitagliptin is mixed according to a certain percentage with specific adjuvant, substantially overcome poor stability present in prior art, complex manufacturing, the defect of large-scale production can not be carried out, be surprised to find that the tablet that the method prepares has more excellent dissolution simultaneously.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of sitagliptin pharmaceutical composition and preparation method thereof.
Background technology
Sitagliptin is developed by Merck & Co., Inc. and lists, and this medicine listed in the U.S. in October, 2006, by April, 2008, and the several countries listing in Europe of this medicine.In October, 2007, this medicine is approved by the FDA in the United States the therapeutic alliance with metformin.
Phosphoric acid sitagliptin sheet is that first approval is for the DPP-4 inhibitor treating type 2 diabetes mellitus, β apoptosis can be suppressed, promote β cell neogenesis, increase type 2 diabetes mellitus patient's β cell quantity, substantially reduce patient blood glucose, and the patient losing efficacy sulfa drugs still has significant blood sugar reducing function.Phosphoric acid sitagliptin sheet mainly realizes the glycemic control to type 2 diabetes mellitus patient by routing motion and diet control.The chemical name of phosphoric acid sitagliptin is (3R)-3-amino-1-[5,6 dihydro-3-Trifluoromethyl-1s, 2,4-triazol [4,3-a] pyrazine-7(8H)-yl]-4-(2,4,5-trifluorophenyls)-1-butanone monophosphate monohydrate, shown in its structure such as formula (1):
Prior art customary preparation methods prepares sitagliptin preparation, because of the physicochemical property of sitagliptin material, easily causes that to prepare mobility of particle in tablet bad, sticking, poor stability, release is relatively low, complex process, production cost is high, it is difficult to realize industrialized big production.
In order to improve production quality, overcome can not industrialization produce problem, We conducted design and the research of substantial amounts of technical scheme, choose optimum prescription and technique, solve above-mentioned technological deficiency.
Sitagliptin Pharmaceutical composition prepared by the present invention, use and sitagliptin is mixed according to a certain percentage with specific adjuvant, substantially overcome poor stability present in prior art, complex manufacturing, the defect of large-scale production can not be carried out, be surprised to find that the tablet that the method prepares has more excellent dissolution simultaneously.
Summary of the invention
It is an object of the invention to provide a kind of pharmaceutical composition Han sitagliptin, mixed according to a certain percentage with microcrystalline Cellulose and calcium hydrogen phosphate by phosphoric acid sitagliptin, said composition formula is simple, and mature preparation process, result of extraction is good.
It is a further object to provide a kind of method preparing sitagliptin pharmaceutical composition.
The present invention is by the following technical solutions:
The pharmaceutical composition containing sitagliptin that the present invention relates to uses wet granule compression tablet, it is provided that the applicable prescription of tablet of preparing in addition to containing active component, possibly together with diluent, appropriate disintegrating agent and lubricant can be contained as required simultaneously.
Specifically, the pharmaceutical composition containing sitagliptin of the present invention, containing phosphoric acid sitagliptin and diluent, wherein phosphoric acid sitagliptin accounts for the percentage by weight of whole tablet weight is 30-40%, and it is 50-60% that diluent accounts for the percentage by weight of whole tablet weight.
Microcrystalline Cellulose and calcium hydrogen phosphate are the diluent of pharmaceutical composition of the present invention, and the weight ratio of microcrystalline Cellulose and calcium hydrogen phosphate is 1-1.5.Appropriate lubricant and disintegrating agent can be contained as required, lubricant is selected from one or more in magnesium stearate, Pulvis Talci and sodium stearyl fumarate, and disintegrating agent is selected from crospovidone, cross-linking sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose and pregelatinized Starch.
Preferably, above-mentioned sitagliptin pharmaceutical composition, wherein said lubricant is magnesium stearate, and described disintegrating agent is cross-linking sodium carboxymethyl cellulose.
The invention have the characteristics that and diluent is selected, find out sitagliptin and two kinds of necessary proportion relations of diluent so that prepared tablet stability is good, has preferable dissolution, the problem simultaneously also solving large-scale industrial production.Complete it is critical only that of the present invention: the selection of diluent, the ratio of sitagliptin and two kinds of diluent controls.
In the pharmaceutical composition of the present invention, each component accounts for the percentage by weight of whole tablet weight and is:
Phosphoric acid sitagliptin 30-40%
Microcrystalline Cellulose 25-30%
Calcium hydrogen phosphate 20-30%
Disintegrating agent 2%
Lubricant 4%
Coating materials 4%
Specifically, the preferred scheme of the present invention is, prescription forms:
Phosphoric acid sitagliptin 40%
Microcrystalline Cellulose 25%
Calcium hydrogen phosphate 25%
Disintegrating agent 2%
Lubricant 4%
Coating materials 4%
It is a further object to provide a kind of method preparing above-mentioned sitagliptin pharmaceutical composition, comprise the following steps:
1) preparation of supplementary material and process: phosphoric acid sitagliptin and other adjuvants are crossed 80 mesh sieves respectively standby；
2) weigh and mix: calculating inventory according to recipe quantity through double verification and weigh above-mentioned supplementary material respectively；
3) mixing: after the phosphoric acid sitagliptin of recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, then mix with the microcrystalline Cellulose of recipe quantity so that it is be sufficiently mixed uniformly；
4) pelletizing: added by 50% ethanol water in the material of mix homogeneously, prepare the soft material of suitable stiff, use 20 eye mesh screens to pelletize, gained granule should lack fine powder, neat without strip；
5) it is dried: prepared granule is dried to moisture≤5.0% under the conditions of 60 DEG C ± 5 DEG C；
6) granulate: dried granule is used 20 eye mesh screen granulate；
7) always mix: mix disintegrating agent outside adding and mix lubricant is uniform, to be tested；
8) intermediate inspection: measure granule content, calculates loading amount；
9) tabletting: according to the actual tablet weight of result of calculation gained, regulates machine, tabletting；
10) coating: with 70% ethanol, the film coating agent of recipe quantity is configured to the solution that solid content is 10%, regulates coating pan rotating speed, inlet temperature, pressure, is coated；
11) pack according to the requirement of product, put in storage after inspection.
Below by concrete experimental program, the invention will be further described:
That follows tablet is typically prepared principle and existing technical scheme, and we devise pre-prescription:
Preparation technology:
The phosphoric acid sitagliptin weighing recipe quantity is first mixed homogeneously with the dibastic sodium phosphate of recipe quantity, the microcrystalline Cellulose adding recipe quantity mixed 80 mesh sieves, so that it is sufficiently mixed, soft material processed, pelletize with 20 eye mesh screens, it is dried under the temperature conditions of 60 DEG C ± 5 DEG C, pelletize with 20 eye mesh screens again, add cross-linking sodium carboxymethyl cellulose and magnesium stearate mix homogeneously, tabletting, coating, to obtain final product.
By the trial-production to prescription 1 ~ prescription 3, screen prescription from indexs of correlation such as character, hardness, friability, angle of repose, disintegration phenomenon respectively.
Table 1
Being shown by above result of the test, prescription 1-4 mobility of particle is all preferable, but the disintegration time of prescription 4 relatively prescription 1-3 disintegration time is long.
Prescription 1-4 is carried out dissolution determination:
Dissolution method (Chinese Pharmacopoeia two annex XC the second methods of version in 2010) is with water 500ml as dissolution medium, rotating speed is 50 turns per minute, operates in accordance with the law, takes solution at 5,10,15,20,30 minutes respectively appropriate, filter and fluid infusion, take subsequent filtrate as need testing solution；Separately take sitagliptin reference substance about 20mg, accurately weighed, put in 100ml measuring bottle, add that methanol is the most ultrasonic makes dissolving, adding dissolution medium to scale, shake up, precision measures 2ml and puts in 100ml measuring bottle, add dissolution medium to scale, shaking up, precision measures 5ml and puts in 100ml measuring bottle, adds dissolution medium to scale, shake up, compare product solution.Precision measures need testing solution and each 100 l of reference substance solution, is injected separately into chromatograph of liquid, records chromatogram, measures according to the chromatographic condition under assay item, the stripping quantity of the sitagliptin in going out every by external standard method with calculated by peak area.
Table 2
Separately being shown by above result of the test, prescription 1-3 relatively prescription 4 has preferable dissolution, and wherein the result of extraction of prescription 3 is optimum.
Film coating can be with taste masking, and shading and Film coated tablets are smooth, wear-resisting, and outward appearance and transport to preparation all have improvement result.
Additionally, pharmaceutical composition of the present invention can also contain biguanides, described biguanides is preferably metformin, and preferred pharmaceutical dosage is 500mg.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail, it should be understood that the non-scope being only limitted to these embodiments of the scope of the present invention.
Embodiment 1
(1) prescription
Phosphoric acid sitagliptin 128.5
Microcrystalline Cellulose 80g
Calcium hydrogen phosphate 80g
Cross-linking sodium carboxymethyl cellulose 6.5g
Magnesium stearate 12.5g
Coating materials 12.5g
50% ethanol water is appropriate
Make 1000
(2) preparation method
1) preparation of supplementary material and process: phosphoric acid sitagliptin and other adjuvants are crossed 80 mesh sieves respectively standby；
2) weigh and mix: calculating inventory according to recipe quantity through double verification and weigh above-mentioned supplementary material respectively；
3) mixing: after the phosphoric acid sitagliptin of recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, then mix with the microcrystalline Cellulose of recipe quantity so that it is be sufficiently mixed uniformly；
4) pelletizing: added by 50% ethanol water in the material of mix homogeneously, prepare the soft material of suitable stiff, use 20 eye mesh screens to pelletize, gained granule should lack fine powder, neat without strip；
5) it is dried: prepared granule is dried to moisture≤5.0% under the conditions of 60 DEG C ± 5 DEG C；
6) granulate: dried granule is used 20 eye mesh screen granulate；
7) always mix: outside adding, mix cross-linking sodium carboxymethyl cellulose and magnesium stearate mix homogeneously, to be tested；
8) intermediate inspection: measure granule content, calculates loading amount；
9) tabletting: according to the actual tablet weight of result of calculation gained, regulates machine, tabletting；
10) coating: with 70% ethanol, the film coating agent of recipe quantity is configured to the solution that solid content is 10%, regulates coating pan rotating speed, inlet temperature, pressure, is coated；
11) pack according to the requirement of product, put in storage after inspection.
Embodiment 2
(1) prescription
Phosphoric acid sitagliptin 128.5g
Microcrystalline Cellulose 128.5g
Calcium hydrogen phosphate 128.5g
Cross-linking sodium carboxymethyl cellulose 6.5g
Magnesium stearate 12.5g
Coating materials 12.5g
50% ethanol water is appropriate
Make 1000
(2) preparation method is with embodiment 1.
Embodiment 3
(1) prescription
Phosphoric acid sitagliptin 128.5g
Microcrystalline Cellulose 96.5g
Calcium hydrogen phosphate 64.5g
Cross-linking sodium carboxymethyl cellulose 6.5g
Magnesium stearate 12.5g
Coating materials 12.5g
50% ethanol water is appropriate
Make 1000
(2) preparation method is with embodiment 1.
Embodiment 4
Phosphoric acid sitagliptin 128.5g
Metformin 500g
Microcrystalline Cellulose 80g
Calcium hydrogen phosphate 80g
Cross-linking sodium carboxymethyl cellulose 13g
Magnesium stearate 25g
Coating materials 25g
50% ethanol water is appropriate
Make 1000
1) phosphoric acid sitagliptin, metformin, microcrystalline Cellulose and calcium hydrogen phosphate are dried, pulverize, cross 100 mesh sieves；
2)
The microcrystalline Cellulose and the calcium hydrogen phosphate that take recipe quantity are mixed homogeneously with sound of laughing row spit of fland, west, are subsequently adding metformin, soft material processed, cross 20 eye mesh screens and pelletize, obtain the wet granular of compound recipe；
3)
Above-mentioned compound recipe wet granular is dried under the conditions of 60 DEG C to moisture less than 5%, obtains the dry granule of compound recipe；
4)
Dry for above-mentioned compound recipe granule is crossed 20 eye mesh screen granulate, adds cross-linking sodium carboxymethyl cellulose and magnesium stearate, mix homogeneously, tabletting, film coating and get final product.
Test example 1
Embodiment 1,2 and 3 is had the detection of related substance, dissolution and uniformity of dosage units
From result above, each check item of embodiment 1,2 and 3 all meets regulation, formulation and technology simple possible, steady quality.
Test example 2
The dissolution determination of the embodiment of the present invention 4
According to 2010 editions dissolution methods of Chinese Pharmacopoeia (annex XC the second method), with the HCl solution 900mL of pH 1.2 as solvent, temperature is 37 ± 0.5 DEG C, rotating speed is 50r/min, solution 10mL is taken respectively at 0,5,10,15,30,45,60 min, filter with 0.45 μm microporous filter membrane, take subsequent filtrate, and immediately supplement pH 1.2 HCl solution 10mL in a reservoir.Take subsequent filtrate sample introduction 20 μ L, record chromatographic peak area, measurement result substitute into standard curve and try to achieve the stripping quantity of a time point Li Gelieting, calibrated after i.e. obtain accumulation dissolution.Take in subsequent filtrate 1mL to 10mL volumetric flask, sample introduction 20 μ L after constant volume, record chromatographic peak area, measurement result substitute into standard curve and try to achieve the stripping quantity of time point metformin, calibrated after i.e. obtain accumulation dissolution.Medicine total release percentage is calculated as follows: wherein CiFor drug level (μ g mL-1)；For release medium volume (mL)；For fluid replacement volume (mL)；W is example weight (mg)；FPercentage composition (%) for preparation of Chinese medicine.
Sitagliptin, the dissolution test result of metformin
Claims (8)
1. the pharmaceutical composition of a sitagliptin, it is characterised in that containing phosphoric acid sitagliptin and diluent, wherein phosphoric acid sitagliptin accounts for the percentage by weight of whole tablet weight is 30-40%, and it is 50-60% that diluent accounts for the percentage by weight of whole tablet weight.
Sitagliptin pharmaceutical composition the most according to claim 1, it is characterised in that described diluent is selected from microcrystalline Cellulose and calcium hydrogen phosphate, and the weight ratio of microcrystalline Cellulose and calcium hydrogen phosphate is 1-1.5.
Sitagliptin pharmaceutical composition the most according to claim 1 and 2, it is characterised in that possibly together with lubricant and disintegrating agent.
Sitagliptin pharmaceutical composition the most according to claim 1, it is characterised in that possibly together with biguanide antidiabetic medicament.
Sitagliptin pharmaceutical composition the most according to claim 3, it is characterised in that each component and account for the percentage by weight of whole tablet weight and be:
Phosphoric acid sitagliptin 30-40%
Microcrystalline Cellulose 25-30%
Calcium hydrogen phosphate 20-30%
Disintegrating agent 2%
Lubricant 4%
Coating materials 4%.
Sitagliptin pharmaceutical composition the most according to claim 5, it is characterised in that each component and account for the percentage by weight of whole tablet weight and be:
Phosphoric acid sitagliptin 40%
Microcrystalline Cellulose 25%
Calcium hydrogen phosphate 25%
Disintegrating agent 2%
Lubricant 4%
Coating materials 4%.
7. the method for the sitagliptin pharmaceutical composition that a kind is prepared as described in claim 5-6 any one, concretely comprise the following steps: take phosphoric acid sitagliptin and adjuvant sieves, standby, the phosphoric acid sitagliptin weighing recipe quantity is mixed homogeneously with the adjuvant of recipe quantity, soft material processed, it is dried, granulate, additional mix lubricant, tabletting, coating, to obtain final product.
Preparation method the most according to claim 7, it is characterised in that comprise the following steps:
1) preparation of supplementary material and process: phosphoric acid sitagliptin and other adjuvants are crossed 80 mesh sieves respectively standby；
2) weigh and mix: calculating inventory according to recipe quantity through double verification and weigh above-mentioned supplementary material respectively；
3) mixing: after the phosphoric acid sitagliptin of recipe quantity is first mixed homogeneously with the calcium hydrogen phosphate of recipe quantity, then mix with the microcrystalline Cellulose of recipe quantity so that it is be sufficiently mixed uniformly；
4) pelletizing: added by 50% ethanol water in the material of mix homogeneously, prepare the soft material of suitable stiff, use 20 eye mesh screens to pelletize, gained granule should lack fine powder, neat without strip；
5) it is dried: prepared granule is dried to moisture≤5.0% under the conditions of 60 DEG C ± 5 DEG C；
6) granulate: dried granule is used 20 eye mesh screen granulate；
7) always mix: mix disintegrating agent outside adding and mix lubricant is uniform, to be tested；
8) intermediate inspection: measure granule content, calculates loading amount；
9) tabletting: according to the actual tablet weight of result of calculation gained, regulates machine, tabletting；
10) coating: with 70% ethanol, the film coating agent of recipe quantity is configured to the solution that solid content is 10%, regulates coating pan rotating speed, inlet temperature, pressure, is coated；
11) pack according to the requirement of product, put in storage after inspection.
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| CN201510215392.8A CN106176653A (en) | 2015-04-30 | 2015-04-30 | A kind of pharmaceutical composition of sitagliptin |
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| CN201510215392.8A CN106176653A (en) | 2015-04-30 | 2015-04-30 | A kind of pharmaceutical composition of sitagliptin |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109157522A (en) * | 2018-09-18 | 2019-01-08 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical composition and its preparation method and application comprising Xi Gelieting or its officinal salt |
| CN110559270A (en) * | 2019-09-17 | 2019-12-13 | 扬子江药业集团广州海瑞药业有限公司 | Sitagliptin phosphate pharmaceutical composition and preparation method thereof |
| CN113750060A (en) * | 2021-08-03 | 2021-12-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of sitagliptin phosphate tablets |
| CN113945661A (en) * | 2021-10-21 | 2022-01-18 | 南通联亚药业有限公司 | Analysis method for measuring release rate of sitagliptin metformin hydrochloride sustained release tablets |
| CN116459227A (en) * | 2023-05-11 | 2023-07-21 | 宙晟智维生命科学(上海)有限公司 | Sitagliptin tablet and preparation method thereof |
-
2015
- 2015-04-30 CN CN201510215392.8A patent/CN106176653A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109157522A (en) * | 2018-09-18 | 2019-01-08 | 石药集团中奇制药技术（石家庄）有限公司 | Pharmaceutical composition and its preparation method and application comprising Xi Gelieting or its officinal salt |
| CN110559270A (en) * | 2019-09-17 | 2019-12-13 | 扬子江药业集团广州海瑞药业有限公司 | Sitagliptin phosphate pharmaceutical composition and preparation method thereof |
| CN110559270B (en) * | 2019-09-17 | 2020-06-23 | 扬子江药业集团广州海瑞药业有限公司 | Sitagliptin phosphate pharmaceutical composition and preparation method thereof |
| CN113750060A (en) * | 2021-08-03 | 2021-12-07 | 湖南复瑞生物医药技术有限责任公司 | Preparation method of sitagliptin phosphate tablets |
| CN113945661A (en) * | 2021-10-21 | 2022-01-18 | 南通联亚药业有限公司 | Analysis method for measuring release rate of sitagliptin metformin hydrochloride sustained release tablets |
| CN116459227A (en) * | 2023-05-11 | 2023-07-21 | 宙晟智维生命科学(上海)有限公司 | Sitagliptin tablet and preparation method thereof |
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