CN105233300A - Stable vildagliptin composition and preparation method thereof - Google Patents
Stable vildagliptin composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a stable vildagliptin composition and a preparation method thereof. The vildagliptin tablet contains active components of vildagliptin, 7.5%-22.5% of dextrin, 51%-79% of a filler, 0.5%-8% of a disintegration agent, 0.25%-1% of a lubricant and other pharmaceutically acceptable excipients. The preparation has good stability, fast disintegration and high dissolution. The direct compression method adopted by the invention has the advantages of short production period, simple operation and reduced production cost, and is favorable to industrial production.
Description
Technical field
The invention belongs to chemical pharmacy field, relate generally to a kind of stable vildagliptin composition and method of making the same.
Background technology
In recent decades, along with the aging of growth in the living standard, living-pattern preservation and population, diabetes prevalence presents global ascendant trend, becomes the Chronic Non-Communicable Diseases of the 3rd serious harm health of masses after cardiovascular and cerebrovascular disease, tumor.In diabetes, 90% is type 2 diabetes mellitus, and type 1 diabetes accounts for 4-6%, and the diabetes accounting of other types is less.
Type 2 diabetes mellitus is feature with insulin resistant, shows as the exhaustion of beta Cell of islet Progressive symmetric erythrokeratodermia, thus hypoinsulinism after causing glucose load, and damage incretin is to the reaction of sugar.Long-term hyperglycemia may cause serious blood capillary and macrovascular complications, thus effective glycemic control can significantly reduce diabetic complication sickness rate and case fatality rate.In Course of Diabetes Treatment, because beta Cell of islet quantity and function Progressive symmetric erythrokeratodermia decline, reduce the effectiveness of orally-taken blood sugar reducing medicine, injection of exogenous of finally having to insulin.Incretin, by acting on a series of pathophysiological processes of type 2 diabetes mellitus, comprises islet beta cell function exhaustion and poor blood glucose control etc., better can play the effect of antidiabetic drug.Incretin is divided into two large classes: glucagon sample tire-1(GLP-1) analog and DPP-4 inhibitor.
After glucose stimulates, beta Cell of islet starts excreting insulin.After oral glucose, the insulin of islet β cell is than the secretion increasing of insulin after intravenous glucose load, finds the insulinoptropic peptides (GIP) that endogenous glucose relies on and the plain sample peptide of islets of langerhans blood glucose-1(GLP-1 thus) take part in the adjustment process of blood glucose.Under normal physiological status, feed hindgut is insulinotropic activates the adjustment participating in blood glucose, and after diabetics glucose load, incretin reaction reduces, and the secretion of GLP-1 is impaired.Continuous injection GLP-1 can improve the insulin secretion that glucose stimulates, and maintain the normal level of blood glucose, GLP-1 becomes the Effective target site for the treatment of diabetes.
GLP-1 is a kind of peptide hormone secreted by Intestinal L cells, can promote that GLP-1 is secreted into blood vessel, thus play its physiological function during food digestion.GLP-1 has different physiological roles: transcribing of induction proinsulin gene, promotes biology and the secretion of insulin; Promote Beta cell proliferation differentiation, suppress β apoptosis; Suppress the secretion of glucagon; Postpone gastric emptying, appetite control, reduce food intake.But the half-life of GLP-1 very short (<2min), very soon by dipeptidase-4(DPP-4) be hydrolyzed and inactivation.Suppress DPP-4 to the reduction of GLP-1, increasing GLP-1 level in circulation is the Effective target site for the treatment of diabetes.DPP-4 inhibitor effectively can delay the degraded of incretin, strengthens the activity of GLP-1, thus increases the insulin secretion of sugar mediation, the secretion of glucagon suppression.Thus DPP-4 inhibitor becomes the study hotspot of antidiabetic thing.
JIUYUE in 2007 28 days vildagliptin (Vildagliptin) obtains EU Committee's approval, trade name Galvus.First go on the market with Ireland in European Union member countries and Norway.Vildagliptin be Novartis of Switzerland research and development belong to DPP IV (DPP-4) inhibitor together.It has selectivity, competitiveness, reversible DPP-4 inhibitor.Vildagliptin forms DPP-4 complex and the activity suppressing this enzyme by being combined with DPP-4, thus improve the concentration of GLP-l, the glucose in absorption body is made mainly to rely on GLP-1 and pancreotropic hormone polypeptide (GIP) decomposition utilization, reach and maintain concentration of glucose in body, reduce Glucagon concentrations, thus reduce blood glucose.Vildagliptin is due to its good clinical effectiveness, and untoward reaction receives people less and more and more pays close attention to.
CN101618216B discloses a kind of tablet, its preparation method and the pharmaceutical formulation that are formed by DPP IV (DPP-IV) inhibitor (i.e. vildagliptin) compound direct compression.US20080602168 discloses a kind of novel form having duplicature.EP12187333 discloses tablet, its preparation method and the pharmaceutical formulation that DPP-4 inhibitor (i.e. vildagliptin) compound is formed through dry granulation process.CN201310182784.X discloses a kind of not containing the vildagliptin compositions of stearic acid magnesium salt.CN200680002589.2 discloses formula and the method for direct compression.But the problem such as stability and patient's poor compliance improving vildagliptin dosage form all not yet in effect.
Those skilled in the art are known, in order to prepare compressed tablets, and optional three kinds of techniques usually: wet granulation, direct compression and dry granulation, usually preferred wet granulation compared with direct compression.Needing to add moist soft material in wet granulation, therefore adopting wet granulation for being unsuitable for wet heat-labile crude drug.Dry granulation method comprises mixing, by pre-for composition tabletting, dry sieving, lubrication and compacting, complicated operation, increases production cost.Direct compression is not only simple to operate, and shortens the production cycle, reduces production cost.
The heavy difficulty of the large multi-flavor of existing vildagliptin tablet is swallowed, and onset is slow, and make its application clinically receive certain restriction, vildagliptin also becomes industrial a great problem to damp and hot instability simultaneously.
Magnesium stearate is one of lubricant commonly used in preparation, effectively can improve the mobility of powder, be conducive to the technological operation of film-making, but, magnesium stearate is the compound of the multiple solid organic acid of magnesium, the degradation reaction of active component may be affected with active component generation coordination, thus affect the bioavailability of medicine.Invention technician furthers investigate vildagliptin slice prescription and passing through of technique, find that magnesium stearate is as conventional lubricants, its consumption is on the stability of medicine and have important impact the disintegration of medicine, consumption is too low or need not, make often sticking phenomenon to occur in tableting processes, consumption is too high, makes the disintegration time of medicine long, and bioavailability reduces.
The present invention is by the further investigation to said preparation, by raw material medicated bag with in cyclodextrin, medicine stability significantly improves, further research finds that cyclodextrin effectively can improve the character of medicine, increase the dissolubility of medicine, improve bioavailability, improve medicine stability, improve bad smell, reduce and stimulate.Vildagliptin is carried out cyclodextrin bag and after, reduce the Exposure of medicine and taste bud, improve the compliance of patient medication.
Finally, the present invention is by the screening to a large amount of prescription, provide the compositions containing vildagliptin cyclodextrin inclusion compound that a kind of stability is high, disintegration rate is fast, bioavailability is high, not only simple, the applicable large-scale production of preparation method of this dosage form, and the compliance of patient improves, and extends clinical practice.
Summary of the invention
A stable vildagliptin compositions, this said composition contains vildagliptin, cyclodextrin and other pharmaceutically acceptable excipient, it is characterized in that in said composition, vildagliptin is cyclodextrin clathrate.
Wherein pharmaceutically acceptable excipient can be selected from filler 51%-79%(weight ratio), disintegrating agent 0.5%-8%(weight ratio), lubricant (weight ratio) 0.25%-1% and other pharmaceutically acceptable carriers.
Cyclodextrin described in said composition be selected from schardinger dextrin, powder-beta-dextrin, γ-dextrin, hydroxypropyl-schardinger dextrin, hydroxy propyl-Beta-dextrin, hydroxypropyl-γ-dextrin, carboxymethyl-powder-beta-dextrin, dimethyl-powder-beta-dextrin and tertbutyl ether-powder-beta-dextrin one or more.
Wherein the content of said composition cyclodextrin is 7.5% ~ 27.5%.
Wherein in compositions, filler can be selected from one or more in corn starch, sucrose, Lactis Anhydrous, pregelatinized Starch, microcrystalline Cellulose, mannitol.
Wherein the filler of compositions can also be microcrystalline Cellulose and Lactis Anhydrous, and the two ratio is 1:1-3:1.
Disintegrating agent wherein in compositions is selected from one or more in dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, wherein preferred Sodium Hydroxymethyl Stalcs.
Wherein in compositions, lubricant can be selected from magnesium stearate, micropowder silica gel, Pulvis Talci, wherein preferred magnesium stearate.
This vildagliptin compositions, adopt direct compression process, preparation method is as follows:
(1) vildagliptin, dextrin, filler, disintegrating agent, lubricant are crossed 35 mesh sieves respectively;
(2) take vildagliptin and the cyclodextrin of recipe quantity, prepare vildagliptin cyclodextrin clathrate;
(3) vildagliptin clathrate is mixed homogeneously with filler, then add disintegrating agent;
(4) said mixture and lubricant are mixed, direct compression.
The hardness of the vildagliptin sheet prepared by the present invention is 7-9kp.
Accompanying drawing explanation
Fig. 1 is the stripping drug release profiles figure of the vildagliptin sheet of embodiment 1-8 and comparative example 1-3.
Detailed description of the invention
Sheet heavily maintains 200mg, and every batch is 1000
embodiment 1
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Schardinger dextrin | 15.0 | 7.50 |
| Lactis Anhydrous | 76.5 | 38.25 |
| Microcrystalline Cellulose | 76.5 | 38.25 |
| Carboxymethylstach sodium | 6.0 | 3.00 |
| Magnesium stearate | 1.0 | 0.5 |
Preparation method: by vildagliptin
,α
-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate cross 35 mesh sieves respectively, 25g vildagliptin will be taken, 15g schardinger dextrin prepares vildagliptin-schardinger dextrin clathrate, clathrate is mixed with 76.5g Lactis Anhydrous, add 76.5g microcrystalline Cellulose and 6.0g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 1.0g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 2
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Schardinger dextrin | 25.0 | 12.50 |
| Lactis Anhydrous | 47.7 | 23.85 |
| Microcrystalline Cellulose | 95.3 | 47.65 |
| Carboxymethylstach sodium | 6.0 | 3.00 |
| Magnesium stearate | 1.0 | 0.50 |
Preparation method: by vildagliptin
,α
-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate cross 35 mesh sieves respectively.25g vildagliptin will be taken, 25g schardinger dextrin prepares vildagliptin-schardinger dextrin clathrate, vildagliptin-schardinger dextrin clathrate is mixed with 47.7g Lactis Anhydrous, add 95.3g microcrystalline Cellulose and 6.0g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 1.0g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 3
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25．0 | 12.50 |
| Schardinger dextrin | 35.0 | 17.50 |
| Lactis Anhydrous | 33.25 | 16.63 |
| Microcrystalline Cellulose | 99.75 | 48.88 |
| Carboxymethylstach sodium | 8.0 | 4.00 |
| Magnesium stearate | 1.0 | 0.50 |
Preparation method: by vildagliptin
,α
-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate cross 35 mesh sieves respectively.25g vildagliptin will be taken, 35g schardinger dextrin prepares vildagliptin-schardinger dextrin clathrate, vildagliptin-schardinger dextrin clathrate is mixed with 33.25g Lactis Anhydrous, add 99.75g microcrystalline Cellulose and 8g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 1.0g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 4
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Powder-beta-dextrin | 55.0 | 27.50 |
| Lactis Anhydrous | 37.2 | 18.60 |
| Microcrystalline Cellulose | 74.3 | 37.15 |
| Carboxymethylstach sodium | 8.0 | 4.00 |
| Magnesium stearate | 0.5 | 0.25 |
Preparation method: by vildagliptin
,β
-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate cross 35 mesh sieves respectively.25g vildagliptin will be taken, 55g powder-beta-dextrin will prepare vildagliptin-powder-beta-dextrin clathrate compound, by vildagliptin
-β
-cyclodextrin inclusion compound mixes with 37.2g Lactis Anhydrous, then adds 74.3g microcrystalline Cellulose and 8g carboxymethylstach sodium, mix homogeneously, finally adds the mixing of 0.5g magnesium stearate, carries out tabletting with conventional tablet presses.
embodiment 5
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Hydroxypropyl-schardinger dextrin | 35.0 | 17.50 |
| Lactis Anhydrous | 43.2 | 21.60 |
| Microcrystalline Cellulose | 86.3 | 43.15 |
| Carboxymethylstach sodium | 10.0 | 5.00 |
| Magnesium stearate | 0.5 | 0.25 |
Preparation method: vildagliptin, hydroxypropyl-schardinger dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are crossed 35 mesh sieves respectively.Take 25g vildagliptin, 35g hydroxypropyl-schardinger dextrin prepares vildagliptin-hydroxypropyl-schardinger dextrin clathrate, vildagliptin-hydroxypropyl-schardinger dextrin clathrate is mixed with 43.2g Lactis Anhydrous, add 86.3g microcrystalline Cellulose and 10g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 0.5g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 6
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Hydroxypropyl-schardinger dextrin | 35．0 | 17.50 |
| Lactis Anhydrous | 44．0 | 22.00 |
| Microcrystalline Cellulose | 88.0 | 44.00 |
| Carboxymethylstach sodium | 6.0 | 3.00 |
| Magnesium stearate | 2.0 | 1.00 |
Preparation method: vildagliptin, hydroxypropyl-schardinger dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are crossed 35 mesh sieves respectively.Take 25g vildagliptin, 35g hydroxypropyl-schardinger dextrin prepares vildagliptin-hydroxypropyl-schardinger dextrin clathrate, vildagliptin-hydroxypropyl-schardinger dextrin clathrate is mixed with 44g Lactis Anhydrous, add 88g microcrystalline Cellulose and 6g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 2.0g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 7
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| γ-dextrin | 15.0 | 7.50 |
| Lactis Anhydrous | 52.6 | 26.30 |
| Microcrystalline Cellulose | 105.4 | 52.70 |
| Carboxymethylstach sodium | 1.0 | 0.50 |
| Magnesium stearate | 1.0 | 0.50 |
Preparation method: vildagliptin, γ-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are crossed 35 mesh sieves respectively.Take 25g vildagliptin, vildagliptin-γ-cyclodextrin inclusion compound prepared by 15g γ-dextrin, vildagliptin-γ-cyclodextrin inclusion compound is mixed with 52.6g Lactis Anhydrous, add 105.4g microcrystalline Cellulose and 1g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 1.0g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 8
Preparation prescription:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| γ-dextrin | 55.0 | 27.50 |
| Lactis Anhydrous | 34.0 | 17.00 |
| Microcrystalline Cellulose | 68.0 | 34.00 |
| Carboxymethylstach sodium | 16.0 | 8.00 |
| Magnesium stearate | 2.0 | 1.00 |
Preparation method: vildagliptin, γ-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate are crossed 35 mesh sieves respectively.Take 25g vildagliptin, vildagliptin-γ-cyclodextrin inclusion compound prepared by 55g γ-dextrin, vildagliptin-γ-cyclodextrin inclusion compound is mixed with 34.0g Lactis Anhydrous, add 68.0g microcrystalline Cellulose and 16g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 2.0g magnesium stearate, carry out tabletting with conventional tablet presses.
comparative example 1 according to CN200680002589.2 preparation preparation
Pharmaceutical formulation:
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 50.0 | 25.00 |
| Lactis Anhydrous | 47.82 | 23.91 |
| Microcrystalline Cellulose | 95.68 | 47.84 |
| Carboxymethylstach sodium | 4.0 | 2.00 |
| Magnesium stearate | 2．5 | 1.25 |
Preparation method: 50g vildagliptin is mixed with the microcrystalline Cellulose of 95.68g, the Lactis Anhydrous of 47.82g and 4g carboxymethyl starch sodium, each composition is pre-mixed together in business hopper blender, then the screen cloth of 500 μm or 850 μm is passed through, mixture is again mixed in hopper blender, then mixes and make the tablet of every 25mg size containing 0.8mg magnesium stearate into the magnesium stearate that must measure.Blend step in each step carries out ensureing uniformity of mixture under about 150-450 turns.After again mixing in hopper blender, can by mixture tabletting in conventional tablet presses.
comparative example 2
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Schardinger dextrin | 35.0 | 17.50 |
| Lactis Anhydrous | 43.3 | 21.65 |
| Microcrystalline Cellulose | 86.7 | 43.35 |
| Carboxymethylstach sodium | 6.0 | 3.00 |
| Magnesium stearate | 4.0 | 2.00 |
Preparation method: by vildagliptin
-α
-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate cross 35 mesh sieves respectively.The 25g vildagliptin and the 35.0g schardinger dextrin that take recipe quantity prepare vildagliptin-schardinger dextrin clathrate, vildagliptin-schardinger dextrin clathrate is mixed with 43.3g Lactis Anhydrous, add 86.7g microcrystalline Cellulose and 6g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 4.0g magnesium stearate, carry out tabletting with conventional tablet presses.
comparative example 3
| Composition | Content (g/1000 sheet) | Weight ratio (%) |
| Vildagliptin | 25.0 | 12.50 |
| Schardinger dextrin | 75.0 | 17.50 |
| Lactis Anhydrous | 21.75 | 10.88 |
| Microcrystalline Cellulose | 65.25 | 32.62 |
| Carboxymethylstach sodium | 12.0 | 6.00 |
| Magnesium stearate | 1.0 | 0.50 |
Preparation method: by vildagliptin
-α
-dextrin, Lactis Anhydrous, microcrystalline Cellulose, carboxymethyl starch sodium, magnesium stearate cross 35 mesh sieves respectively.The 25g vildagliptin and the 75.0g schardinger dextrin that take recipe quantity prepare vildagliptin-schardinger dextrin clathrate, vildagliptin-schardinger dextrin clathrate is mixed with 21.75g Lactis Anhydrous, add 65.25g microcrystalline Cellulose and 12g carboxymethylstach sodium again, mix homogeneously, finally add the mixing of 1.0g magnesium stearate, carry out tabletting with conventional tablet presses.
embodiment 9 compacting tablet related properties are out investigated
The result of table 1 embodiment 1-8 and comparative example 1-3 preparation related properties
From above result, the tablet appearance obtained by the present invention is excellent, and disintegration rate is fast, and obtained tablet all within 10min, disintegrate occurs, and shortens the drug effect time significantly
the mensuration of embodiment 10 dissolution
By above-described embodiment prescription, according to stripping algoscopy (Chinese Pharmacopoeia version in 2010 two annex XC second methods), dissolution medium is water, temperature is 37 DEG C, rotating speed per minute 50 turns, operate in accordance with the law, be determined at the dissolution of 5,10,15,30,45 minutes under different dissolution medium, and compare with the former medicine that grinds.
The dissolution results of preparation prepared by table 2 embodiment 1-8 and comparative example 1-3
| Time (min) dissolution % | 0 | 5 | 10 | 15 | 30 | 45 |
| Comparative example 1 | 0 | 67.1 | 78.4 | 83.1 | 84.2 | 85.1 |
| Comparative example 2 | 0 | 72.0 | 79.5 | 82.2 | 83.8 | 84.3 |
| Comparative example 3 | 0 | 70.2 | 80.1 | 83.1 | 84.9 | 85.4 |
| Embodiment 1 | 0 | 77.0 | 92.3 | 93.5 | 94.1 | 94.8 |
| Embodiment 2 | 0 | 84.0 | 92.6 | 93.1 | 93.2 | 94.0 |
| Embodiment 3 | 0 | 74.5 | 92.5 | 93.8 | 94.6 | 95.7 |
| Embodiment 4 | 0 | 85.5 | 94.8 | 95.9 | 97.8 | 99.1 |
| Embodiment 5 | 0 | 82.9 | 92.7 | 94.0 | 96.3 | 97.5 |
| Embodiment 6 | 0 | 80.6 | 91.9 | 93.6 | 95.4 | 96.8 |
| Embodiment 7 | 0 | 78.6 | 91.4 | 93.5 | 94.2 | 95.6 |
| Embodiment 8 | 0 | 79.3 | 91.8 | 93.7 | 94.3 | 95.1 |
As seen from the results in Table 2, vildagliptin sheet dissolution rate provided by the present invention is fast, and dissolution is significantly increased compared with comparative example preparation, and drug effect is fast, after this can the drug release profiles of held stationary, and drug level reaches stable state, can improve the biology in body.
the research of embodiment 11 preparation stability
Severe cruel test (60 DEG C ± 2 DEG C is carried out respectively to tablet obtained in embodiment 1 ~ 8 and comparative example 1 ~ 3, RH75% ± 5%) and accelerated test (40 DEG C ± 2 DEG C, RH75% ± 5%), investigate the stability of preparation, result is as shown in tables 2 and 3.The assay method of stability: the test method in " China's coastal port two annex (XIXC) " of writing according to " chemicals stability study technological guidance principle " and Chinese Pharmacopoeia Commission in " medicine stability test guideline " gets this product simulation listing packaging (being encapsulated into Aluminum-plastic composite bag with medicinal desiccant after aluminum-plastic packaged), be placed in 60 DEG C ± 2 DEG C respectively, 0 is placed continuously in RH75% ± 5%, 7, 14, sampling in 21 days, 40 DEG C ± 2 DEG C, in RH75% ± 5% climatic chamber, continuous placement 6 months, in 1, 2, 3, sample during June, HPLC method measures the degraded percentage ratio of principal agent in preparation, result as shown in tables 2 and 3.
The severe cruel test (60 DEG C ± 2 DEG C, RH75% ± 5%) of preparation prepared by table 2 embodiment and comparative example
Results contrast
| Time (my god) | 0 | 7 | 14 | 21 |
| Comparative example 1 | 0.45 | 1.50 | 3.50 | 5.80 |
| Comparative example 2 | 0.42 | 1.20 | 2.60 | 4.02 |
| Comparative example 3 | 0.35 | 1.10 | 2.70 | 4.60 |
| Embodiment 1 | 0.20 | 0.56 | 1.23 | 2.40 |
| Embodiment 2 | 0.21 | 0.68 | 1.42 | 2.46 |
| Embodiment 3 | 0.22 | 0.72 | 1.57 | 2.31 |
| Embodiment 4 | 0.19 | 0.59 | 1.31 | 2.29 |
| Embodiment 5 | 0.18 | 0.60 | 1.28 | 2.30 |
| Embodiment 6 | 0.25 | 0.70 | 1.32 | 2.40 |
| Embodiment 7 | 0.20 | 0.61 | 1.34 | 2.42 |
| Embodiment 8 | 0.23 | 0.62 | 1.40 | 2.58 |
The accelerated test (40 DEG C ± 2 DEG C, RH75% ± 5%) of preparation prepared by table 3 embodiment and comparative example
Results contrast
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Comparative example 1 | 0.45 | 1.34 | 2.86 | 3.46 | 4.28 |
| Comparative example 2 | 0.42 | 1.35 | 2.57 | 2.89 | 3.34 |
| Comparative example 3 | 0.35 | 1.20 | 2.34 | 2.78 | 3.21 |
| Embodiment 1 | 0.20 | 0.34 | 1.02 | 1.55 | 2.06 |
| Embodiment 2 | 0.21 | 0.40 | 1.15 | 1.64 | 2.14 |
| Embodiment 3 | 0.22 | 0.38 | 1.34 | 1.85 | 2.27 |
| Embodiment 4 | 0.19 | 0.35 | 1.27 | 1.57 | 2.08 |
| Embodiment 5 | 0.18 | 0.39 | 1.29 | 1.63 | 2.11 |
| Embodiment 6 | 0.25 | 0.51 | 1.18 | 1.48 | 2.16 |
| Embodiment 7 | 0.20 | 0.45 | 1.37 | 1.89 | 2.54 |
| Embodiment 8 | 0.23 | 0.42 | 1.20 | 1.72 | 2.37 |
In table 2, table 3, percentage sign is the degraded percentage rate of limaprost cyclodextrin clathrate.From the data of table 2 and table 3, the vildagliptin tablet stability adopting the present invention to prepare is good, solve the problem of the physicochemical property extremely unstable of principal agent own, severe cruel test and the display of accelerated test result, the content of tablet catabolite prepared by the present invention is before the deadline lower, avoids the generation of side effect and untoward reaction in clinical practice.
Claims (10)
1. a stable vildagliptin compositions, said composition contains vildagliptin, cyclodextrin and other pharmaceutically acceptable excipient, it is characterized in that in said composition, vildagliptin is cyclodextrin clathrate.
2. compositions according to claim 1, it is characterized in that pharmaceutically acceptable excipient can be selected from filler 51%-79%(weight ratio), disintegrating agent 0.5%-8%(weight ratio), lubricant (weight ratio) 0.25%-1% and other pharmaceutically acceptable carriers.
3. vildagliptin compositions according to claim 1, it is characterized in that, described cyclodextrin be selected from schardinger dextrin, powder-beta-dextrin, γ-dextrin, hydroxypropyl-schardinger dextrin, hydroxy propyl-Beta-dextrin, hydroxypropyl-γ-dextrin, carboxymethyl-powder-beta-dextrin, dimethyl-powder-beta-dextrin and tertbutyl ether-powder-beta-dextrin one or more.
4., according to the compositions described in claim 1 or 2 or 3, it is characterized in that the content of cyclodextrin is 7.5% ~ 27.5%.
5. according to the vildagliptin compositions described in claim 1 ~ 2, it is characterized in that, filler can be selected from one or more in corn starch, sucrose, Lactis Anhydrous, pregelatinized Starch, microcrystalline Cellulose, mannitol.
6. vildagliptin compositions according to claim 3, is characterized in that, filler is microcrystalline Cellulose and Lactis Anhydrous, and the two ratio is 1:1-3:1.
7. vildagliptin compositions according to claim 1, it is characterized in that one or more that disintegrating agent is selected from dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, wherein preferred Sodium Hydroxymethyl Stalcs.
8. vildagliptin compositions according to claim 1, is characterized in that lubricant can be selected from magnesium stearate, micropowder silica gel, Pulvis Talci, wherein preferred magnesium stearate.
9. a stable vildagliptin compositions, adopt direct compression process, preparation method is as follows:
(1) vildagliptin, dextrin, filler, disintegrating agent, lubricant are crossed 35 mesh sieves respectively;
(2) take vildagliptin and the cyclodextrin of recipe quantity, prepare vildagliptin cyclodextrin clathrate;
(3) vildagliptin clathrate is mixed homogeneously with filler, then adds disintegrating agent;
(4) said mixture and lubricant are mixed, direct compression.
10. the preparation method of vildagliptin according to claim 9, is characterized in that, the hardness of vildagliptin sheet is 7-9kp.
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