CN105769796B - A kind of pharmaceutical preparation and preparation method thereof containing vildagliptin and Metformin hydrochloride - Google Patents
A kind of pharmaceutical preparation and preparation method thereof containing vildagliptin and Metformin hydrochloride Download PDFInfo
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- CN105769796B CN105769796B CN201610287871.5A CN201610287871A CN105769796B CN 105769796 B CN105769796 B CN 105769796B CN 201610287871 A CN201610287871 A CN 201610287871A CN 105769796 B CN105769796 B CN 105769796B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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Abstract
The present invention provides a kind of vildagliptins and the composition of Metformin hydrochloride and preparation method thereof, composition in the present invention includes label and film-coating, label includes main ingredient and auxiliary material, and main ingredient includes vildagliptin and Metformin hydrochloride, and auxiliary material includes adhesive and lubricant；Composition produced by the present invention solves the problems such as vildagliptin dissolution rate is bad, and uniformity of dosage units is poor and stability is bad, and the preparation method is simple, and process is saved, and reduces production cost, is suitble to industrialization large-scale production.
Description
Technical field
The invention belongs to pharmaceutical technology fields, relate generally to one kind using vildagliptin and Metformin hydrochloride as active ingredient
Oral preparation.
Background technique
Diabetes have become one of highest 5 kinds of diseases of whole world morbidity and mortality, especially with the development such as China, Africa
Middle country increases more significant.It is a kind of chronic endocrine system disease, is persistently increased with blood glucose as main clinical manifestation, according to hair
Cause of disease because, be classified as insulin-dependent type 1 diabetes and two kinds of diabetes B of non-insulin-dependent, and 2 types are sugared
The patient populations of urine disease at least account for 90% or more of diabetic's sum.However for diabetes B, there has been no orders so far
The satisfied therapeutic agent of people, therefore there is an urgent need in the art to develop the new drug that can be used in treating diabetes B.
Metformin hydrochloride is current developed country in the world still in the oral class antihyperglycemic drug used and 2 types
The drug first of diabetic especially endomorphy type patient, melbine are by inhibiting hepatic glucose production and increasing outer
Week intake glucose reduces insulin resistance and reduces blood glucose.When melbine poor blood glucose control is used alone, with dimension lattice
Spit of fland drug combination is arranged, effect concentrates on metabolic deficiency, more effectively control blood glucose, and reduces the incidence of hypoglycemia.Play two medicines
While synergistic effect, the adverse reaction of drug is also reduced.Also blood glucose is preferably controlled, prevents and delays diabetes chronic simultaneously
Send out the generation of disease.
Vildagliptin (vildagliptin) is a kind of dipeptidyl peptidase IV (DPP-IV) inhibitor, by inhibiting DPP-IV
Activity, reducing the degradation speed of glucagon release peptide IGLP-1, and then insulin is stimulated under high blood glucose concentration
Secretion, cell Proliferation play anti-type-2 diabetes mellitus hair function with breaking up and enhancing the approach such as satietion.At present no matter single medicine
Treatment or combination therapy all show good safety and tolerance, have a good effect, and are current treatment diabetes
Hot spot in drug research.Therefore this product is that the choosing of the ideal for the treatment of diabetes B is used in combination with melbine.
Melbine (Metformin), clinically commonly uses its hydrochloride, i.e. Metformin hydrochloride, its chemical name is 1,
1- dimethylbiguanide hydrochloride, relative molecular mass 165.63, molecular formula C4H11N5HCl.
Vildagliptin chemical name are as follows: 1- [[(3- hydroxyl -1- adamantyl) amino] acetyl group] -2- cyano-(S)-four
Hydrogen pyrrolidines.Molecular formula is C17H15N3O2, relative molecular mass 303.4.
On November 14th, 2007, the melbine vildagliptin piece (Eucreas of Novartis Co., Ltd's research and development®) obtained for the first time in European Union
It must ratify listing, it is bad or just in the type 2 diabetic patient of combination therapy for still being controlled through metformin monotherapy blood glucose.
The dosage strengths of the composite tablet are vildagliptin/Metformin hydrochloride 50mg/500mg, 50mg/850mg or 50mg/
1000mg。
Patent application CN1400908A discloses the connection containing inhibitors of dipeptidyl IV He other antidiabetic medicines
Administration form is closed, the prior art is can effectively solve and individually takes common hypoglycemic medicine or vildagliptin not and can be effectively controlled II type sugar
The defect of disease is urinated, while there is effectively control blood glucose, harmonious protection inner skin cell function, reduction diabetic complication and other effects,
But and not specifically disclose corresponding compound preparation and preparation method thereof.
The patent application CN101277688A of Novartis Co., Ltd discloses the formulation of a kind of melbine and vildagliptin,
The preferred preparation method of disclosed composite tablet is, first melbine and adhesive fusion method are pelletized, then with vildagliptin
And other auxiliary materials mixing after direct tablet compressing or granulation after tabletting.Although composition and preparation method that this application provides can be certain
The compressibility of the raising product of degree, but this technique poor reproducibility, loss amount are larger；And it is not easy industrialized production, manufacturing cost
It is high.Also it is unfavorable for many patients simultaneously to take.
Chinese invention patent 201410110433.2 discloses the compound preparation preparation of Metformin hydrochloride and vildagliptin
Method, using double compression dry granulation, such method production sales volume is low, produces controllability and reproducibility is poor.
Chinese invention patent CN201410568123.5 discloses a kind of vildagliptin, metformin hydrochloride compound preparation
Metformin hydrochloride is used air-flow crushing by preparation method, is first mixed with suitable auxiliary material, dry or wet granulation, then with dimension
Ge Lieting, magnesium stearate carry out mixed pressuring plate, prepare the compound preparation of Metformin hydrochloride and vildagliptin.
Summary of the invention
The purpose of the present invention is to provide a kind of vildagliptin and melbine pharmaceutical preparation and preparation methods.It include: work
Property ingredient vildagliptin and Metformin hydrochloride, adhesive；
Wherein the vildagliptin is vildagliptin or its officinal salt；The melbine is melbine or it can medicine
With salt, preferably melbine or Metformin hydrochloride.
Wherein the dosage mass ratio of the vildagliptin and melbine is as follows.
The hydroxypropylcellulose of described adhesive 1000 ~ 6000mpas of apparent viscosity preferably in 1%~2% aqueous solution, it is excellent
It selects HPC-HF and apparent viscosity is the hydroxypropyl methylcellulose of 5 ~ 20mpas, preferably HPMC-E6 in 3%~10% aqueous solution.
The lubricant is preferably magnesium stearate, and dosage is preferably the 0.1 ~ 5% of composition weight, and further preferred 0.5
%.The addition of lubricant can prevent plain piece sticking in tableting processes.
Composition described above can also include other pharmaceutically available excipient, such as filler or glidant.In group
It closes in object preparation method, the present invention faces following challenge: (1) dosage of melbine is big, and the dosage of vildagliptin is small, and there are mixed
Close problem of non-uniform.(2) melbine raw material is crystallization powder, and dosage is big, and being not easy wet (dry) method granulation production is to compare to be difficult to
It executes, direct compression method is commonly used in the preparation of the tablet of low-dose drugs, and there are technological difficulties in preparation process.(3) it makes
The mode of grain generally includes wet granulation, dry granulation, melt granulation, fluidized bed granulation etc..Wherein due to the scarcity of equipment, melt
Melt granulation in production using less, and fluidized bed granulation is big due to being lost, which is also not the first choice of production.It is common preferred
Method of granulating: wet granulation and dry granulation.
Composition provided by the invention is first pelletized melbine and adhesive using wet process or dry granulation, so
Direct tablet compressing after mixing afterwards with vildagliptin and other excipient can improve the compressibility of drug, improve dissolution rate and stability.
Wherein the property and dosage of adhesive have considerable degree of influence, the patent application CN101277688A of Novartis Co., Ltd to compressibility
Embodiment in preferably with hydroxypropyl methylcellulose (Klucel EXF) be adhesive, dosage is substantially 7.5% ~ 10%, in inventor
It is disclosed and is found in the research and repetitive process of prescription and method, though the compressibility of powder has a degree of improvement,
Prepared particle loosely contains that fine powder is more, and mobility is owed, and mobility of particle is general in tableting processes, and plain piece compares
Pine.It finds in research process of the invention, is changed by the variation of adhesive in prescription and auxiliary material and preparation method, it can
Obviously further to improve compressibility, the mobility of melbine and vildagliptin powder, the friability of tablet < 0.5%, work
Skill repeatability, can operate.Said preparation is remarkably improved the bioavilability of Metformin hydrochloride simultaneously.
Vildagliptin and combination with metformin object are prepared the present invention provides a kind of, is the mode of wet granulation, Wei Gelie
Spit of fland is first mixed with HPC-HF, HPMC-E6；After being mixed again with Metformin hydrochloride；The adhesive system of HPMC aqueous solution is added
Grain, by prepared particle drying, then mix lubricant is uniform, tabletting.The present invention provides another kinds to prepare vildagliptin
It is the mode of dry granulation, hydroxypropylcellulose-HF, the hydroxypropyl of Metformin hydrochloride and recipe quantity 1/2 with combination with metformin object
Methylcellulose-E6 is first mixed, dry granulation, and 24 mesh whole grains are spare；The hydroxypropylcellulose-of vildagliptin and remaining recipe quantity
HF, hypromellose-E6 mixing；It is mixed again with Metformin hydrochloride particle, then mix lubricant is uniform, tabletting.This
The tablet of invention preparation preferably uses special-shaped stamping, and prepared tablet: the character of plain piece meets Chinese Pharmacopoeia 2015
Four tablet general rules of version；4~30KN of tablet hardness；The friability of tablet is lower than 0.5%.
Detailed description of the invention:
Fig. 1 is that embodiment 1 and original grind product vildagliptin Drug-time curve figure；
Fig. 2 is that embodiment 1 and original grind product melbine Drug-time curve figure.
Specific embodiment
Embodiment 1:
Preparation process:
Metformin hydrochloride, vildagliptin, hydroxypropylcellulose-HF, hypromellose-E6 are crossed into 80 meshes respectively,
It is spare；The aqueous solution of 6% hypromellose-E6 is prepared simultaneously, it is spare.
Weigh Metformin hydrochloride, vildagliptin, hydroxypropylcellulose-HF, hypromellose-respectively by recipe quantity
The amount of the supplementary materials such as E6 first mixes well the materials such as vildagliptin and hydroxypropylcellulose-HF, hypromellose-E6,
It being mixed well again with Metformin hydrochloride, the aqueous solution of 6% hypromellose-E6 is added, softwood processed is pelletized, and 60~80
DEG C drying, whole grain (24 mesh whole grain), be added magnesium stearate, mix；Semi-finished product (indexs such as granule content, loss on drying) are examined.
Tabletting, packaging, product inspection obtain sample 1.
Embodiment 2:
Preparation process:
Metformin hydrochloride, vildagliptin, hydroxypropylcellulose-HXF, hypromellose-E6 are crossed into 80 mesh respectively
Sieve, it is spare；Hydroxypropylcellulose-the HXF, carbomer, hypromellose-E6 of Metformin hydrochloride and recipe quantity 1/2 are first mixed
It closes, dry granulation, 24 mesh whole grains are spare；Hydroxypropylcellulose-HXF, the hydroxypropyl methylcellulose of vildagliptin and remaining recipe quantity
Element-E6 mixing；It is mixed again with Metformin hydrochloride particle, magnesium stearate is then added, mixed；Semi-finished product (do by granule content
The indexs such as dry weightlessness) it examines.Tabletting, packaging, product inspection obtain sample 2.
Comparative example:
Metformin hydrochloride, vildagliptin, hypromellose-E6 are crossed into 80 meshes respectively, it is spare；It prepares simultaneously
The aqueous solution of 6% hypromellose-E6, it is spare.
Weigh the amount of the supplementary materials such as Metformin hydrochloride, vildagliptin, hypromellose-E6 respectively by recipe quantity,
First the materials such as vildagliptin and hypromellose-E6 are mixed well, then are mixed well with Metformin hydrochloride, are added
The aqueous solution of 6% hypromellose-E6, softwood processed, granulation, 60~80 DEG C of drying, whole grains (24 mesh whole grain) are added stearic
Sour magnesium mixes；Semi-finished product (indexs such as granule content, loss on drying) are examined.Tabletting, packaging, product inspection obtain comparative example sample
Product.
Dissolution comparison test
Above preparation obtained and import preparation are compared into test.
Dissolution rate takes this product, according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 first method), calculates
The amount of dissolution of every middle vildagliptin and Metformin hydrochloride.The vildagliptin diformin tablet country there is no manufacturing enterprise, belong into
Its trade name of mouth: specification: 50mg/500mg, 50mg/85mg, 50mg/1000mg, manufacturing enterprise: Novartis Pharma
Steim AG。
Table 1:50mg/500mg import sample is compared with the dissolution rate (%) of self-control sample vildagliptin
2: 50mg/850mg import sample of table is compared with the dissolution rate (%) of self-control sample vildagliptin
Table 3:50mg/1000mg import sample is compared with the dissolution rate (%) of self-control sample vildagliptin
4: 50mg/500mg import sample of table is compared with the dissolution rate (%) of self-control sample Metformin hydrochloride
Table 5:50mg/850mg import sample is compared with the dissolution rate (%) of self-control sample Metformin hydrochloride
Table 6:50mg/1000mg import sample is compared with the dissolution rate (%) of self-control sample Metformin hydrochloride
The result shows that: the dissolution of the vildagliptin metformin hydrochloride tablet made of embodiment 1 and embodiment 2 and listing sample
Product dissolved corrosion is almost the same, and comparative example preparation sample 50/850mg and 50/1000mg specification and original grind product dissolve out it is different
It causes.
Stability contrast test
Influence factor test: Example, comparative example and original grind commercially available product and place 1 in 40 ± 2 DEG C, 75% ± 5%RH condition
A month, 6 months are detected related substance, and are compared with 0 day sample.
Table 7: import sample is compared with the impurity (%) of self-control sample vildagliptin
| Total impurities (%) | Import sample | Embodiment 1 | Embodiment 2 |
| 0d | 0.43 | 0.05 | 0.06 |
| 1 month | 0.51 | 0.06 | 0.07 |
| 6 months | 0.62 | 0.08 | 0.09 |
| Total impurities (%) | Import sample | Embodiment 1 | Embodiment 2 |
Conclusion: sample quality prepared by embodiment 1 and embodiment 2 is stablized, and total impurities are substantially less than import sample and right
Ratio sample.Uniformity of dosage units comparative test
Uniformity of dosage units: Example, comparative example and original grind product, detect vildagliptin uniformity of dosage units respectively.
8 original of table grinds product compared with the impurity (%) for making sample vildagliptin by oneself
| Sample | Original grinds product | Embodiment 1 | Embodiment 2 | Comparative example |
| Uniformity of dosage units (A+2.2S) | 5.3 | 3.1 | 2.2 | 4.8 |
Conclusion: the sample size uniformity prepared by embodiment 1 and embodiment 2 is better than import sample and comparative example.
Bioavilability
Health male Beagle dog 6 is selected, weight is (10 ± 1.0) kg.The unused any drug of 14d before testing, with reality
1d 20:00 is fasted before testing, and test morning on same day 7:00 is taken by prescribed dose by test preparation or control formulation, medication on an empty stomach
4h is fed afterwards.Dosage regimen uses two preparation binary cycle trial designs.6 tested dogs are divided into 2 groups of first, second, first week
Phase first group takes vildagliptin melbine (embodiment 1) 1, and second group takes vildagliptin melbine (Yuan Yanpin) l piece；
The exchange of second round first group second group is taken.2 kinds of preparations are sent down with 50 m L water.2 intertrial interval 28d.Before medication
(0h) and medication after 0.5,0.75,1.0,1.5,2.0,3.0,4.0,5.0,6.0,8.0,12.0,16.0,24.0h it is quiet by forelimb
Arteries and veins takes blood 3.0ml to be placed in anticoagulant tube, analyzes for drug concentration.Vildagliptin Drug-time curve figure is shown in Fig. 1, when melbine medicine
Curve graph is shown in Fig. 2.
Test result: from Fig. 1 and Fig. 2 as it can be seen that vildagliptin diformin tablet (embodiment 1) of the invention after the tablet has been ingested 2
In hour, Beagle dog blood concentration illustrates that composition of the invention is easy than vildagliptin diformin tablet (Yuan Yanpin) height
It absorbs, has the characteristics that rapid-action；By calculating, when reference preparation bioavilability is 100%, Wei Gelie of the embodiment of the present invention
The bioavilability in spit of fland is 122.6%, and the bioavilability of melbine is 124.1%, it was demonstrated that composition of the invention have compared with
High bioavilability.
Claims (3)
1. a kind of pharmaceutical preparation containing vildagliptin and Metformin hydrochloride, it is characterised in that by the material comprising following components
It is prepared:
Wherein adhesive choosing is made of hydroxypropylcellulose, hypromellose and carbomer, the hydroxypropylcellulose
Apparent viscosity is 1000~6000mpas in 1%~2% aqueous solution, and the hypromellose is 3%~10%
Apparent viscosity is 5~20mpas in aqueous solution.
2. the pharmaceutical preparation containing vildagliptin and Metformin hydrochloride as described in claim 1, which is characterized in that Wei Gelie
Spit of fland: hydroxypropylcellulose: carbomer: the ratio of hypromellose is 50:11:1:9,50:25:3:19,50:30:5:22.
3. the preparation method of the described in any item pharmaceutical preparations containing vildagliptin and Metformin hydrochloride of claim 1~2,
It is characterized in that, preparation process is as follows:
(1) Metformin hydrochloride, vildagliptin, hydroxypropylcellulose, hypromellose are crossed into 80 meshes respectively；
(2) Metformin hydrochloride is first mixed with the hydroxypropylcellulose of recipe quantity 1/2, carbomer, hypromellose, dry method system
Grain；Vildagliptin is mixed with the hydroxypropylcellulose of remaining recipe quantity, hypromellose；It is mixed with Metformin hydrochloride particle again
It closes, magnesium stearate is then added, mix, tabletting to obtain the final product.
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| CN201610287871.5A CN105769796B (en) | 2016-05-04 | 2016-05-04 | A kind of pharmaceutical preparation and preparation method thereof containing vildagliptin and Metformin hydrochloride |
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| CN116327769A (en) * | 2021-12-16 | 2023-06-27 | 重庆圣华曦药业股份有限公司 | Pharmaceutical composition containing sitagliptin phosphate and metformin hydrochloride and preparation method thereof |
Citations (4)
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|---|---|---|---|---|
| CN101277688A (en) * | 2005-09-29 | 2008-10-01 | 诺瓦提斯公司 | Formulation comprising metformin and vildagli ptin |
| CN103845326A (en) * | 2014-03-24 | 2014-06-11 | 江苏奥赛康药业股份有限公司 | Compound composition of vildagliptin and melbine and preparation method thereof |
| CN104288144A (en) * | 2014-10-22 | 2015-01-21 | 上海麦步医药科技有限公司 | Method for preparing compound preparation containing vildagliptin and metformin hydrochloride |
| WO2015097234A1 (en) * | 2013-12-23 | 2015-07-02 | Krka, D. D. Novo Mesto | Pharmaceutical composition of dpp-iv inhibitor in combination with metformin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL2938362T3 (en) * | 2012-12-27 | 2017-07-31 | Zentiva Saglik Ürünleri San. Ve Tic. A.S. | Dry granulation process for producing tablet compositions of metformin and compositions thereof |
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- 2016-05-04 CN CN201610287871.5A patent/CN105769796B/en active Active
Patent Citations (4)
| 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 |
| WO2015097234A1 (en) * | 2013-12-23 | 2015-07-02 | Krka, D. D. Novo Mesto | Pharmaceutical composition of dpp-iv inhibitor in combination with metformin |
| CN103845326A (en) * | 2014-03-24 | 2014-06-11 | 江苏奥赛康药业股份有限公司 | Compound composition of vildagliptin and melbine and preparation method thereof |
| CN104288144A (en) * | 2014-10-22 | 2015-01-21 | 上海麦步医药科技有限公司 | Method for preparing compound preparation containing vildagliptin and metformin hydrochloride |
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