CN103735544A - Preparing process for vildagliptin/metformin hydrochloride compound preparation - Google Patents
Preparing process for vildagliptin/metformin hydrochloride compound preparation Download PDFInfo
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- CN103735544A CN103735544A CN201410050520.3A CN201410050520A CN103735544A CN 103735544 A CN103735544 A CN 103735544A CN 201410050520 A CN201410050520 A CN 201410050520A CN 103735544 A CN103735544 A CN 103735544A
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- vildagliptin
- metformin hydrochloride
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Abstract
The invention provides a preparing process for a vildagliptin/metformin hydrochloride compound preparation. The preparing process comprises the following steps: (1) adding vildagliptin, metformin hydrochloride, magnesium aluminosilicate and hydroxy propyl cellulose into ethanol or isopropanol to form a dispersion liquid; (2) spraying and drying the dispersion liquid obtained in the step (1) to obtain spherical active matter-containing powder; (3) sieving and selecting the active matter-containing powder with particle size of 75 to 150 microns, which is obtained through the method, adding 1% of magnesium stearate, and directly pressing to form a tablet. The preparing process has the advantage that the unexpected satisfaction effects of uniform fluidity of integral materials and storage stability of the preparation are realized.
Description
Technical field
This area belongs to medical technical field, is specifically related to a kind of preparation method of the Pharmaceutical composition that contains vildagliptin and metformin hydrochloride.
Background technology
Vildagliptin (vildagliptin) is a kind of DPP IV (DPP-IV) inhibitor, also claim incretin reinforcing agent, by suppressing the activity of DPP-IV, reduce the degradation speed of pancreas hyperglycemia sample peptide I GLP-1, and then under hyperglycemia concentration, stimulate the secretion of insulin, and can be by postponing gastric emptying, glucagon suppression discharges, promotes beta Cell of islet propagation and differentiation and strengthen the approach such as satietion bring into play anti-type 2 diabetes mellitus function.
Metformin hydrochloride does not promote insulin secretion, and its blood sugar reducing function is mainly and promotes fatty tissue ingestion of glucose, and muscular tissue anerobic glycolysis is increased, and increases the utilization of glucose, can also reduce glucose through gastral absorption.
Vildagliptin and metformin hydrochloride all to treatment diabetes etc. effectively, provide to comprise these two kinds of medicines and have high clinical application as the preparation (drug regimen) of active component.
Patent of invention CN101277688B has disclosed a kind of formulation that comprises metformin and vildagliptin.We find that vildagliptin is to damp and hot unstable, and in preparation process vildagliptin and the poor fluidity of metformin hydrochloride own, compressibility is bad.A kind of free-pouring binding compositions need to be provided, and it can be pressed into the firm tablet that active component wherein has acceptable In Vitro Dissolution character and good stability.Typically, excipient is joined in formulation to give good mobility and mobility to suppressed material.By pre-treatment step, give this class character as wet granulation, slugging method or crystallization.
The inventor, by vildagliptin and metformin hydrochloride compound preparation are studied, finds that conventional wet granulation, slugging method are difficult to address the above problem.And not yet find that there is bibliographical information and adopt the dry concrete technology to the pelletize of vildagliptin/metformin hydrochloride compound preparation compound preparation of spraying.The inventor is in the spray-drying process process of research vildagliptin/metformin hydrochloride compound preparation, through screening, find, we can adopt ethanol and isopropyl alcohol as solvent or decentralized photo, add aluminium-magnesium silicate simultaneously, aspect the mobility of preparation storage stability and the whole homogeneous of material, producing beat all promising result.
Summary of the invention
The problems referred to above that exist for prior art, the applicant provides a kind of spray-drying process method of vildagliptin/metformin hydrochloride compound preparation, has prepared a kind of Pharmaceutical composition that contains vildagliptin and metformin hydrochloride.The powder of active substance of the present invention is fine and smooth, mobility mobility is better, and the stability of compound preparation is better, is applicable to large-scale production.
Technical scheme of the present invention is as follows:
(1) vildagliptin, metformin hydrochloride, aluminium-magnesium silicate and hydroxypropyl cellulose are joined in ethanol or isopropyl alcohol, form dispersion liquid.
(2) dispersion liquid step (1) being obtained is sprayed dry, obtain the spherical powder containing active substance, spray-dired parameter is: inlet temperature is 60～90 ℃, nozzle place temperature is 30～50 ℃, air mass flow is 10～30m3/h, charging rate is 10～40ml/min, and air pressure is 0.1～0.4mpa.
(3) screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate, then is directly used for being pressed into tablet.
Wherein in step (1) vildagliptin to take the addition of dry weight basis be 1.5%～20%, it is 80%～98.5% that metformin hydrochloride be take the addition of dry weight basis, aluminium-magnesium silicate consumption is 0.5～2.1%, hydroxypropyl cellulose 5～12%.
Further, the consumption of ethanol or isopropyl alcohol is vildagliptin and metformin hydrochloride active substance gross weight 3～5 times in step (1).
The technique effect that the present invention is useful is:
The invention provides a kind of preparation technology who is suitable for the improved formulations of vildagliptin and metformin hydrochloride oral use, main purpose of the present invention is for active substance poor stability, the bad technical problem of mobility in vildagliptin and metformin hydrochloride compound preparation, a kind of solution is provided, and spray-dired parameter is selected and the interpolation of aluminium-magnesium silicate is key point of the present invention.Found that and adopt ethanol and isopropyl alcohol as solvent or decentralized photo, add aluminium-magnesium silicate simultaneously, adopt spray drying granulation, active material particle mobility is better, and moisture is low, and formulation products stability is better.
The specific embodiment
Following examples further describe the present invention, and still, these embodiment are only for the present invention is described, rather than limitation of the scope of the invention.
Embodiment 1:
Prescription:
| Composition | Amount/sheet |
| Vildagliptin | 50mg |
| Metformin hydrochloride | 1000mg |
| Hydroxypropyl cellulose | 130mg |
| Aluminium-magnesium silicate | 6mg |
| Magnesium stearate | 12mg |
Production method:
50.0g vildagliptin, 1.0kg metformin hydrochloride are joined in the ethanol of 3 times of quality of active substance and stir, then add 6g aluminium-magnesium silicate and 130g hydroxypropyl cellulose to form uniform dispersion.The liquid configuring, by fluid bed, is sprayed dry, material moisture 1%.Dry material is by shaking screen, and screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate, is directly used for being pressed into tablet.Processing parameter is as follows:
Embodiment 2～6:
Production method:
With reference to the method for embodiment 1, vildagliptin, metformin hydrochloride are joined in solvent, then add aluminium-magnesium silicate and hydroxypropyl cellulose to form uniform dispersion according to embodiment 2～6 prescriptions.Then following embodiment 2～6 technological parameters of reference are sprayed by fluid bed and are dried, material moisture 1%, screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate then to be directly used for being pressed into tablet.
Comparative example 1: Direct spraying seasoning (not adding aluminium-magnesium silicate)
Do not add aluminium-magnesium silicate to adopt the dry method of Direct spraying, technique of the present invention has been done to contrast test, relevant comparative example's prescription is as follows:
Comparative example 1 prescription
Comparative example's 1.1 production methods:
Prescription with reference to comparative example 1.1 joins vildagliptin, metformin hydrochloride and hydroxypropyl cellulose in ethanol, forms dispersion liquid.Then with reference to the technological parameter in embodiment 1 preparation method, spray dry, material moisture 1%.Screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate, is directly used for being pressed into tablet.
Comparative example's 1.2 production methods:
Prescription with reference to comparative example 1.2 joins vildagliptin, metformin hydrochloride and hydroxypropyl cellulose in isopropyl alcohol, forms dispersion liquid.Then with reference to the technological parameter in embodiment 3 preparation methoies, spray dry, material moisture 1%.Screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate, is directly used for being pressed into tablet.
Comparative example's 1.3 production methods:
Prescription with reference to comparative example 1.3 joins vildagliptin, metformin hydrochloride and hydroxypropyl cellulose in ethanol, forms dispersion liquid.Then with reference to the technological parameter in embodiment 4 preparation methoies, spray dry, material moisture 1%.Screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate, is directly used for being pressed into tablet.
Comparative example 2: wet granulation process
According to comparative example 2, write out a prescription 50.0g vildagliptin, 1.0kg metformin hydrochloride and 130.0g hydroxypropyl cellulose mix homogeneously, the alcohol granulation that adds 600.0g, wet grain is 2.5% by being dried to moisture through 60 ℃ after 18 mesh sieves, dry granular, by 18 mesh sieve granulate, adds magnesium stearate with reference to the method tabletting of embodiment 1.
Comparative example's 2 prescriptions
| Composition | Amount/sheet |
| Vildagliptin | 50mg |
| Metformin hydrochloride | 1000mg |
| Hydroxypropyl cellulose | 130mg |
| Magnesium stearate | 10mg |
The fluidity testing of active substance:
Do not adopt the active material powder of the dry method gained of Direct spraying to carry out test angle of repose with adding aluminium-magnesium silicate the active substance of drying process with atomizing gained of the present invention, contrast the difference of its mobility.Test angle of repose is used the intelligent intelligent Powder Physical tester of BT-1001 of Dandong Bai Te to detect, and result is as follows:
As can be seen from the above results, after adding aluminium-magnesium silicate spraying dry in technique of the present invention, gained active material powder is significantly less than the prescription that does not add aluminium-magnesium silicate angle of repose, show the present invention add aluminium-magnesium silicate spraying dry after gained active substance powder mobility better.
Preparation stability test:
In thering is HDPE (high density polyethylene (HDPE)) bottle of desiccant sealing, open at 40 ℃/75%RH, 25 ℃/65%RH and 40 ℃/75%RH, shelf-stability research, stability conditions is as follows:
Remarks: M represents the moon.
Adopt high performance liquid chromatogram to test the impurity content of each sample, stability test result is as shown in the table:
By above experimental result, can be found out, selected embodiment transfers postpone in aforementioned stable condition, its related substance variation tendency has larger difference, use the related substance rate of increase of sample prepared by drying process with atomizing of the present invention to be significantly less than and use common wet granulation technology, add the spray-dired technique of aluminium-magnesium silicate simultaneously and do not increase significantly aspect product stability with respect to adding aluminium-magnesium silicate drying process with atomizing.
Claims (3)
1. a preparation technology for vildagliptin/metformin hydrochloride compound preparation, is characterized in that comprising following steps:
(1) vildagliptin, metformin hydrochloride, aluminium-magnesium silicate and hydroxypropyl cellulose are joined in ethanol or isopropyl alcohol, form dispersion liquid.
(2) dispersion liquid step (1) being obtained is sprayed dry, obtain the spherical powder containing active substance, spray-dired parameter is: inlet temperature is 60～90 ℃, nozzle place temperature is 30～50 ℃, air mass flow is 10～30m3/h, charging rate is 10～40ml/min, and air pressure is 0.1～0.4mpa.
(3) screening selects particle diameter by said method, to make the powder containing active substance between 75 μ m～150 μ m, adds 1% magnesium stearate, then is directly used for being pressed into tablet.
2. the preparation technology of vildagliptin/metformin hydrochloride compound preparation claimed in claim 1, it is characterized in that it is 1.5%～20% that vildagliptin be take the addition of dry weight basis, it is 80%～98.5% that metformin hydrochloride be take the addition of dry weight basis, aluminium-magnesium silicate with the consumption of dry weight basis 0.5～2.1%, hydroxypropyl cellulose with the consumption of dry weight basis 5～12%.
3. the preparation technology of vildagliptin/metformin hydrochloride compound preparation claimed in claim 1, the consumption that it is characterized in that ethanol or isopropyl alcohol is 3～5 times of active substance gross weight.
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| CN201410050520.3A CN103735544B (en) | 2014-02-14 | 2014-02-14 | A kind of preparation technology of vildagliptin/metformin hydrochloride compound preparation |
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| CN201410050520.3A CN103735544B (en) | 2014-02-14 | 2014-02-14 | A kind of preparation technology of vildagliptin/metformin hydrochloride compound preparation |
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| CN103735544B CN103735544B (en) | 2015-08-19 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105193752A (en) * | 2015-10-27 | 2015-12-30 | 石家庄康贺威药业有限公司 | Vildagliptin tablet and preparation method thereof |
| CN106580960A (en) * | 2015-10-19 | 2017-04-26 | 南京优科制药有限公司 | Preparation method of vildagliptin and metformin hydrochloride compound preparation |
| CN110128699A (en) * | 2019-06-03 | 2019-08-16 | 江苏极易新材料有限公司 | A kind of method of composite antioxidant granulating |
Citations (2)
| 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 |
| CN101365432A (en) * | 2005-12-16 | 2009-02-11 | 默克公司 | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin |
-
2014
- 2014-02-14 CN CN201410050520.3A patent/CN103735544B/en active Active
Patent Citations (2)
| 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 |
| CN101365432A (en) * | 2005-12-16 | 2009-02-11 | 默克公司 | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin |
Non-Patent Citations (1)
| Title |
|---|
| 刘春平等: "粉末直接压片法概述及其应用思考", 《北方药学》, vol. 9, no. 9, 31 December 2012 (2012-12-31), pages 27 - 28 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106580960A (en) * | 2015-10-19 | 2017-04-26 | 南京优科制药有限公司 | Preparation method of vildagliptin and metformin hydrochloride compound preparation |
| CN105193752A (en) * | 2015-10-27 | 2015-12-30 | 石家庄康贺威药业有限公司 | Vildagliptin tablet and preparation method thereof |
| CN105193752B (en) * | 2015-10-27 | 2018-03-30 | 石家庄康贺威药业有限公司 | A kind of vildagliptin tablet and preparation method thereof |
| CN110128699A (en) * | 2019-06-03 | 2019-08-16 | 江苏极易新材料有限公司 | A kind of method of composite antioxidant granulating |
| CN110128699B (en) * | 2019-06-03 | 2021-03-16 | 江苏极易新材料有限公司 | Method for granulating composite antioxidant |
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| Publication number | Publication date |
|---|---|
| CN103735544B (en) | 2015-08-19 |
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Address after: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Patentee after: Nanjing Huawei Medicine Technology Group Co Ltd Address before: Cheng Wei Road Nanjing city Jiangsu province 210046 Xianlin University No. 9 Patentee before: Nanjing Huawe Medical Science & Technology Development Co., Ltd. |
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