CN103505466B - Solid compound preparation containing metformin hydrochloride and glimepiride and its production and use - Google Patents
Solid compound preparation containing metformin hydrochloride and glimepiride and its production and use Download PDFInfo
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- CN103505466B CN103505466B CN201210205288.7A CN201210205288A CN103505466B CN 103505466 B CN103505466 B CN 103505466B CN 201210205288 A CN201210205288 A CN 201210205288A CN 103505466 B CN103505466 B CN 103505466B
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Abstract
The invention provides a kind of solid compound preparation containing metformin hydrochloride and glimepiride, described solid compound preparation is made up of metformin hydrochloride granule and glimepiride granule, metformin hydrochloride and binding agent is comprised in described metformin hydrochloride granule, comprise glimepiride, water ease of solubility filler, disintegrating agent and binding agent in described glimepiride granule, in wherein said solid compound preparation, do not comprise water not easily soluble filler.Present invention also offers preparation method and the purposes of above-mentioned solid compound preparation.Solid compound preparation of the present invention and ordinary preparation and adopt water not easily soluble filler preparation compared with, the dissolution rate of glimepiride can be significantly improved, and effectively reduce the interaction of two kinds of principal agents, thus reduce the recruitment of related impurities in put procedure, constant product quality and homogeneity is good, improves effectiveness and the safety of patient medication.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically, the present invention relates to a kind of solid compound preparation containing metformin hydrochloride and glimepiride and its production and use.
Background technology
Metformin hydrochloride and glimepiride are treats type Ⅱdiabetes mellitus medication, their use in conjunction has synergy, is applicable to be used alone sulfonylurea and effectively can not controls the patient of blood glucose or take the patient that sulfonylurea and metformin carry out therapeutic alliance simultaneously.
The use in conjunction of metformin hydrochloride and glimepiride, existing application and open in patent at home and abroad, the US Patent No. 2003018028A1 of such as Wyeth of U.S. application, the world patent WO9903477A1 etc. of drugmaker of Smithkline Beecham of U.S. application.
Application at home and abroad in a large number about the formulation patent of metformin hydrochloride and glimepiride use in conjunction, as patents such as the KR20040076535 that WO2007103563A2, US2004219212A1 and handok drugmaker of Korea S apply for, all be designed to the compound recipe sustained-release preparation containing metformin hydrochloride and glimepiride, wherein glimepiride is immediate release section, and metformin hydrochloride is slow controlled release portion.
For the common quick release preparation of metformin hydrochloride and glimepiride, such as tablet, and its formulation study such as double-layer tablet, three-layer tablet, dry coated tablet, dispersible tablet, oral cavity disintegration tablet, chewable tablet, effervescent tablet, capsule, microcapsule, enteric coated capsule, granule or dry suspension of the application's design and preparation method have no pertinent literature report.
For the common quick release preparation of metformin hydrochloride and glimepiride, such as tablet, its preparation method normally adds suitable binding agent soft material, granulation by after metformin hydrochloride, glimepiride and the mix homogeneously such as disintegrating agent, filler, adds the even rear tabletting of mix lubricant and obtain after drying.But, the applicant finds under study for action, the tablet prepared by said method, and glimepiride dissolution rate is slower, do not reach the dissolution rate of external import ordinary tablet Ya Moli (French Sanofi-Aventis drugmaker product, the Yuan Yan manufacturer of glimepiride tablet).According to the technical requirement at national new drug reviewing center, in compound preparation, the quality standard of each principal agent is according to the quality level requirement of commercialized product unitary agent, the dissolution of arbitrary principal agent just must not may ratify clinical research or launch lower than the quality standard of commercialized product, therefore, this preparation technology can not reach associated specifications.And also find there is obvious interaction between metformin, glimepiride in test, the tablet that this preparation method obtains related impurities of glimepiride in study on the stability obviously increases.
Therefore, need to develop a kind of solid compound preparation containing metformin hydrochloride and glimepiride, make it have good dissolution rate and stability.
Summary of the invention
One object of the present invention is, provide a kind of solid compound preparation containing metformin hydrochloride and glimepiride, said preparation homogeneity is good, stability is high, dissolution is good and preparation technology simple, easy industrialization.
Another object of the present invention is, provides a kind of method preparing above-mentioned solid compound preparation.
Another object of the present invention is, provides the purposes of above-mentioned solid compound preparation.
For contributing to understanding the present invention, define some terms below.Term defined herein has the implication that those of ordinary skill in the related art of the present invention understand usually.
Unless otherwise indicated, term used herein " water ease of solubility filler " refers to that, at 25 DEG C ± 2 DEG C temperature, weight is the filler of 1g, and jolting can be dissolved completely being less than in 30ml water after 30 seconds.
Unless otherwise indicated, term used herein " water is soluble filler not easily " refers to that, at 25 DEG C ± 2 DEG C temperature, weight is the filler of 1g, and jolting can not be dissolved completely being less than in 30ml water after 30 seconds.
Unless otherwise indicated, adjuvant that term used herein " pharmaceutically acceptable adjuvant " refers to countries in the world Drug Administration approval, that can be used in pharmaceutical production manufacture, such as filler, disintegrating agent, binding agent, lubricant, excipient, coloring agent, pH adjusting agent, correctives, sweeting agent, spice, fluidizer etc.
In order to solve the problem, the present inventor has carried out conscientious research in the R&D process to metformin hydrochloride and glimepiride conventional tablet.
Because glimepiride is poorly water soluble drugs, domestic listing tablet generally adopts Tween 80 (polyoxyethylene sorbitan fatty acid ester 80) to be solubilizing agent, to improve its dissolution rate, reaches associated specifications.Described by all having the use research of solubilizing agent in document " preparation process for glimepiride tablet improvement " (Luo little Rong etc., Chinese Pharmaceutical, the 17th volume the 10th phase in 2008,47 pages), patent CN1874774B.But in study on the stability, the use of solubilizing agent Tween 80 etc. makes glimepiride related substance increase, bad stability, and tablet places the jaundice of rear outward appearance, obfuscation for a long time, affects the compliance of patient consumes.
In addition, because metformin hydrochloride raw material compressibility is very poor, in the preparation technology of granule, especially specification is more than or equal to the tablet of 500mg, to prescription, moisture requirement high (require that adjuvant compressibility is good, addition is many, and moisture General Requirements is at 1.5-5.0 % by weight), otherwise easily occur that top is split, unilateral soft, the problem such as friability is poor, do not meet the general specification of tablet.
In preparation process research, metformin hydrochloride pellet moisture can be increased to more than 1.5 % by weight, but finds that tablet hardness is excessive in test, affects the dissolution of glimepiride, does not meet bound requirements.This situation makes research and development difficulty strengthen further.
Adopt a kind of principal agent and suitable pharmaceutic adjuvant to granulate, another kind of principal agent is not granulated, and to pulverize rear fine powder directly with the form of principal agent, adds or does not add suitable pharmaceutic adjuvant, mixing with aforementioned granules of main drug.Study through the present inventor; by glimepiride (every sheet content is 1-2mg); directly mix with metformin granule; adopt the mode of dilution of progressively increasing; glimepiride content uniformity does not reach the General Requirements (A+1.80S≤15) of tablet; and the related substance of glimepiride directly mixes with above-mentioned supplementary material, granulate, have no improvement compared with tablet forming technique.By metformin hydrochloride (every sheet content is 250-1000mg), directly mix with glimepiride granule, adopt the mode of dilution of progressively increasing, result shows, granule poor compressibility, and friability does not reach the General Requirements (≤1.0%) of tablet.
Study favorite outer discovery, tabletting again after metformin and glimepiride are individually granulated, and select water ease of solubility filler in adjuvant, as sugar (such as lactose, sucrose, dextrose etc.), polysaccharide (such as dextrates, glucosan, maltodextrin, glucosan etc.), polyhydric alcohol (such as mannitol, xylitol, Sorbitol etc.) etc. and do not add water not easily soluble filler, the tablet of gained with by metformin, glimepiride respectively with containing starch, the tablet prepared again of granulating after the adjuvant mix homogeneously of the water such as microcrystalline Cellulose not easily soluble filler is compared, the dissolution rate of glimepiride is obviously accelerated, and metformin, interaction between glimepiride reduces, relative substance obviously reduces, constant product quality and homogeneity is good.
Therefore, the object of the invention is to be achieved through the following technical solutions:
On the one hand, the invention provides a kind of solid compound preparation containing metformin hydrochloride and glimepiride, described solid compound preparation is made up of metformin hydrochloride granule and glimepiride granule, metformin hydrochloride and binding agent is comprised in described metformin hydrochloride granule, comprise glimepiride, water ease of solubility filler, disintegrating agent and binding agent in described glimepiride granule, in wherein said solid compound preparation, do not comprise water not easily soluble filler.
Preferably, other the pharmaceutically acceptable adjuvants except binding agent are also comprised in described metformin hydrochloride granule.
Preferably, described other pharmaceutically acceptable adjuvants except binding agent are selected from one or more in water ease of solubility filler, disintegrating agent and lubricant.
Preferably, other the pharmaceutically acceptable adjuvants dewatered outside ease of solubility filler, disintegrating agent and binding agent are also comprised in described glimepiride granule.
Preferably, other the pharmaceutically acceptable adjuvants dewatered described in outside ease of solubility filler, disintegrating agent and binding agent are lubricant.
Preferably, by the metformin hydrochloride of 100 weight portions in described metformin hydrochloride granule, comprise the metformin hydrochloride of 100 weight portions and the binding agent of 1 ~ 7.5 weight portion; Alternatively, by the metformin hydrochloride of 100 weight portions in described metformin hydrochloride granule, also comprise in the water ease of solubility filler of 1 ~ 50 weight portion, the disintegrating agent of 1 ~ 5 weight portion and the lubricant of 0.1 ~ 2 weight portion one or more.
Preferably, by the glimepiride of 100 weight portions in described glimepiride granule, comprise the glimepiride of 100 weight portions, the water ease of solubility filler of 75 ~ 7500 weight portions, the disintegrating agent of 25 ~ 250 weight portions and the binding agent of 2.5 ~ 125 weight portions; Alternatively, by the glimepiride of 100 weight portions in described glimepiride granule, the lubricant of 2.5 ~ 50 weight portions is also comprised.
Preferably, wherein, in described solid compound preparation, the weight ratio of metformin hydrochloride and glimepiride is 1000:1 ~ 10.
Preferably, described water ease of solubility filler is selected from one or more in sugar, polysaccharide and polyhydric alcohol.
Preferably, described sugar is selected from one or more in lactose, sucrose and dextrose.
Preferably, described polysaccharide is one or more in dextrates, glucosan and maltodextrin.
Preferably, described polyhydric alcohol is selected from one or more in mannitol, xylitol and Sorbitol.
Preferably, described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium and polyvinylpolypyrrolidone.
Preferably, described binding agent is polyvidone k25 and/or polyvidone k30.Find in the granule research process of glimepiride, adopt polyvidone k25 and/or k30 to be binding agent, with employing polyvidone k90, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch etc. as compared with binding agent, glimepiride stability has clear improvement.
Preferably, described lubricant is selected from one or more in Pulvis Talci, stearate, stearic acid and lightweight micropowder silica gel.
Preferably, described metformin hydrochloride granule and/or glimepiride granule mixed mutually with other pharmaceutically acceptable adjuvant before the described solid compound preparation of preparation.
Preferably, described pharmaceutically acceptable adjuvant is in addition selected from one or more in water ease of solubility filler, disintegrating agent, binding agent and lubricant.
Preferably, any one in the solubilizing agents such as Tween 80, polysorbate60, polysorbate40, polysorbas20, sodium lauryl sulphate and poloxamer is not comprised in described solid compound preparation.
Preferably, in described metformin hydrochloride granule, the particle diameter of contained metformin hydrochloride is 2 ~ 1000 μm, is preferably 150 ~ 1000 μm.
Preferably, in described glimepiride granule, the particle diameter of contained glimepiride is 0.01 ~ 50 μm, is preferably 1 ~ 20 μm.
Preferably, described solid preparation is conventional tablet, double-layer tablet, multilayer tablet, dry coated tablet, dispersible tablet, oral cavity disintegration tablet, chewable tablet, effervescent tablet, capsule, microcapsule, enteric coated capsule, granule or dry suspension; Be preferably conventional tablet, double-layer tablet, capsule or dry coated tablet.
Solid preparation of the present invention can coating or not coating.Coating can use seed-coating machine to prepare, can film coating, sugar-coat, enteric coating, release membranes clothing.And two kinds or more coated substrate can be used, coating additive can be used.
Solid preparation of the present invention can stamp the label or letter being convenient to differentiate, also can have divisural line for separating.
Solid preparation of the present invention can be circular, oval, capsule shape; Be preferably circular tablet.
Solid preparation Orally-administrable of the present invention or parenteral safety deliver medicine to mammal (such as mice, rat, rabbit, cat, Canis familiaris L., cattle, horse, monkey, gorilla and the mankind and other).
In solid preparation of the present invention, the effective dose of metformin hydrochloride is generally grown up (60kg) every consumption per day 1 ~ 5000mg, is preferably 250 ~ 3000mg every day.
In solid preparation of the present invention, the effective dose of glimepiride is generally grown up (60kg) every consumption per day 0.1 ~ 50mg, is preferably 1 ~ 16mg every day.
Solid preparation of the present invention daily 1 ~ 3 time, is preferably every day 1 ~ 2 time.Before the meal or meal time take.
Solid preparation of the present invention is preferably glimepiride/metformin hydrochloride: 1mg/250mg, 1mg/500mg, 2mg/500mg, 4mg/1000mg.
On the other hand, the invention provides a kind of preparation method of above-mentioned solid preparation, comprising:
(1) respectively metformin hydrochloride and glimepiride are pulverized in advance;
(2) adopt pharmaceutically acceptable method, by metformin hydrochloride powder obtained in step (1) and binding agent, or make granule with binding agent and other the pharmaceutically acceptable adjuvants except binding agent; Optionally, gained granule is mixed homogeneously with other pharmaceutically acceptable adjuvant and is obtained granulate mixture;
(3) pharmaceutically acceptable method is adopted, by glimepiride powder obtained in step (1) and water ease of solubility filler, disintegrating agent and binding agent, or make granule with water ease of solubility filler, disintegrating agent, binding agent and other the pharmaceutically acceptable adjuvants dewatered outside ease of solubility filler, disintegrating agent and binding agent; Optionally, gained granule is mixed homogeneously with other pharmaceutically acceptable adjuvant and is obtained granulate mixture;
(4) pharmaceutically acceptable method is adopted to prepare solid preparation by the glimepiride granule obtained in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture.
Preferably, in step (1), metformin hydrochloride pulverizes rear particle size range is 2 ~ 1000 μm, is preferably 150 ~ 1000 μm;
After glimepiride micronization, particle size range is 0.01 ~ 50 μm, is preferably 1 ~ 20 μm.
Preferably, wet granulation, dry granulation or fluidizing fluid-bed granulation is adopted in step (2) and/or step (3).
Preferably, wherein obtained in step (2) metformin hydrochloride granule or the moisture of granulate mixture are 0.3 ~ 1.5 % by weight.Metformin pellet moisture is strict controlled in the scope of 0.3 ~ 1.5 % by weight, can suppress and obtain the qualified tablet of friability.
Preferably; wherein step (4) is the wherein a kind of tabletted by the glimepiride granule that obtains in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture, is prepared into dry coated tablet with another granule or mixture.
Preferably; wherein step (4) be the glimepiride granule obtained in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture are mixed with other proper auxiliary materials or with other blank granules, medicine-containing particle, adopt pharmaceutically acceptable method to make double-layer tablet or multilayer tablet.
Preferably, wherein step (4) is by after the glimepiride granule that obtains in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture mix homogeneously, compacting conventional tablet.The technique preparing conventional tablet is simple, lower to equipment requirements, thus cost savings.
Mixing of materials of the present invention can use V-Mixer or bucket to mix machine mixing.
Preferably, the preparation method of the solid preparation of hydrochloric metformin of the present invention and glimepiride, comprising:
(1) respectively metformin hydrochloride and glimepiride are pulverized in advance;
(2) metformin hydrochloride and the binding agent of recipe quantity is got, or mix homogeneously with binding agent and other the pharmaceutically acceptable adjuvants except binding agent, soft material processed, granulate, drying obtains metformin hydrochloride granule, optionally, mix homogeneously with other pharmaceutically acceptable adjuvant further and obtain granulate mixture;
(3) glimepiride and water ease of solubility filler, disintegrating agent and the binding agent of recipe quantity is got, or mix homogeneously with water ease of solubility filler, disintegrating agent, binding agent and other the pharmaceutically acceptable adjuvants dewatered outside ease of solubility filler, disintegrating agent and binding agent, soft material processed, granulate, drying obtains glimepiride granule, optionally, mix homogeneously with other pharmaceutically acceptable adjuvant further and obtain granulate mixture;
(4) take two parts granule of gained in step (2) and (3) in principal agent ratio, optionally, add other pharmaceutically acceptable adjuvant mix homogeneously, obtain the hybrid particles containing two kinds of principal agents;
(5a) get the hybrid particles obtained in step (4), adopt rotary tablet machine compacting conventional tablet;
(5b) the metformin hydrochloride granule or granulate mixture that obtain in step (2) is got, and the glimepiride granule obtained in step (3) or granulate mixture, adopt rotary double-layer tablet machine compacting double-layer tablet;
(5c) A: get the glimepiride granule or granulate mixture that obtain in step (3), adopts rotary tablet machine compacting conventional tablet;
B: get the tablet obtained in the metformin hydrochloride granule or granulate mixture and steps A obtained in step (2), adopts rotary cored machine compressed dry coated tablet;
(5d) the metformin hydrochloride granule or granulate mixture tabletted that obtain in step (2) is got, and the glimepiride granule obtained in (3) or granulate mixture, adopt rotary cored machine compressed dry coated tablet.
(5e) the metformin hydrochloride granule or granulate mixture tabletted that obtain in step (2) is got; (3) the glimepiride granule obtained in or granulate mixture; the blank granules prepared with other pharmaceutically acceptable prescriptions and method, adopts rotary tablet machine compacting to obtain three-layer tablet.
Another aspect, the invention provides above-mentioned solid preparation and is preparing the purposes prevented and/or treated in the medicine of diabetes, diabetic complication, obesity, hyperlipidemia, coronary heart disease, high blood pressure disease.
Solid preparation of the present invention can with one or more medicines (concomitant drugs) drug combination, comprise Remedies for diabetes, treating diabetic complications agent, bariatrician agent, hyperlipidemia therapeutic agent, coronary heart disease treatment agent, abrupt antihypertensive therapy agent etc.Can with suitable ratio two kinds and above such active component used in combination.By using concomitant drugs, excellent therapeutic effect can be obtained.
The solid preparation of hydrochloric metformin of the present invention and glimepiride, solid preparation is prepared by different technologies method again after individually preparing granule by selecting suitable adjuvant and two kinds of medicinal components, the solid preparation obtained compared with prior art significantly improves dissolution and the stability of medicine, compared with the preparation prepared with common preparation method or the preparation containing water not easily soluble filler, product significantly improves the dissolution rate of glimepiride, and effectively reduce the interaction of two kinds of principal agents, thus reduce the recruitment of related impurities in put procedure, improve the safety of patient medication.Preparation technology of the present invention is simple, is easy to industrialization.Medicine in this solid preparation has the medicinal effects significantly reducing blood sugar in diabetic patients and increase patient insulin's sensitivity, and two kinds of medicines are taken simultaneously has synergism, can reduce drug use amount.Solid preparation of the present invention can be used as Remedies for diabetes etc., and has fabulous glimepiride and the stripping property of metformin hydrochloride.Glimepiride component also has outstanding stability in the solid preparation and preparation method of this invention.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Glimepiride Dissolution profiles in Fig. 1 embodiment 1-5, comparative example 1-2 and reference substance Ya Moli;
Tablet glimepiride Related substances separation collection of illustrative plates (0 day) in Fig. 2 embodiment 1;
Tablet glimepiride Related substances separation collection of illustrative plates (0 day) in Fig. 3 comparative example 1;
Tablet glimepiride Related substances separation collection of illustrative plates (40 DEG C of accelerated tests, 3 months) in Fig. 4 embodiment 1;
Tablet glimepiride Related substances separation collection of illustrative plates (40 DEG C of accelerated tests, 3 months) in Fig. 5 comparative example 1.
Detailed description of the invention
To do the present invention below in conjunction with following embodiment and experimental example and further describe in detail, it does not also mean that restriction the present invention.
Instrument and equipment: High Speed Stirring Machine (profit sky, Xi'an SHK-6 type); fluid bed (German UNI-GLATT); multidirectional mixer (Wenzhou little human relations HD-5 type); rotary tablet machine (sky, Shanghai closes ZP-5 type); rotary double-layer tablet machine (Shanghai Tianxiang is good for platform ZPW-21 type), rotary cored machine (Shanghai Tianxiang is good for platform ZPW22 type).
In the examples below that, various adjuvant all meets prescription and the import adjuvant quality standard of Chinese Pharmacopoeia (2010 editions two).
Metformin hydrochloride and glimepiride are pulverized all in advance, and wherein metformin hydrochloride pulverizes rear particle diameter is 150-1000 μm; Particle diameter after glimepiride micronization is 1-20 μm.
Reference substance determination of glimepiride in tablet Ya Moli is purchased from Sanofi-Aventis drugmaker.
Reference substance metformin hydrochloride tablet agent glucophage is purchased from Bristol Myers Squibb Pharma Co..
embodiment 1
Get metformin hydrochloride 1000.5g (particle diameter 200 μm) and lactose 20.2g; mannitol 30.1g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k30 aqueous solution (15%; w/w) 91.4g, soft material processed, waves granulator; fluid bed drying obtains metformin hydrochloride granule, pellet moisture 0.75 % by weight.
Get glimepiride 40.0g(particle diameter 2.5 μm) and lactose 200.8g, sucrose 100g, cross-linking sodium carboxymethyl cellulose 18.0g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k25 aqueous solution (10%; w/w) 74.2g soft material; wave granulator, fluid bed drying obtains glimepiride granule.
According to granule content result of calculation, get part above-mentioned metformin hydrochloride granule 530.5g, glimepiride granule 18.5g mixes, first get the metformin hydrochloride granule that glimepiride granule 18.5g adds 1/3 weight, cross-linking sodium carboxymethyl cellulose 12.5g, put multidirectional mixer and mix 5 minutes, 5 minutes are remixed after being added by surplus metformin hydrochloride granule, the circular die of diameter 11 millimeters is adopted with 5kg pressure, use rotary tablet machine is suppressed, and obtains metformin hydrochloride/glimepiride (500mg/2mg) about 1000 tablets of typical circular tablets.
embodiment 2
Get metformin hydrochloride 1000.5g(particle diameter 1000 μm) and maltodextrin 30.2g, polyvinylpolypyrrolidone 58g; add polyvidone k30 aqueous solution (15%; w/w) 89.4g; High Speed Stirring Machine is adopted to be pre-mixed evenly; soft material processed; wave granulator; fluid bed drying obtains metformin hydrochloride granule; pellet moisture 0.3 % by weight; add cross-linking sodium carboxymethyl cellulose 18g, magnesium stearate 5.2g, micropowder silica gel 5.1g; put multidirectional mixer to mix 5 minutes and make evenly, obtain the mixture of hydrochloric metformin granule.
Get glimepiride 40.2g(particle diameter 20 μm) and lactose 1200.6g, dextrates 1200g; xylitol 600.3g, polyvinylpolypyrrolidone 50.1g, mix homogeneously, adds polyvidone k25 aqueous solution (20%; w/w) 247.3g soft material; wave granulator, fluid bed drying obtains glimepiride granule, adds carboxymethyl starch sodium 40.2g; calcium stearate 5.3g; Pulvis Talci 2.5g, micropowder silica gel 2.5g put multidirectional mixer and mix 5 minutes and make evenly, obtain the mixture containing glimepiride granule.
According to granule content result of calculation, get the mixture 535g of the above-mentioned hydrochloric metformin granule of part, the mixture 158.5g containing glimepiride granule, adopt the circular die of diameter 11 millimeters, adopt rotary double-layer tablet machine compacting double-layer tablet, obtain metformin hydrochloride/glimepiride (500mg/2mg) about 1000.
embodiment 3
Get metformin hydrochloride 1000.3g(particle diameter 150 μm) and mannitol 401g, dextrose 55.2g; Dextran 45 g, add polyvidone k25 aqueous solution (15%; w/w) 180.5g; High Speed Stirring Machine is adopted to be pre-mixed evenly; soft material processed; wave granulator; fluid bed drying obtains metformin hydrochloride granule; pellet moisture 1.5 % by weight; add carboxymethyl starch sodium 18.1g, zinc stearate 4.3g, Pulvis Talci 2.2g, micropowder silica gel 2.0g; put multidirectional mixer to mix 5 minutes and make evenly, obtain the mixture of hydrochloric metformin granule.
Get glimepiride 40.2g(particle diameter 1.0 μm) and lactose 300.3g, dextrates 300g, cross-linking sodium carboxymethyl cellulose 30.1g; mix homogeneously; add polyvidone k30 aqueous solution (10%; w/w) 153.2g soft material; wave granulator, fluid bed drying obtains glimepiride granule, adds cross-linking sodium carboxymethyl cellulose 20.5g, magnesium stearate 20.0g; put multidirectional mixer to mix 5 minutes and make evenly, obtain the mixture containing glimepiride granule.
According to granule content result of calculation; get part above-mentioned metformin hydrochloride granulate mixture 772g, glimepiride granulate mixture 36.0g; adopt rotary cored machine first by glimepiride granulate mixture tabletted; be pressed into dry coated tablet by the mode of metformin hydrochloride particle encapsulation glimepiride tablet again, obtain metformin hydrochloride/glimepiride (500mg/2mg) about 1000.
embodiment 4
Get metformin hydrochloride 1000.1g(particle diameter 520 μm) and lactose 30.5g; xylitol 20.1g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k25 aqueous solution (15%; w/w) 98.1g, soft material processed, waves granulator; fluid bed drying obtains metformin hydrochloride granule, pellet moisture 1.2 % by weight.
Get glimepiride 40.1g(particle diameter 15.0 μm) and lactose 200.1g, Sorbitol 100g, cross-linking sodium carboxymethyl cellulose 18.2g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k25 aqueous solution (10%; w/w) 74.9g soft material; wave granulator, fluid bed drying obtains glimepiride granule.
According to granule content result of calculation, get part above-mentioned metformin hydrochloride granule 530.0g, glimepiride granule 9.5g mixes, first get the metformin hydrochloride granule that glimepiride granule 9.5g adds 1/3 weight, cross-linking sodium carboxymethyl cellulose 12.5g, stearic acid 5.0g, micropowder silica gel 5g, put multidirectional mixer and mix 5 minutes, 5 minutes are remixed after being added by surplus metformin hydrochloride granule, the circular die of diameter 11 millimeters is adopted with 5kg pressure, use rotary tablet machine is suppressed, obtain metformin hydrochloride/glimepiride (500mg/1mg) about 1000 tablets of typical circular tablets.
embodiment 5
Get metformin hydrochloride 1000.3g(particle diameter 750 μm), adopt High Speed Stirring Machine to stir 3min in advance, add polyvidone k30 aqueous solution (50%; w/w) 150.6g, soft material processed, waves granulator; fluid bed drying obtains metformin hydrochloride granule, pellet moisture 0.5 % by weight.
Get glimepiride 40.2g(particle diameter 10 μm) and lactose 100.6g, glucosan 20g, polyvinylpolypyrrolidone 400.1g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k25 aqueous solution (10%; w/w) 78.2g soft material; wave granulator, fluid bed drying obtains glimepiride granule.
According to granule content result of calculation, get part above-mentioned metformin hydrochloride granule 530.9g, glimepiride granule 29.3g mixes, first get the metformin hydrochloride granule that glimepiride granule 29.3g adds 1/3 weight, cross-linking sodium carboxymethyl cellulose 12.5g, stearic acid 5.1g, Pulvis Talci 3.7g, put multidirectional mixer and mix 5 minutes, 5 minutes are remixed after being added by surplus metformin hydrochloride granule, the circular die of diameter 9 millimeters is adopted with 5kg pressure, use rotary tablet machine is suppressed, obtain metformin hydrochloride/glimepiride (250mg/1mg) about 2000 tablets of typical circular tablets.
comparative example 1
Get metformin hydrochloride 1000.2g(particle diameter 150 μm), glimepiride 4.0g(micronization; particle diameter 1.0 μm) and lactose 80.2g, microcrystalline Cellulose 120.1g; get glimepiride and microcrystalline Cellulose 4.0g; mix homogeneously; and adopt the dilution method that progressively increases to mix homogeneously with other adjuvants and metformin hydrochloride, adopt High Speed Stirring Machine to add polyvidone k30 aqueous solution (15%, w/w) 95.1g soft material; wave granulator, fluid bed drying obtains dry granule.Get the above-mentioned granule 615.2g of part, add cross-linking sodium carboxymethyl cellulose 22.5g, microcrystalline Cellulose 15.1g, magnesium stearate 12.5g, putting multidirectional mixer mixes 5 minutes and makes evenly, the circular die of diameter 11 millimeters is adopted with 5kg pressure, use rotary tablet machine is suppressed, and obtains metformin hydrochloride/glimepiride (500mg/2mg) about 1000 tablets of typical circular tablets.
comparative example 2
Get metformin hydrochloride (particle diameter 200 μm) 1000.5g and starch 20.4g; microcrystalline Cellulose 30.3g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k30 aqueous solution (15%; w/w) 91.0g, soft material processed, waves granulator; fluid bed drying obtains metformin hydrochloride granule, pellet moisture 0.76 % by weight.
Get glimepiride 40.0g(particle diameter 2.5 μm) and microcrystalline Cellulose 200.8g, dextrin 100g, cross-linking sodium carboxymethyl cellulose 18.0g; adopting High Speed Stirring Machine to be pre-mixed 3min makes evenly; add polyvidone k25 aqueous solution (10%; w/w) 76.4g soft material; wave granulator, fluid bed drying obtains glimepiride granule.
According to granule content result of calculation, get part above-mentioned metformin hydrochloride granule 530.8g, glimepiride granule 18.9g mixes, first get the metformin hydrochloride granule that glimepiride granule 18.9g adds 1/3 weight, cross-linking sodium carboxymethyl cellulose 12.5g, put multidirectional mixer and mix 5 minutes, 5 minutes are remixed after being added by surplus metformin hydrochloride granule, the circular die of diameter 11 millimeters is adopted with 5kg pressure, use rotary tablet machine is suppressed, and obtains metformin hydrochloride/glimepiride (500mg/2mg) about 1000 tablets of typical circular tablets.
experimental example 1
According to Chinese Pharmacopoeia (2010 editions two) annex dissolution method, with the rotating speed of paddle method 75 revs/min, adopt 900ml buffer salt (37 DEG C, pH value 7.8) measure the dissolution of glimepiride in embodiment 1-5, comparative example 1-2 and determination of glimepiride in tablet reference substance Ya Moli, the results are shown in Table 1 and Fig. 1.
The dissolution (%) of table 1 glimepiride
| Dissolution time (min) | 5 | 10 | 15 | 30 | 60 |
| Embodiment 1 | 65.6 | 85.6 | 96.8 | 100.8 | 100.9 |
| Embodiment 2 | 63.4 | 82.3 | 94.5 | 98.4 | 99.6 |
| Embodiment 3 | 67.8 | 81.9 | 95.6 | 99.7 | 99.9 |
| Embodiment 4 | 70.4 | 83.6 | 97.8 | 100.0 | 100.1 |
| Embodiment 5 | 72.1 | 89.6 | 98.1 | 100.6 | 100.7 |
| Comparative example 1 | 12.8 | 27.1 | 36.2 | 56.6 | 79.9 |
| Comparative example 2 | 18.5 | 33.6 | 57.4 | 72.9 | 91.1 |
| Sub-MORLEY | 70.1 | 84.3 | 95.1 | 100.8 | 100.9 |
experimental example 2
According to Chinese Pharmacopoeia (2010 editions two) annex dissolution method, with the rotating speed of paddle method 50 revs/min, adopt 900ml water (37 DEG C) to measure the dissolution of metformin hydrochloride in embodiment 1-5, comparative example 1-2 and metformin hydrochloride tablet agent reference substance glucophage, the results are shown in Table 2.
The dissolution (%) of table 2 metformin hydrochloride
| Dissolution time (min) | 5 | 10 | 15 | 30 | 60 |
| Embodiment 1 | 96.8 | 101.4 | 101.2 | 101.6 | 101.2 |
| Embodiment 2 | 95.3 | 100.2 | 100.3 | 100.1 | 100.2 |
| Embodiment 3 | 94.9 | 99.5 | 99.3 | 99.2 | 99.4 |
| Embodiment 4 | 96.4 | 100.1 | 100.0 | 100.2 | 100.2 |
| Embodiment 5 | 95.9 | 101.0 | 101.3 | 101.4 | 101.2 |
| Comparative example 1 | 65.4 | 89.2 | 100.1 | 100.5 | 100.3 |
| Comparative example 2 | 75.1 | 95.3 | 100.0 | 100.0 | 100.1 |
| Glucophage | 73.2 | 84.0 | 100.3 | 100.1 | 100.2 |
From the experimental result in experimental example 1 and 2, the solid compound preparation of metformin hydrochloride of the present invention and glimepiride, due to metformin hydrochloride and glimepiride are individually granulated, and adopt water ease of solubility filler and do not contain water not easily soluble filler, relative to the compound preparation in comparative example, by metformin, glimepiride and disintegrating agent, the filler microcrystalline Cellulose of ease of solubility (water not), granulate after the mix homogeneously such as lubricant, tabletting is compared, glimepiride dissolution is obviously accelerated, the quality level of glimepiride tablet former triturate Ya Moli (French Sanofi-Aventis drugmaker) can be reached, reach the associated specifications at national new drug reviewing center.Dissolution and the former triturate glucophage (Bristol-Myers Squibb Co.) of metformin hydrochloride are basically identical.
experimental example 3
According to the Related substances separation method of glimepiride in American Pharmacopeia (USP32), adopt InertsilODS-3C18 chromatographic column (4.6*250mm), acetonitrile-pH value 2.0 phosphate buffer (45:55) is to tablet 0 day and accelerated test (40 DEG C in embodiment 1-5, comparative example 1-2 and determination of glimepiride in tablet reference substance Ya Moli, RH75%, 6 months) the related substance situation of change of glimepiride is examined or check in sample, stability study data in Table 3-1, wherein in embodiment 1 and comparative example 1 tablet glimepiride Related substances separation collection of illustrative plates the results are shown in accompanying drawing 2 ~ 5.
Table 3-1 glimepiride accelerated test (40 DEG C, RH75%) stability data
| Related substance (area normalization, %) | 0 month | January | February | March | June |
| Embodiment 1 | 0.21 | 0.26 | 0.32 | 0.45 | 0.86 |
| Embodiment 2 | 0.23 | 0.29 | 0.37 | 0.55 | 0.89 |
| Embodiment 3 | 0.20 | 0.24 | 0.36 | 0.48 | 0.90 |
| Embodiment 4 | 0.22 | 0.29 | 0.39 | 0.47 | 0.85 |
| Embodiment 5 | 0.21 | 0.28 | 0.36 | 0.44 | 0.82 |
| Comparative example 1 | 0.23 | 0.56 | 0.82 | 1.45 | 3.27 |
| Comparative example 2 | 0.22 | 0.25 | 0.34 | 0.47 | 0.97 |
| Sub-MORLEY | 0.35 | 0.59 | 0.85 | 1.07 | 2.12 |
With above-mentioned experimental technique, to tablet 0 day and long-term stable experiment (25 DEG C in embodiment 1-5, comparative example 1-2 and determination of glimepiride in tablet reference substance Ya Moli, RH60%, 12 months) the related substance situation of change of glimepiride is examined or check in sample, and stability study data are in Table 3-2.
Table 3-2 glimepiride long term test (25 DEG C, RH60%) stability data
| Related substance (area normalization, %) | 0 month | March | June | JIUYUE | December |
| Embodiment 1 | 0.21 | 0.23 | 0.24 | 0.26 | 0.29 |
| Embodiment 2 | 0.23 | 0.25 | 0.27 | 0.28 | 0.29 |
| Embodiment 3 | 0.20 | 0.2 1 | 0.23 | 0.25 | 0.26 |
| Embodiment 4 | 0.22 | 0.23 | 0.25 | 0.27 | 0.30 |
| Embodiment 5 | 0.21 | 0.22 | 0.23 | 0.24 | 0.26 |
| Comparative example 1 | 0.23 | 0.32 | 0.48 | 0.76 | 0.97 |
| Comparative example 2 | 0.22 | 0.23 | 0.25 | 0.27 | 0.30 |
| Sub-MORLEY | 0.35 | 0.40 | 0.45 | 0.57 | 0.74 |
From the experimental result contrast table 3-1, table 3-2 and accompanying drawing 2 ~ 5, the solid compound preparation of metformin hydrochloride of the present invention and glimepiride is relative to the compound preparation in comparative example, interaction between metformin, glimepiride reduces, glimepiride relative substance obviously reduces, and glimepiride component has outstanding stability in solid preparation of the present invention and preparation method.
experimental example 4
According to the Related substances separation chromatographic condition of glimepiride in American Pharmacopeia (USP32), adopt InertsilODS-3C18 chromatographic column (4.6*250mm), acetonitrile-pH value 2.0 phosphate buffer (45:55) is examined or check the content uniformity of glimepiride in embodiment 1-5, and data is in table 4.
Table 4 glimepiride Content uniformity test result
experimental example 5
According to Chinese Pharmacopoeia version in 2010 two annex friability inspection techniques, check sample, data is in table 5.
Table 5 glimepiride diformin tablet friability check result
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| Friability (%) | 0.05 | 0.08 | 0.07 | 0.06 | 0.04 |
As can be seen from table 4,5, the tablet that this preparation prescription technique prepares has the good content uniformity of glimepiride and friability, meets industrialization production requirements, and convenient transport and preservation, have stronger practicality.
Claims (43)
1. one kind contains the solid compound preparation of metformin hydrochloride and glimepiride, it is characterized in that, described solid compound preparation is made up of metformin hydrochloride granule and glimepiride granule, metformin hydrochloride and binding agent is comprised in described metformin hydrochloride granule, comprise glimepiride, water ease of solubility filler, disintegrating agent and binding agent in described glimepiride granule, in wherein said solid compound preparation, do not comprise water not easily soluble filler.
2. solid compound preparation according to claim 1, wherein, also comprises other the pharmaceutically acceptable adjuvants except binding agent in described metformin hydrochloride granule.
3. solid compound preparation according to claim 2, wherein, described other pharmaceutically acceptable adjuvants except binding agent be selected from water ease of solubility filler, disintegrating agent and lubricant one or more.
4. solid compound preparation according to claim 1, wherein, also comprises other the pharmaceutically acceptable adjuvants dewatered outside ease of solubility filler, disintegrating agent and binding agent in described glimepiride granule.
5. solid compound preparation according to claim 4, wherein, described in other the pharmaceutically acceptable adjuvants dewatered outside ease of solubility filler, disintegrating agent and binding agent be lubricant.
6. the solid compound preparation according to any one of Claims 1 to 5, wherein, by the metformin hydrochloride of 100 weight portions in described metformin hydrochloride granule, comprises the metformin hydrochloride of 100 weight portions and the binding agent of 1 ~ 7.5 weight portion.
7. solid compound preparation according to claim 6, wherein, by the metformin hydrochloride of 100 weight portions in described metformin hydrochloride granule, also comprise in the water ease of solubility filler of 1 ~ 50 weight portion, the disintegrating agent of 1 ~ 5 weight portion and the lubricant of 0.1 ~ 2 weight portion one or more.
8. the solid compound preparation according to any one of Claims 1 to 5, wherein, by the glimepiride of 100 weight portions in described glimepiride granule, comprise the glimepiride of 100 weight portions, the water ease of solubility filler of 75 ~ 7500 weight portions, the disintegrating agent of 25 ~ 250 weight portions and the binding agent of 2.5 ~ 125 weight portions.
9. solid compound preparation according to claim 8, wherein, by the glimepiride of 100 weight portions in described glimepiride granule, also comprises the lubricant of 2.5 ~ 50 weight portions.
10. the solid compound preparation according to any one of Claims 1 to 5, wherein, in described solid compound preparation, the weight ratio of metformin hydrochloride and glimepiride is 1000:1 ~ 10.
11. solid compound preparation according to any one of Claims 1 to 5, wherein, described water ease of solubility filler be selected from sugar and polyhydric alcohol one or more.
12. solid compound preparation according to any one of Claims 1 to 5, wherein, described water ease of solubility filler is polysaccharide.
13. solid compound preparation according to claim 11, wherein, described sugar be selected from lactose, sucrose and dextrose one or more.
14. solid compound preparation according to claim 12, wherein, described polysaccharide is one or more in dextrates, glucosan and maltodextrin.
15. solid compound preparation according to claim 11, wherein, described polyhydric alcohol be selected from mannitol, xylitol and Sorbitol one or more.
16. solid compound preparation according to any one of Claims 1 to 5, wherein, described disintegrating agent be selected from cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium and polyvinylpolypyrrolidone one or more.
17. solid compound preparation according to any one of Claims 1 to 5, wherein, described binding agent is polyvidone k25 and/or polyvidone k30.
18. solid compound preparation according to claim 3 or 5, wherein, described lubricant be selected from Pulvis Talci, stearate, stearic acid and lightweight micropowder silica gel one or more.
19. solid compound preparation according to claim 7, wherein, described lubricant be selected from Pulvis Talci, stearate, stearic acid and lightweight micropowder silica gel one or more.
20. solid compound preparation according to claim 9, wherein, described lubricant be selected from Pulvis Talci, stearate, stearic acid and lightweight micropowder silica gel one or more.
21. solid compound preparation according to any one of Claims 1 to 5, wherein, described metformin hydrochloride granule and/or glimepiride granule mixed mutually with other pharmaceutically acceptable adjuvant before the described solid compound preparation of preparation.
22. solid compound preparation according to claim 21, wherein, described pharmaceutically acceptable adjuvant be in addition selected from water ease of solubility filler, disintegrating agent, binding agent and lubricant one or more.
23. solid compound preparation according to any one of Claims 1 to 5, wherein, do not comprise any one in Tween 80, polysorbate60, polysorbate40, polysorbas20, sodium lauryl sulphate and poloxamer in described solid compound preparation.
24. solid compound preparation according to any one of Claims 1 to 5, wherein, in described metformin hydrochloride granule, the particle diameter of contained metformin hydrochloride is 2 ~ 1000 μm.
25. solid compound preparation according to claim 24, wherein, in described metformin hydrochloride granule, the particle diameter of contained metformin hydrochloride is 150 ~ 1000 μm.
26. solid compound preparation according to any one of Claims 1 to 5, wherein, in described glimepiride granule, the particle diameter of contained glimepiride is 0.01 ~ 50 μm.
27. solid compound preparation according to claim 26, wherein, in described glimepiride granule, the particle diameter of contained glimepiride is 1 ~ 20 μm.
28. solid compound preparation according to any one of Claims 1 to 5, wherein, described solid compound preparation is conventional tablet, double-layer tablet, three-layer tablet, dry coated tablet, dispersible tablet, oral cavity disintegration tablet, chewable tablet, effervescent tablet, capsule, microcapsule, enteric coated capsule, granule or dry suspension.
29. solid compound preparation according to claim 28, wherein, described solid compound preparation is conventional tablet, double-layer tablet, three-layer tablet, capsule or dry coated tablet.
The preparation method of the solid compound preparation according to any one of 30. 1 kinds of claim 1 ~ 29, comprising:
(1) respectively metformin hydrochloride and glimepiride are pulverized in advance;
(2) adopt pharmaceutically acceptable method, by metformin hydrochloride powder obtained in step (1) and binding agent, or make granule with binding agent and other the pharmaceutically acceptable adjuvants except binding agent;
(3) pharmaceutically acceptable method is adopted, by glimepiride powder obtained in step (1) and water ease of solubility filler, disintegrating agent and binding agent, or make granule with water ease of solubility filler, disintegrating agent, binding agent and other the pharmaceutically acceptable adjuvants dewatered outside ease of solubility filler, disintegrating agent and binding agent;
(4) pharmaceutically acceptable method is adopted to prepare described solid compound preparation by the glimepiride granule obtained in the metformin hydrochloride granule obtained in step (2) and step (3).
31. preparation methoies according to claim 30, wherein,
Step (2) also comprises the steps: gained granule to mix homogeneously with other pharmaceutically acceptable adjuvant to obtain granulate mixture;
Step (4) is undertaken by following step: adopt pharmaceutically acceptable method to prepare described solid compound preparation by the glimepiride granule obtained in the granulate mixture obtained in step (2) and step (3).
32. preparation methoies according to claim 30, wherein,
Step (3) also comprises the steps: gained granule to mix homogeneously with other pharmaceutically acceptable adjuvant to obtain granulate mixture;
Step (4) is undertaken by following step: adopt pharmaceutically acceptable method to prepare described solid compound preparation by the granulate mixture obtained in the metformin hydrochloride granule obtained in step (2) and step (3).
33. preparation methoies according to claim 31, wherein,
Step (3) also comprises the steps: gained granule to mix homogeneously with other pharmaceutically acceptable adjuvant to obtain granulate mixture;
Step (4) is undertaken by following step: adopt pharmaceutically acceptable method to prepare described solid compound preparation by the granulate mixture obtained in the granulate mixture obtained in step (2) and step (3).
34. preparation methoies according to claim 30, wherein, in step (1), metformin hydrochloride pulverizes rear particle size range is 2 ~ 1000 μm.
35. preparation methoies according to claim 34, wherein, in step (1), metformin hydrochloride pulverizes rear particle size range is 150 ~ 1000 μm.
36. preparation methoies according to claim 30, wherein, in step (1), glimepiride pulverizes rear particle size range is 0.01 ~ 50 μm.
37. preparation methoies according to claim 36, wherein, in step (1), glimepiride pulverizes rear particle size range is 1 ~ 20 μm.
38. preparation methoies according to claim 30, wherein, adopt wet granulation, dry granulation or fluidizing fluid-bed granulation in step (2) and/or step (3).
39. preparation methoies according to any one of claim 30 ~ 38, wherein obtained in step (2) metformin hydrochloride granule or the moisture of granulate mixture are 0.3 ~ 1.5 % by weight.
40. preparation methoies according to any one of claim 30 ~ 38; wherein step (4) is the wherein a kind of tabletted by the glimepiride granule that obtains in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture, is prepared into dry coated tablet with another granule or mixture.
41. preparation methoies according to any one of claim 30 ~ 38; wherein step (4) be the glimepiride granule obtained in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture are mixed with other proper auxiliary materials or with other blank granules, medicine-containing particle, adopt pharmaceutically acceptable method to make double-layer tablet or three-layer tablet.
42. preparation methoies according to any one of claim 30 ~ 38; wherein step (4) is by after the glimepiride granule that obtains in the metformin hydrochloride granule obtained in step (2) or granulate mixture and step (3) or granulate mixture mix homogeneously, compacting conventional tablet.
Solid compound preparation according to any one of 43. claim 1 ~ 29 is preparing the purposes prevented and/or treated in the medicine of diabetes, diabetic complication, obesity, hyperlipidemia, coronary heart disease or high blood pressure disease.
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| CN113143940A (en) * | 2020-12-30 | 2021-07-23 | 成都恒瑞制药有限公司 | Preparation method of antidiabetic pharmaceutical composition |
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| CN1568952A (en) * | 2004-04-28 | 2005-01-26 | 贵州圣济堂制药有限公司 | Peroral blood sugar reducing compound pharmaceutical preparation |
| WO2008050987A1 (en) * | 2006-10-23 | 2008-05-02 | Hanall Pharmaceutical Co., Ltd. | Combination formulation with controlled release comprising metformin and glimepiride |
| CN101984974A (en) * | 2010-11-15 | 2011-03-16 | 山东新华制药股份有限公司 | Preparation method of pharmaceutical composition for treating type II diabetes |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1568952A (en) * | 2004-04-28 | 2005-01-26 | 贵州圣济堂制药有限公司 | Peroral blood sugar reducing compound pharmaceutical preparation |
| WO2008050987A1 (en) * | 2006-10-23 | 2008-05-02 | Hanall Pharmaceutical Co., Ltd. | Combination formulation with controlled release comprising metformin and glimepiride |
| CN101984974A (en) * | 2010-11-15 | 2011-03-16 | 山东新华制药股份有限公司 | Preparation method of pharmaceutical composition for treating type II diabetes |
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| CN108299271A (en) * | 2018-01-29 | 2018-07-20 | 重庆医科大学 | A kind of adduct and its preparation and use |
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