CN104224783A - Medicine composition containing repaglinide and metformin and preparation method of medicine composition - Google Patents
Medicine composition containing repaglinide and metformin and preparation method of medicine composition Download PDFInfo
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Abstract
The invention discloses medicine composition containing repaglinide and metformin and a preparation method of the medicine composition. A tablet is proportionally composited by meglumine, silicon dioxide, microcrystalline cellulose, lauryl sodium sulfate, hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, magnesium stearate, repaglinide and metformin hydrochloride, repaglinide and metformin are granulated with a multistep mixing method in combination of a stirring, cutting and granulation technology, the compressibility of granules is guaranteed, meanwhile, the content uniformity of repaglinide is improved, the dissolution rate of metformin in the tablet is increased, the process is simple, and the medicine composition is suitable for industrial production.
Description
Technical field
The present invention belongs to field of pharmaceutical preparations, is specifically related to a kind of pharmaceutical composition containing repaglinide metformin and preparation method thereof.
Background technology
Type Ⅱdiabetes mellitus is the common multiple chronic metabolic disease of serious harm human health, and prolonged illness can cause multisystem, multi viscera progressive injury, effectively controls the development that blood glucose can delay complication.At present, there is no radical cure method to type Ⅱdiabetes mellitus, great majority are on the basis of diet and exercise therapy, and scientific and reasonable antidiabetic drug of making good use of ensures that can patient up to standard for a long time, successful treatment, reduces the key of complication.
Metformin (Metformin), chemistry Metformin (structure is as shown in formula I) by name, is current most widely used antidiabetic drug, in the treatment of type 2 diabetes mellitus, has critical role.Metformin, by promoting glucose at the anaerobic metabolism of liver and suppressing glyconeogenesis, effectively can reduce glycogen and export, and reduces intestinal to the absorption of glucose, and can increase picked-up and the utilization of periphery glucose, improve the sensitivity of insulin.Metformin can also improve Body Mass Index, improves Body Mass Index and has mainly come by affecting lipid metabolism.
Repaglinide (Repaglinide), (structure is as shown in formula II for-2-carbonyl ethyl benzoic acid for chemistry (S)-2-ethyoxyl-4-[2-[3-methyl isophthalic acid-[2-(piperidino) phenyl]-butane group]-amino] by name, a kind of benzoic acid derivative), be the novel non-sulphanylureas Insulin secretagogues of one.The specific receptor of repaglinide on beta Cell of islet film is combined, and the potassium channel that on β cell membrane, ATP relies on is closed, suppresses potassium ion from β cell drain, cause membrane depolarization, calcium channel is open, flow of calcium ions, promote insulin secretion, thus reduce blood glucose.Its effect is faster than sulfonylurea, therefore hypoglycemic activity is very fast after the meal, the glucose regulating taken when Chang Zuowei has meal.
In diabetics, what have increases based on fasting glucose, and what have increases based on post-prandial glycemia, and the two having all increases, and also has more complicated hypertensions, hyperlipidemia, coronary disease patient.In order to improve the compliance of patient, develop repaglinide metformin compound tablet, wherein metformin effectively reduces blood glucose, repaglinide promotes insulin secretion, and Papillary plays complementation, synergism, significantly controls blood glucose on the one hand, the damage of islet beta cell function can be reduced simultaneously, hypoglycemia occurs few, and without untoward reaction such as body weight increases, patient tolerability is good.
In order to improve the compliance of patient, develop the repaglinide metformin compound tablet being used for the treatment of type Ⅱdiabetes mellitus, wherein metformin effectively reduces blood glucose, repaglinide promotes insulin secretion, and Papillary plays complementation, synergism, significantly controls blood glucose on the one hand, the damage of islet beta cell function can be reduced simultaneously, hypoglycemia occurs few, and without untoward reaction such as body weight increases, patient tolerability is good.
U.S. FDA ratifies repaglinide/metformin Compound Tablet (PrandiMet) listing of Novo Nordisk Co., Ltd (Novo Nordisk) for 2008, and the specification of this compound tablet is repaglinide/metformin hydrochloride lmg/500mg and 2mg/500mg.This tablet is first is also the dose formulations uniquely getting permission quick-acting short secretion medicine repaglinide and the euglycemic agent metformin hydrochloride gone on the market so far.The repaglinide of this compound tablet lmg/500mg and 2mg/500mg and corresponding dosage and metformin hydrochloride single medicine preparation coupling bioequivalence similar temperament.
CN101516347 discloses a kind of pharmaceutical composition of unit dosage forms, comprise the repaglinide with metformin or its salt binding, wherein the preformulation of repaglinide had the dissolution characteristic had nothing to do with pH value and the relative humidity being less than about 25% before mixing with metformin or its salt; With choose any one kind of them or multiple pharmaceutically acceptable excipient, and provide preparation method.
CN102218064A discloses a kind of by repaglinide and the metformin Pharmaceutical composition and preparation method thereof as active ingredient, and said composition comprises a) medicament active composition repaglinide and metformin and b) pharmaceutic adjuvant; The weight portion of described active constituents of medicine is repaglinide 0.1 ~ 10 part, metformin 100 ~ 1500 parts; Described pharmaceutic adjuvant is filler, disintegrating agent, binding agent, correctives, lubricant and swellability adjuvant; Wherein said repaglinide is repaglinide crystal; Its repaglinide crystal adopting particle diameter very little.
CN101756971A discloses a kind of solid composite medicament containing metformin hydrochloride repaglinide, is the metformin hydrochloride of 10 μm ~ 200 μm and pharmaceutically acceptable carrier containing repaglinide and particle diameter D90.
Repaglinide/metformicomposition composition disclosed in CN102319245A is made up of repaglinide, metformin, filler, disintegrating agent, binding agent, cosolvent and lubricant, and wherein repaglinide joins as an aqueous solution in metformin and adjuvant to carry out wet granulation.
CN103356615A discloses a kind of tablet capsule that repaglinide and diformin tablet are housed, be made up of the tablet in capsule and capsule, capsule comprises utricule and lower utricule, in capsule, at least filling active component is the tablet of metformin, and at least filling active component is the tablet of repaglinide.Be not in contact with each other between various active component in the tablet capsule provided, thus obtain stability tablet capsule better, easy to process.The method not easily realizes industrialization.
CN103070864A provides and a kind ofly comprises pharmaceutical composition of active component repaglinide and metformin hydrochloride and preparation method thereof, metformin hydrochloride is first made granule by hot melt granulation technique by the method, by one-step palletizing technology, repaglinide solution is sprayed directly on on metformin hydrochloride granule again, then is prepared into tablet after adding partial supplementary material.
CN102813652A discloses a kind of repaglinide metformin hydrochloride dispersible tablet, and it consists of: metformin hydrochloride is 500mg, and content is between 80% ~ 90%; Repaglinide is 0.5 ~ 2.0mg, and content is between 0.01% ~ 0.05%; It is lactose that preferred pharmaceutical carrier comprises filler, and content is 5% ~ 10%; Disintegrating agent is polyvinylpolypyrrolidone, and content is 0.1% ~ 5%; Correctives is green apple essence, and content is 0.05% ~ 0.1%; Lubricant is Pulvis Talci, and content is 0.04% ~ 0.06%; Binding agent is ethanol in proper amount.
CN103251593A, CN103251594A disclose a kind of Repaglinide/metformicomposition composition, it comprises: the pharmaceutic adjuvant of the metformin hydrochloride of 500 weight portions, the repaglinide of 0.5 ~ 5 weight portion and 10 ~ 200 weight portions, described pharmaceutic adjuvant includes but not limited to filler, disintegrating agent, binding agent, alkaline agent, lubricant, and provides preparation method.
103385878A discloses a kind of Pharmaceutical composition containing repaglinide and metformin hydrochloride, it is characterized in that except active component repaglinide and metformin hydrochloride, also containing the optional one of meglumine, poloxamer, polyoxyethylene, microcrystalline Cellulose, sorbitol or mannitol, cross-linking sodium carboxymethyl cellulose or the optional one of polyvinylpolypyrrolidone, magnesium stearate, wherein polyoxyethylated molecular weight about 100000.
In repaglinide metformin compound tablet, because repaglinide differs hundreds of times with metformin content, in unit formulation, the content of repaglinide only has several milligrams, and metformin is then hundreds of milligram; And the dissolubility of repaglinide in water is very little, is about 0.005mg/mL, metformin is then water soluble drug.So the conventional means that the above-mentioned pharmaceutical composition prior art containing repaglinide metformin adopts all exists that repaglinide content is uneven, dissolution is lower and can not reach the shortcomings such as synchronous release with metformin.CN102247370A, CN101843617A, CN103371981A etc. then adopt slow controlled release, multilayer tablet means solve this problem, but complex process, cost are high.Therefore, this area still expects have the compositions of more excellent repaglinide metformin and pharmaceutic adjuvant and simple and easy to do preparation method thereof.
Summary of the invention
In order to solve the problems of the technologies described above, the present inventor finds through a large amount of tests, the meglumine of application special ratios, silicon dioxide, microcrystalline Cellulose, sodium lauryl sulphate, hypromellose, polyvinylpolypyrrolidone, magnesium stearate and repaglinide, metformin hydrochloride combines, and with multistep mixing method combination stirring cutting granulation technique, repaglinide metformin is granulated, the compressibility of granule can be ensured, the uniformity of dosage units of tablet China and Sweden Ge Lienai and the dissolution with metformin thereof can be improved again simultaneously, and make the two reach synchronous release, simple process, be applicable to suitability for industrialized production.
Concrete technical scheme of the present invention is as follows:
The invention provides a kind of pharmaceutical composition containing repaglinide metformin, it is made up of the component of following weight portion:
Further, the above-mentioned pharmaceutical composition containing repaglinide metformin is made up of the component of following weight portion:
The present invention also can be made up of the component of following weight portion containing the pharmaceutical composition of repaglinide metformin:
The present invention also provides the preparation method of the above-mentioned pharmaceutical composition containing repaglinide metformin, specifically comprises the following steps:
1) supplementary material process:
By repaglinide crude drug micronization, make its d (0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 80 ~ 120 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the microcrystalline Cellulose of 1/3 ~ 3/4 amount is got, the hypromellose of 1/3 ~ 3/4 amount, the metformin hydrochloride of the polyvinylpolypyrrolidone of 1/3 ~ 2/3 amount, silicon dioxide and 1/4 ~ 1/2 amount, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 1. 30 ~ 50 mesh sieve dispersions, obtain mixture, for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 3 ~ 10% hypromellose aqueous solutions, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 20 ~ 30 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm2, and tabletting, obtains repaglinide metformin element sheet;
6) coating:
By recipe quantity configuration 70% ~ 90% alcoholic solution, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 6% ~ 7%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
The present invention relates to following determination method:
1. the mensuration of repaglinide dissolution
Dissolution Rate Testing in the present invention according to Chinese Pharmacopoeia 2010 editions two annex X C dissolution methods the second method described in mode carry out:
1) preparation of repaglinide reference substance solution
Precision measures repaglinide reference substance and adds dissolve with methanol, and uses purified water, pH1.2 hydrochloric acid solution, pH5.0 citric acid/phosphate buffer, pH6.8 phosphate buffer to be diluted to the solution about containing repaglinide 80 μ g in every 1ml as dissolution medium respectively.
2) dissolution test
The tablet using the embodiment of the present invention to prepare respectively and described contrast tablet drop in stripping rotor as test sample, respectively with the purified water of volume 900mL, pH1.2 hydrochloric acid solution, pH5.0 citric acid/phosphate buffer, pH6.8 phosphate buffer for dissolution medium, at rotating speed 50rpm, stir under the condition that temperature is 37 DEG C.Get solution 10ml (simultaneously supplementing blank dissolution medium 10ml) when stirring 5,10,15,20,30 and 45 minutes from stripping rotor, by the solution that takes out at 3500rpm centrifugal 15 minutes, get supernatant.
3) measurement of dissolution rate
Get above-mentioned repaglinide reference substance solution, and need testing solution 40 μ L prepared by the tablet to be prepared by the embodiment of the present invention and contrast tablet, according to the high performance liquid chromatography described in Chinese Pharmacopoeia 2010 editions two annex V D, calculate tablet and described contrast tablet prepared by the embodiment of the present invention 1 respectively at the dissolution rate of each time point.The computing formula of dissolution rate is:
(A
t/ A
s) × (W
s× D)/C × 100%, wherein:
A
t: the peak area of need testing solution;
A
s: the peak area of reference substance solution;
W
s: reference substance sample weighting amount;
D: the extension rate of reference substance;
C: specification/dissolution medium volume.
2. the mensuration of metformin dissolution
Dissolution Rate Testing in the present invention according to Chinese Pharmacopoeia 2010 editions two annex X C dissolution methods the second method described in mode carry out:
1) preparation of metformin hydrochloride reference substance solution
It is appropriate that precision takes metformin hydrochloride reference substance, is dissolved in water, and is diluted to the solution of about hydrochloric metformin 5 μ g in every 1mL.
2) dissolution test
The tablet using the embodiment of the present invention to prepare respectively and described contrast tablet drop in stripping rotor as test sample, respectively with the purified water of volume 900mL, pH1.2 hydrochloric acid solution, pH5.0 citric acid/phosphate buffer, pH6.8 phosphate buffer for dissolution medium, at rotating speed 50rpm, stir under the condition that temperature is 37 DEG C.Get solution 10ml (simultaneously supplementing blank dissolution medium 10ml) when stirring 5,10,15,20,30 and 45 minutes from stripping rotor, by the solution that takes out at 3500rpm centrifugal 15 minutes, get supernatant and dilute 100 times by purified water.
3) measurement of dissolution rate
Get metformin hydrochloride reference substance solution, and need testing solution prepared by the tablet to be prepared by the embodiment of the present invention and contrast tablet, according to the spectrophotography described in Chinese Pharmacopoeia 2010 editions two annex IV A, trap is measured respectively, calculating tablet prepared by the embodiment of the present invention 1 at 233nm absorbance ratio and describedly contrasting the dissolution rate of tablet at each time point by reference substance solution and need testing solution at the wavelength place of 233nm.Dissolution rate computing formula is:
(A
t/ A
s) × (W
s× D)/C × 100%, wherein:
A
t: the absorbance of need testing solution;
A
s: the absorbance of reference substance solution;
W
s: reference substance sample weighting amount;
D: the extension rate of reference substance;
C: specification/dissolution medium volume.
3. repaglinide determination of related substances method
Repaglinide determination of related substances method is carried out according to the description in Chinese Pharmacopoeia 2010 repaglinide.Described repaglinide related substance includes related substance A, i.e. 4 ~ (carboxymethyl) ~ 2 ~ ethoxybenzoic acid, related substance B, (3 ~ ethyoxyl ~ 4 ~ ethoxy carbonyl ~ phenylacetic acid, related substance C, i.e. (S) ~ 2 ~ ethyoxyl ~ 4 ~ [2 ~ [[2 ~ phenyl ~ 1 ~ [2 ~ (1 ~ piperidyl) phenyl] ethyl] is amino] ~ 2 ~ oxoethyl] benzoic acid.
1) chromatographic condition:
Mobile phase A: potassium dihydrogen phosphate 4.0g, add water 900ml, with phosphorus acid for adjusting pH 3.2, adds water to 1000mL
Mobile phase B: mobile phase A ~ acetonitrile (20:80)
Gradient elution:
Chromatographic column: octadecylsilane chemically bonded silica post
Column temperature: 45 DEG C; Flow velocity: 1.0ml/min; Determined wavelength: 240nm
2) preparation of reference substance solution
The reference substance of precision weighing repaglinide related substance A, related substance B, related substance C, the solution being 2.5 μ g/ml containing repaglinide related substance A, related substance B, related substance C reference substance is made with dissolve with methanol dilution, shake up, in contrast product solution.
3) preparation of need testing solution
Precision takes through the described Tablets of above-mentioned experimental condition process after 10 days and contrast tablet
(being about equivalent to 12.5mg repaglinide), being placed in 25ml volumetric flask, adding proper amount of isopropanol, ultrasonic 5min, is settled to scale with isopropyl alcohol, and the centrifugal 15min of 3500rpm, precision pipettes supernatant 3ml, adds water and is settled to 5ml, shakes up, as need testing solution.
4) preparation of contrast solution
Precision measures above-mentioned need testing solution 1ml, is placed in 100ml volumetric flask, is diluted to scale with mobile phase, shake up, in contrast solution.
Get above-mentioned reference substance solution, need testing solution, each 40 μ L of contrast solution respectively, injection liquid chromatography, record chromatogram.By the external standard method described in Chinese Pharmacopoeia 2010 editions two annex V D, calculate the content of repaglinide related substance A, related substance B, related substance C in each need testing solution.
With repaglinide peak area in contrast solution, the main constituent Self-control method of (4) the not correction up factor according to Chinese Pharmacopoeia 2010 editions two annex V D calculates the content of other unknown impuritie except related substance A, related substance B, related substance C.
4. metformin determination of related substances method:
Metformin determination of related substances method is carried out according to the description in Chinese Pharmacopoeia 2010 metformin hydrochloride tablet.
1) chromatographic condition:
Mobile phase: 1.7% ammonium di-hydrogen phosphate ammonium (by phosphoric acid adjust ph to 3.0) is mobile phase
Determined wavelength: 218nm
Chromatographic column: sulfonic group cation exchange bonded silica gel is filler
Sample size: 10 μ L
Flow velocity: 1.5mL/min
2) preparation of system suitability solution
Get metformin hydrochloride and tripolycyanamide reference substance appropriate, be dissolved in water and dilute the solution making hydrochloric metformin 0.25mg and tripolycyanamide 0.1mg in every 1mL, getting 1mL, be diluted to 50mL with described mobile phase, shake Uniform, as system suitability solution.Get 10 μ L injection liquid chromatographies, record chromatogram, the separating degree at metformin hydrochloride and tripolycyanamide peak should be greater than 10.
3) preparation of dicyandiamide reference substance solution
Precision weighing dicyandiamide reference substance, is dissolved in water and is quantitatively diluted to the solution containing 10 μ g dicyandiamide reference substances in every 1mL, product solution in contrast.
4) preparation of need testing solution
Learn from else's experience the Tablets of above-mentioned experimental condition process after 10 days and contrast tablet
(be about equivalent to 500mg metformin hydrochloride) in right amount, be placed in 100mL volumetric flask, add described mobile phase appropriate, supersound process makes dissolving in 15 minutes, is diluted to scale, shakes up with mobile phase, filters, gets subsequent filtrate as need testing solution.
5) preparation of contrast solution
Precision measures above-mentioned need testing solution 1mL, is placed in 200mL volumetric flask, is diluted to scale with mobile phase, shake up, in contrast solution.
Get above-mentioned reference substance solution, need testing solution, each 10 μ L of contrast solution respectively, injection liquid chromatography, record chromatogram.By the external standard method described in Chinese Pharmacopoeia 2010 editions two annex V D, calculate the content of dicyandiamide in each need testing solution.
With metformin peak area in contrast solution, calculate the content of other unknown impuritie except dicyandiamide with the main constituent Self-control method of (4) the not correction up factor described in Chinese Pharmacopoeia 2010 editions two annex V D.
Pharmaceutical composition containing repaglinide metformin provided by the invention and preparation method thereof has the following advantages:
(1) adopt multistep mixing method to combine and stir the uniformity of dosage units problem that cutting granulation technique solves low content repaglinide in tablet, make repaglinide content in tablets have stable homogeneity.
(2) combination of the meglumine of special ratios, silicon dioxide, microcrystalline Cellulose, sodium lauryl sulphate, hypromellose, polyvinylpolypyrrolidone, magnesium stearate and repaglinide, metformin hydrochloride, both ensure that the compressibility of granule during granulation, turn improve the dissolution of repaglinide and metformin in tablet, and make the two reach synchronous release.
(3) the pharmaceutical composition preparation method containing repaglinide metformin provided by the invention is easy, is easy to realize industrialization.
Detailed description of the invention
Below will the invention will be further described by embodiment, these descriptions are not be further limited content of the present invention.One skilled in the art will understand that the equivalent replacement that content of the present invention is done, or improve accordingly, still belong within protection scope of the present invention.
Embodiment 1 is containing the preparation of the pharmaceutical composition of repaglinide metformin
Prescription:
Preparation method, prepare as follows:
1) supplementary material process:
By repaglinide crude drug micronization, make its d (0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 100 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the microcrystalline Cellulose of about 2/3rds amounts, the hypromellose of 1/2nd amounts is got, the metformin hydrochloride of the polyvinylpolypyrrolidone of about 2/3rds amounts, silicon dioxide and about 1/2nd amounts, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 50 mesh sieve dispersions, obtain mixture 1., for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 4% hypromellose aqueous solution, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 20 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm
2, tabletting, obtains repaglinide metformin element sheet;
6) coating:
Configure 75% alcoholic solution by recipe quantity, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 6%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
Embodiment 2 is containing the preparation of the pharmaceutical composition of repaglinide metformin
Prescription:
Preparation method, prepare as follows:
1) supplementary material process:
By repaglinide crude drug micronization, make its d (0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 120 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the hypromellose of the microcrystalline Cellulose of half amount, half amount is got, the metformin hydrochloride of the polyvinylpolypyrrolidone of 1/3 amount, silicon dioxide and 1/4 amount, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 30 mesh sieve dispersions, obtain mixture 1., for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 5% hypromellose aqueous solution, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 30 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm
2, tabletting, obtains repaglinide metformin element sheet;
6) coating:
Configure 88% alcoholic solution by recipe quantity, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 7%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
Embodiment 3 is containing the preparation of the pharmaceutical composition of repaglinide metformin
Prescription:
Preparation method, prepare as follows:
1) supplementary material process:
By repaglinide crude drug micronization, make its d (0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 120 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the microcrystalline Cellulose of about 2/3rds amounts, the hypromellose of 2/3rds amounts is got, the metformin hydrochloride of the polyvinylpolypyrrolidone of 1/2nd amounts, silicon dioxide and about 1/3rd amounts, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 30 mesh sieve dispersions, obtain mixture 1., for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 5% hypromellose aqueous solution, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 24 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm
2, tabletting, obtains repaglinide metformin element sheet;
6) coating:
Configure 80% alcoholic solution by recipe quantity, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 6.7%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
Embodiment 4 is containing the preparation of the pharmaceutical composition of repaglinide metformin
Prescription:
Preparation method, prepare as follows:
1) supplementary material process:
By repaglinide crude drug micronization, make its d (0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 120 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the microcrystalline Cellulose of about 2/3rds amounts, the hypromellose of 2/3rds amounts is got, the metformin hydrochloride of the polyvinylpolypyrrolidone of 1/2nd amounts, silicon dioxide and about 1/3rd amounts, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 30 mesh sieve dispersions, obtain mixture 1., for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 5% hypromellose aqueous solution, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 24 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm
2, tabletting, obtains repaglinide metformin element sheet;
6) coating:
Configure 80% alcoholic solution by recipe quantity, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 6.7%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
Embodiment 5 is containing the preparation of the pharmaceutical composition of repaglinide metformin
Prescription:
Preparation method, prepare as follows:
1) supplementary material process:
By repaglinide crude drug micronization, make its d (0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 80 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the microcrystalline Cellulose of about 1/3rd amounts, the hypromellose of 1/3rd amounts is got, the metformin hydrochloride of the polyvinylpolypyrrolidone of 1/3rd amounts, silicon dioxide and about 1/4th amounts, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 30 mesh sieve dispersions, obtain mixture 1., for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 10% hypromellose aqueous solution, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 20 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm
2, tabletting, obtains repaglinide metformin element sheet;
6) coating:
Configure 70% alcoholic solution by recipe quantity, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 6.2%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
Test example 1 repaglinide uniformity of dosage units is investigated
According to Chinese Pharmacopoeia version in 2010 two annex Ⅹ E, according to repaglinide content assaying method, repaglinide Content uniformity test is carried out to sample prepared by embodiment 1 ~ 5.Result shows, the A+1.8.S of each sample repaglinide is all less than 10, and meet the requirement that A+1.8.S is all less than 15 completely, its uniformity of dosage units is good.
Test example 2 dissolution is investigated
The repaglinide provided above according to the present invention, metformin hydrochloride dissolution determination method, the sample prepared embodiment 1 ~ 5 has carried out repaglinide, the dissolution of metformin hydrochloride is investigated, and the results are shown in following table 1 ~ table 8:
In table 1pH1.2 medium, metformin hydrochloride stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 60.4％ | 92.1％ | 98.7％ | 97.1％ | 97.8％ | 98.2％ |
| Embodiment 1 | 67.5％ | 98.9％ | 100.8％ | 102.7％ | 102.7％ | 102.1％ |
| Embodiment 2 | 66.1％ | 101.8％ | 101.9％ | 102.3％ | 102.5％ | 102.4％ |
| Embodiment 3 | 66.5％ | 102.3％ | 103.1％ | 104.2％ | 102.6％ | 102.5％ |
| Embodiment 4 | 64.6％ | 99.8％ | 101.0％ | 104.3％ | 103.3％ | 102.4％ |
| Embodiment 5 | 73.3％ | 101.4％ | 102.3％ | 101.9％ | 102.2％ | 103.6％ |
In table 2pH5.0 medium, metformin hydrochloride stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 61.2％ | 93.5％ | 100.4％ | 99.9％ | 100.2％ | 99.4％ |
| Embodiment 1 | 65.6％ | 96.0％ | 97.7％ | 97.2％ | 97.4％ | 98.1％ |
| Embodiment 2 | 63.0％ | 96.1％ | 98.2％ | 97.5％ | 97.8％ | 98.4％ |
| Embodiment 3 | 66.5％ | 95.3％ | 97.4％ | 98.1％ | 98.3％ | 98.4％ |
| Embodiment 4 | 69.2％ | 95.5％ | 98.4％ | 96.1％ | 96.4％ | 97.1％ |
| Embodiment 5 | 72.1％ | 95.5％ | 97.8％ | 97.7％ | 98.2％ | 98.7％ |
In table 3pH6.8 medium, metformin hydrochloride stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 60.4％ | 94.0％ | 100.3％ | 101.4％ | 100.4％ | 100.1％ |
| Embodiment 1 | 63.1％ | 97.7％ | 99.5％ | 100.4％ | 100.2％ | 100.6％ |
| Embodiment 2 | 64.9％ | 96.7％ | 99.5％ | 99.5％ | 100.0％ | 100.3％ |
| Embodiment 3 | 63.9％ | 97.6％ | 99.7％ | 100.2％ | 100.3％ | 100.3％ |
| Embodiment 4 | 54.9％ | 96.3％ | 99.9％ | 101.3％ | 101.9％ | 102.0％ |
| Embodiment 5 | 61.3％ | 98.5％ | 99.1％ | 99.8％ | 99.5％ | 100.0％ |
In table 4 water, metformin hydrochloride stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 57.8％ | 96.0％ | 98.0％ | 98.4％ | 98.4％ | 98.1％ |
| Embodiment 1 | 63.7％ | 98.9％ | 100.8％ | 101.2％ | 101.6％ | 101.6％ |
| Embodiment 2 | 63.9％ | 97.6％ | 99.3％ | 99.7％ | 99.9％ | 100.4％ |
| Embodiment 3 | 63.0％ | 97.7％ | 99.7％ | 100.3％ | 100.4％ | 100.7％ |
| Embodiment 4 | 61.2％ | 99.6％ | 99.7％ | 100.0％ | 101.4％ | 101.1％ |
| Embodiment 5 | 66.3％ | 98.7％ | 101.0％ | 102.0％ | 103.2％ | 102.5％ |
In table 5pH1.2 medium, repaglinide stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 56.4％ | 88.2％ | 97.4％ | 98.5％ | 98.7％ | 97.2％ |
| Embodiment 1 | 67.7％ | 98.9％ | 99.6％ | 100.2％ | 100.6％ | 100.1％ |
| Embodiment 2 | 67.1％ | 96.3％ | 97.4％ | 98.0％ | 98.2％ | 98.6％ |
| Embodiment 3 | 63.6％ | 96.2％ | 97.9％ | 98.3％ | 98.4％ | 99.3％ |
| Embodiment 4 | 67.7％ | 99.3％ | 99.9％ | 101.0％ | 101.0％ | 100.0％ |
| Embodiment 5 | 67.4％ | 100.2％ | 100.2％ | 100.1％ | 101.0％ | 99.7％ |
In table 6pH5.0 medium, repaglinide stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 51.4％ | 86.7％ | 95.6％ | 96.3％ | 96.4％ | 96.8％ |
| Embodiment 1 | 66.6％ | 96.7％ | 99.3％ | 99.5％ | 100.0％ | 99.9％ |
| Embodiment 2 | 65.2％ | 96.7％ | 100.4％ | 100.5％ | 100.6％ | 100.4％ |
| Embodiment 3 | 67.3％ | 97.3％ | 100.3％ | 101.0％ | 101.4％ | 101.2％ |
| Embodiment 4 | 72.7％ | 95.2％ | 96.8％ | 96.9％ | 97.9％ | 99.3％ |
| Embodiment 5 | 53.9％ | 93.3％ | 100.5％ | 99.7％ | 99.3％ | 99.7％ |
In table 7pH6.8 medium, repaglinide stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 60.0％ | 88.9％ | 98.1％ | 98.2％ | 98.7％ | 97.7％ |
| Embodiment 1 | 63.6％ | 98.8％ | 101.0％ | 100.4％ | 101.3％ | 101.5％ |
| Embodiment 2 | 63.4％ | 98.5％ | 100.6％ | 100.1％ | 100.9％ | 101.1％ |
| Embodiment 3 | 64.4％ | 99.1％ | 100.3％ | 100.1％ | 99.9％ | 100.1％ |
| Embodiment 4 | 59.8％ | 100.8％ | 102.3％ | 101.0％ | 102.5％ | 102.2％ |
| Embodiment 5 | 56.0％ | 100.1％ | 100.9％ | 101.0％ | 101.1％ | 101.9％ |
In table 8 water, repaglinide stripping curve investigates result table
| Sample | 5min | 10min | 15min | 20min | 30min | 45min |
| Commercially available PrandiMet | 58.7％ | 90.1％ | 94.9％ | 95.6％ | 96.6％ | 97.2％ |
| Embodiment 1 | 64.5％ | 97.6％ | 99.4％ | 99.7％ | 99.9％ | 100.2％ |
| Embodiment 2 | 65.2％ | 98.2％ | 100.0％ | 100.3％ | 100.7％ | 100.7％ |
| Embodiment 3 | 64.1％ | 98.6％ | 100.0％ | 100.3％ | 100.4％ | 100.9％ |
| Embodiment 4 | 74.4％ | 98.6％ | 100.5％ | 100.6％ | 100.9％ | 100.4％ |
| Embodiment 5 | 61.5％ | 96.3％ | 99.3％ | 99.4％ | 99.5％ | 100.5％ |
From table 1 ~ table 8, with commercially available product
relatively, the present invention is all significantly improved containing the dissolution of pharmaceutical composition two kinds of active component of repaglinide metformin, and repaglinide and metformin hydrochloride reach synchronous release.
Test example 3 study on the stability
According to Chinese Pharmacopoeia version in 2010 two annex XIX C " medicine stability test guideline ", influence factor's test of the pharmaceutical composition containing repaglinide metformin, accelerated test, intermediate conditions and long term test have been carried out to sample prepared by embodiment 1 ~ 5, and with contain the pharmaceutical composition commercially available product of repaglinide metformin
contrast.
Influence factor's result of the test shows: under high humidity RH92.5% condition, and contrast medicine and own product moisture absorption in 5 days are increased weight equal >10%, therefore high wet test adopts RH75% condition.Under high humidity RH75% condition, contrast medicine and the own product moisture absorption rate of body weight gain of 5 days, 10 days all conform with the regulations.Commercially available of two specifications repaglinide related substance under high temperature, high humidity, illumination condition increases all to some extent, and wherein specification (I) high temperature 10 days samples and specification (II) each condition 10 days sample repaglinide impurity summations are all above standard limit and commercially available product to the sensitivity of high temperature, high humidity, illumination condition and impurity growth rate than obvious from film-making.Other inspection items are without significant change.Self-control sample under the high temperature conditions repaglinide related substance slightly increases, but all within the scope of standard limits, under high humidity, illumination condition, each inspection item has no significant change, and shows that the pharmaceutical composition containing repaglinide metformin prepared by the present invention possesses good stability.
Claims (4)
1., containing a pharmaceutical composition for repaglinide metformin, it is characterized in that: be made up of the component of following weight portion:
Repaglinide 0.5 ~ 2.0 part,
Metformin hydrochloride 300 ~ 800 parts,
Microcrystalline Cellulose 50 ~ 200 parts,
Meglumine 1 ~ 5 part,
Sodium lauryl sulphate 2 ~ 5 parts,
Hypromellose 10 ~ 30 parts,
Polyvinylpolypyrrolidone 10 ~ 40 parts,
Silica 1 ~ 3 part,
Magnesium stearate 1 ~ 6 part,
Opadry film coating pre-mix dose 10 ~ 50 parts.
2. the pharmaceutical composition containing repaglinide metformin as claimed in claim 1, is characterized in that: be made up of the component of following weight portion:
Repaglinide 1 part
Metformin hydrochloride 500 parts
Microcrystalline Cellulose 50 ~ 100 parts
Meglumine 1 ~ 5 part
Sodium lauryl sulphate 2 ~ 5 parts
Hypromellose 10 ~ 20 parts
Polyvinylpolypyrrolidone 15 ~ 30 parts
Silica 1 ~ 2 part
Magnesium stearate 2 ~ 4 parts
Opadry film coating pre-mix dose 10 ~ 30 parts.
3. the pharmaceutical composition containing repaglinide metformin as claimed in claim 1, is characterized in that: be made up of the component of following weight portion:
Repaglinide 2 parts
Metformin hydrochloride 500 parts
Microcrystalline Cellulose 50 ~ 100 parts
Meglumine 1 ~ 5 part
Sodium lauryl sulphate 2 ~ 5 parts
Hypromellose 10 ~ 20 parts
Polyvinylpolypyrrolidone 15 ~ 30 parts
Silica 1 ~ 2 part
Magnesium stearate 2 ~ 4 parts
Opadry film coating pre-mix dose 10 ~ 30 parts.
4., as claimed in claim 1 containing the preparation method of the pharmaceutical composition of repaglinide metformin, it is characterized in that: comprise the steps:
1) supplementary material process:
By repaglinide crude drug micronization, make its d(0.9)≤10 μm, for subsequent use;
Metformin hydrochloride 80 ~ 120 mesh sieve is pulverized, for subsequent use;
Polyvinylpolypyrrolidone, meglumine, sodium lauryl sulphate cross 60 mesh sieves, for subsequent use;
2) premix:
A. the microcrystalline Cellulose of 1/3 ~ 3/4 amount is got, the hypromellose of 1/3 ~ 3/4 amount, the metformin hydrochloride of the polyvinylpolypyrrolidone of 1/3 ~ 2/3 amount, silicon dioxide and 1/4 ~ 1/2 amount, drop in Mixers with Multi-direction Movement and mix 5 ~ 10 minutes, again residue metformin hydrochloride is added in mixer and mix 5 ~ 10 minutes, 1. 30 ~ 50 mesh sieve dispersions, obtain mixture, for subsequent use;
B. by repaglinide, meglumine, sodium lauryl sulphate mixing, then add the microcrystalline Cellulose mixing of about equivalent, 60 mesh sieve dispersions, then add the mixing of residue microcrystalline Cellulose, obtain mixture 2., for subsequent use;
C. 1. 2. mixture is mixed 1 time with about equal-volume mixture, drops in mixer, then get mixture 1. equivalent to progressively increase mixing 2 times, mix 5 ~ 10 minutes at every turn, more 1. remaining mixture added, mix 5 ~ 10 minutes, obtain premixing medicated powder, for subsequent use;
3) granulation is dry:
A. residue hypromellose purified water is mixed with 3 ~ 10% hypromellose aqueous solutions, for subsequent use;
B. premixing medicated powder is dropped in granulator, add the hypromellose aqueous solution configured and stir soft material processed, discharging;
C. obtained granule is put in boiling drier dry, control temperature of charge≤50 DEG C, dry 5 ~ 20 minutes, take out material, use oscillating granulator, 20 ~ 30 mesh sieve dispersions, put in boiling drier by granule after dispersion and continue to be dried to moisture≤2.5%, 1. discharging, obtain granule;
4) always mix:
By obtained granule 1., remaining polyvinylpolypyrrolidone drops in Mixers with Multi-direction Movement, just mixed 5 ~ 10 minutes; Again magnesium stearate is dropped into Mixers with Multi-direction Movement, always mixed 3 ~ 5 minutes, obtain hybrid particles 2.;
5) tabletting:
Calculate sheet weight according to granule content, control strip focus on answer tabletting heavy ± 4% scope in, Hardness Control is at 70 ~ 150N/mm2, and tabletting, obtains repaglinide metformin element sheet;
6) coating:
By recipe quantity configuration 70% ~ 90% alcoholic solution, under stirring, slowly add the stomach dissolved film coating pre-mix dose of recipe quantity, continue stirring more than 45 minutes, be made into the coating solution that concentration is about 6% ~ 7%; Plain sheet is dropped in coating pan, preheating, makes sheet bed tempertaure reach more than about 40 DEG C, regulates Burners Positions and whitewashing flow, start coating, control strip bed tempertaure at about 35 DEG C, atomizing pressure 0.2 ~ 0.4Mpa, to recipe quantity configuration coating solution sprayed, whitewashing terminates, to thin membrane coated tablet drying 5 ~ 15 minutes in seed-coating machine, coating terminates, the two green tea produced in Anhui Province of obtained repaglinide diformazan.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20180064817A1 (en) * | 2016-04-23 | 2018-03-08 | Jayendrakumar Dasharathlal Patel | Tamper Resistant Pharmaceutical Composition |
| CN115245495A (en) * | 2022-09-21 | 2022-10-28 | 北京惠之衡生物科技有限公司 | Sitagliptin and metformin tablet and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
| CN103251593A (en) * | 2013-06-04 | 2013-08-21 | 杭州朱养心药业有限公司 | Repaglinide/metformin composition |
| CN104337811A (en) * | 2013-08-02 | 2015-02-11 | 江苏柯菲平医药股份有限公司 | Repaglinide-metformin hydrochloride tablet and preparing method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
| CN103251593A (en) * | 2013-06-04 | 2013-08-21 | 杭州朱养心药业有限公司 | Repaglinide/metformin composition |
| CN104337811A (en) * | 2013-08-02 | 2015-02-11 | 江苏柯菲平医药股份有限公司 | Repaglinide-metformin hydrochloride tablet and preparing method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180064817A1 (en) * | 2016-04-23 | 2018-03-08 | Jayendrakumar Dasharathlal Patel | Tamper Resistant Pharmaceutical Composition |
| CN115245495A (en) * | 2022-09-21 | 2022-10-28 | 北京惠之衡生物科技有限公司 | Sitagliptin and metformin tablet and preparation method thereof |
| CN115245495B (en) * | 2022-09-21 | 2022-12-23 | 北京惠之衡生物科技有限公司 | Sitagliptin and metformin tablet and preparation method thereof |
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