CN111759818A - Metformin hydrochloride sustained release tablet and preparation method thereof - Google Patents
Metformin hydrochloride sustained release tablet and preparation method thereof Download PDFInfo
- Publication number
- CN111759818A CN111759818A CN202010772830.1A CN202010772830A CN111759818A CN 111759818 A CN111759818 A CN 111759818A CN 202010772830 A CN202010772830 A CN 202010772830A CN 111759818 A CN111759818 A CN 111759818A
- Authority
- CN
- China
- Prior art keywords
- release
- coating
- sustained
- metformin hydrochloride
- stirring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a metformin hydrochloride sustained release tablet and a preparation method thereof, wherein the metformin hydrochloride sustained release tablet comprises a tablet core and a coating layer; compared with the existing products sold in the market, the sustained release preparation provided by the invention has more uniform in vitro release, the release rate at 2h in an in vitro release rate test is 15-20%, the release rate at 6 h is 45-55% and the release rate at 12 h is more than 80%, meanwhile, the sustained release preparation can be controlled to be 7-10% uniformly released per hour, the constant release rate is nearly 10 hours, the shelf life of the product is long and can reach 24 months, the problem of poor release stability in the placing process of the sustained release preparation is solved, the release curve of the product at 0 month is equivalent to that of the product at 24 months, the similarity factor f2 is more than 80, the impurity increment in the placing process is small, the impurity increment in 24 months is only 0.015%, the preparation process is simple and feasible, and the sustained release preparation method is worthy of market popularization and application.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a metformin hydrochloride sustained-release tablet and a preparation method thereof.
Background
Metformin hydrochloride is used for type II diabetes patients with unsatisfactory simple diet control, especially obesity and hyperinsulinemia patients, and has the effects of reducing blood sugar and possibly reducing body weight and hyperinsulinemia. The metformin is mainly absorbed by small intestines, the half-life period of absorption is 0.9-2.6 hours, the bioavailability is 50% -60%, the metformin is orally taken for 0.58-2 hours, the plasma concentration reaches the peak value, and the metformin is accumulated in the wall of the gastrointestinal tract at a higher level, which is 10-100 times of the plasma concentration. The saliva content of kidney and liver is more than 2 times of plasma concentration, the metformin structure is stable, the metformin hydrochloride is not combined with plasma protein, the metformin hydrochloride is discharged with urine in an original shape, the cleaning is rapid, the half-life period of plasma is 1.7-4.5 hours, and 90% of the metformin hydrochloride is cleaned within 12 hours. In order to reduce the frequency of taking, metformin hydrochloride sustained release tablets are on the market at present, and the metformin hydrochloride sustained release tablets are used as hypoglycemic agents and have the effects of improving the blood sugar tolerance of type 2 diabetes patients and reducing the basic and postprandial blood sugar.
The existing metformin hydrochloride sustained release tablet still has the following technical problems: 1. sudden or uneven release of the drug, large fluctuation of blood concentration in a patient body and enhanced side effect; 2. the poor dissolution stability is easy to occur in the placement process, so that the blood concentration fluctuation at the later stage of the shelf life is large, and the side effect is increased; 3. during shelf life storage, the impurity increment is large, and certain safety risks exist.
Disclosure of Invention
The invention aims to provide a metformin hydrochloride sustained-release tablet and a preparation method thereof.
The purpose of the invention is realized by the following technical scheme:
the metformin hydrochloride sustained release tablet comprises a tablet core and a coating layer, wherein the tablet core and the coating layer are prepared by two times of guniting coating, the tablet core is prepared by taking a blank pill core as a base mould and tabletting through the first guniting coating; the coating layer is prepared by spraying slurry for the second time on the basis of the tablet core.
Preferably, the first guniting coating takes metformin hydrochloride, a slow-release material and an anti-sticking agent as coating materials.
Preferably, in any of the above schemes, the second guniting coating is a slow-release coating layer, and microcrystalline cellulose, hypromellose sodium, hypromellose, and polyethylene glycol 200 are used as coating materials.
Preferably, in any of the above schemes, the slow release material is one or more of methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hypromellose, povidone, carbomer, and sodium alginate.
In any of the above embodiments, preferably, the antisticking agent is one or more of silicon dioxide, talc, magnesium stearate, and calcium stearate.
In any of the above schemes, the preferable total mass ratio of the blank pellet core to the metformin hydrochloride, the slow release material and the anti-sticking agent is 1: 0.4-1.
The inventor finds that the specific slow-release material is matched with the specific anti-sticking agent and matched with the specific preparation process, so that the metformin hydrochloride can be uniformly dispersed on the framework material, the metformin hydrochloride is uniformly distributed on the blank pellet core, and finally the drug release process is more uniform.
Preferably, in any of the above schemes, the sustained-release material is composed of ethyl cellulose and carbomer, and the mass ratio of the sustained-release material to the carbomer is 1: 0.2 to 0.6.
In any of the above schemes, preferably, the anti-sticking agent is silicon dioxide, wherein the particle size of the silicon dioxide is 60-100 μm; the mass ratio of the silicon dioxide to the carbomer is 1: 1.
In any of the above schemes, preferably, the mass ratio of the metformin hydrochloride to the sustained-release material is 1: 0.4-0.8.
In order to ensure that the dissolution uniformity is good in the process of placing the release stability, in any of the above schemes, the slow release coating layer is preferably composed of the following substances, by weight, 20-30 parts of microcrystalline cellulose, 10-20 parts of hydroxypropyl methylcellulose sodium, 50-80 parts of hydroxypropyl methylcellulose and 2005-10 parts of polyethylene glycol; the weight of the slow release coating layer is 3-5% of the tablet.
Reasonable sodium metabisulfite and quantity cooperation above-mentioned slow release coating layer can make stability place in-process product impurity increment less, make the release process more even simultaneously, above-mentioned arbitrary scheme preferred, the slow release coating layer comprises the material of following weight ratio, its characterized in that: 22-26 parts of microcrystalline cellulose, 15-18 parts of hydroxypropyl methylcellulose sodium, 62-67 parts of hydroxypropyl methylcellulose, 2007-9 parts of polyethylene glycol and 3-7 parts of sodium metabisulfite; the weight of the slow release coating layer is 3-5% of the tablet.
The invention also provides a preparation method of the metformin hydrochloride sustained release tablet, which comprises the following steps:
(1) carrying out first pretreatment on a guniting coating material;
(2) preparing a first guniting coating material;
(3) coating by spraying slurry for the first time;
(4) tabletting:
(5) second guniting coating pretreatment:
(6) mixing:
(7) preparing a second spraying coating solution:
(8) and (5) coating by spraying slurry for the second time.
Preferably, the pretreatment process of the first guniting coating material is as follows: respectively crushing the metformin hydrochloride and the sustained-release material, and sieving with a 100-mesh sieve for later use; crushing the anti-sticking agent to powder with the particle size of 60-100 mu m for later use; and then putting the metformin hydrochloride, the slow release material and the anti-sticking agent into a three-dimensional motion mixer, mixing for 20-30 minutes, and taking out to obtain mixed powder 1 for later use.
Preferably, in any of the above schemes, the slow release material is one or more of methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hypromellose, povidone, carbomer and sodium alginate; the antisticking agent is one or more of silicon dioxide, talcum powder, magnesium stearate and calcium stearate;
or the slow release material is ethyl cellulose and carbomer; the anti-sticking agent is silicon dioxide.
In any of the above embodiments, preferably, the first guniting coating material is prepared by a method comprising: and (2) placing the ethanol solution with the volume fraction of 60-70% in a tank with stirring, setting the stirring speed to be 50-70 r/min, stirring, slowly adding the mixed powder 1 prepared in the step (1) under continuous stirring, continuing stirring for 1-2 h after the addition is finished, completely dispersing the mixed powder, taking out, and sieving by a 100-mesh sieve to obtain a first-time guniting coating material for later use.
In any of the above embodiments, preferably, the first guniting coating process comprises: placing the blank pellet core into a coating pan, adjusting the rotating speed of a main machine to be 1.3-1.6 rpm, rotating the coating pan, adjusting the height of a spray gun to be 120-150 mm away from the hollow pellet core, setting the hot air temperature to be 60-80 ℃, setting the exhaust rotating speed to be 40-60%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 16-40 rpm when the outlet temperature reaches 26-32 ℃, keeping the liquid supply flow at 200-280 g/min for spraying and coating, closing the peristaltic pump after spraying, continuously rotating and drying for 6-8 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to the room temperature to obtain coated sustained-release pellets, and discharging.
Preferably, in any of the above embodiments, the tabletting process is: and (4) placing the coated sustained-release pellets prepared in the step (3) into a rotary tablet press for tabletting, controlling the hardness to be 5-8 kg, and tabletting to obtain sustained-release tablet cores.
In any of the above embodiments, preferably, the pretreatment process of the second gunning coating material is: pulverizing the slow-release coating layer material and sieving with a 100-mesh sieve for later use; putting polyethylene glycol 200 into 10-12 times of 70% ethanol solution by weight, and slightly heating to dissolve to obtain polyethylene glycol 200 ethanol solution for later use; preferably, the material of the slow-release coating layer is one or more of microcrystalline cellulose, hydroxypropyl methylcellulose sodium, hydroxypropyl methylcellulose and sodium metabisulfite.
Preferably, in any of the above embodiments, the mixing process is: and (3) placing the screened slow-release coating layer material into a three-dimensional motion mixer, mixing for 10-15 minutes, taking out, and obtaining mixed powder 2 for later use, wherein preferably, the slow-release coating layer material is one or more of microcrystalline cellulose, hydroxypropyl methylcellulose sodium, hydroxypropyl methylcellulose and sodium metabisulfite.
In any of the above embodiments, preferably, the preparation method of the second guniting coating material comprises: and (3) placing the ethanol solution with the volume fraction of 60% -70% in a stirring liquid storage tank, setting the stirring speed to be 50-70 r/min, stirring, slowly adding the ethanol solution of polyethylene glycol 200 in the step (5) under continuous stirring, continuously stirring for 3-5 minutes after the addition is finished, slowly adding the mixed powder 2, continuously stirring for 1-2 hours after the addition is finished, completely dispersing the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a second-time guniting coating material for later use.
In any of the above embodiments, preferably, the second guniting coating process comprises: placing the sustained-release tablet core into a coating pan, adjusting the rotating speed of a main machine to be 2.0-2.5 rpm, rotating the coating pan, adjusting the height of a spray gun to be 130-170 mm away from the tablet bed, setting the hot air temperature to be 60-80 ℃, setting the exhaust rotating speed to be 40-60%, maintaining the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 16-40 rpm when the outlet temperature reaches 26-32 ℃, keeping the liquid supply flow at 180-250 g/min for spraying and coating, closing the peristaltic pump after spraying, continuously rotating and drying for 6-8 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature, obtaining the metformin hydrochloride sustained-release tablet, and discharging the product until the coating weight is increased by 3-4%.
The invention has the following beneficial effects:
compared with the current market products, the sustained release preparation provided by the invention has more uniform in vitro release, the average release degree at 2h is 15-20%, the average release degree at 6 h is 45-55% and the average release degree at 12 h is more than 80% in an in vitro release degree test, meanwhile, the release rate can be controlled to be 7-10% per hour for uniform release, the constant speed release is nearly 10 hours, so the side effect is smaller, the safety is higher, on the other hand, the shelf life of the product is long and can reach 24 months, the problem of poor release stability in the placing process of the invention is solved, the release curve of the product at 0 month is equivalent to that of the product at 24 months, the similar factor f2 is more than 80, the impurity increment in the placing process is small, the impurity increment in the placing process is only 0.015%, the preparation process is simple and feasible, and the sustained release preparation method is worthy of market popularization.
Drawings
FIG. 1: release profiles of preferred examples 1, 2, 3 and commercial products according to the invention.
Detailed Description
The present invention is described in detail below by way of examples, it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adaptations of the present invention based on the above-described disclosure.
Example 1
A preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
1. pretreatment of a first guniting coating material: 3.5 parts of metformin hydrochloride, 2 parts of ethyl cellulose and 0.4 part of carbomer are respectively crushed and sieved by a 100-mesh sieve for later use; 0.4 part of silicon dioxide is taken and crushed to powder with the particle size of 60-100 mu m for standby; then putting metformin hydrochloride, ethyl cellulose, carbomer and silicon dioxide into a three-dimensional motion mixer, mixing for 20 minutes, and taking out to obtain mixed powder 1 for later use;
2. preparing a first guniting coating material: taking an ethanol solution with the volume fraction of 60%, placing the ethanol solution in a tank with stirring, setting the stirring speed to be 50 r/min, stirring, slowly adding the mixed powder 1 prepared in the step 1 under continuous stirring, continuing stirring for 1h after the addition is finished, completely dispersing the mixed powder, taking out, and sieving by using a 100-mesh sieve to obtain a first-time guniting coating material for later use;
3. coating by spraying slurry for the first time: putting 8 parts of blank pellet cores into a coating pan, adjusting the rotating speed of a main machine to be 1.3rpm, rotating the coating pan, adjusting the height of a spray gun to be 120mm away from the hollow pellet cores, setting the temperature of hot air to be 60 ℃, adjusting the rotating speed of exhaust to be 40%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 16rpm when the outlet temperature reaches 26 ℃, keeping the liquid supply flow at 200g/min for spraying and coating, closing the peristaltic pump after spraying is finished, continuously rotating and drying for 6 minutes under the condition of coating temperature, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain coated sustained-release pellets, and discharging;
4. tabletting: placing the coated sustained-release pellets prepared in the step 3 into a rotary tablet press for tabletting, controlling the hardness to be 5-8 kg, and tabletting to obtain sustained-release tablet cores;
5. second guniting coating pretreatment: respectively crushing 22 parts of microcrystalline cellulose, 15 parts of hydroxypropyl methylcellulose sodium, 62 parts of hydroxypropyl methylcellulose and 3 parts of sodium metabisulfite, and sieving with a 100-mesh sieve for later use; putting 2007 parts of polyethylene glycol into 10 times of 70% ethanol solution by weight, and slightly heating to dissolve to obtain polyethylene glycol 200 ethanol solution for later use;
6. mixing: placing the sieved microcrystalline cellulose, sodium hydroxypropyl methylcellulose, hydroxypropyl methylcellulose and sodium metabisulfite into a three-dimensional motion mixer, mixing for 10 minutes, and taking out to obtain mixed powder 2 for later use;
7. preparing a second spraying coating solution: placing the ethanol solution with the volume fraction of 60% in a stirring liquid storage tank, setting the stirring speed to be 50 r/min, stirring, slowly adding the ethanol solution of polyethylene glycol 200 in the step 5 under continuous stirring, continuously stirring for 3 minutes after the addition is finished, then slowly adding the mixed powder 2, continuously stirring for 1 hour after the addition is finished, completely dispersing the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a second guniting coating material for later use;
8. and (3) coating by spraying slurry for the second time: placing the sustained-release tablet core in a coating pan, adjusting the rotating speed of a main machine to be 2.0rpm, rotating the coating pan, adjusting the height of a spray gun to be 130mm away from the tablet bed, setting the temperature of hot air to be 60 ℃, adjusting the rotating speed of air exhaust to be 40%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 16rpm when the outlet temperature reaches 26 ℃, keeping the liquid supply flow at 180g/min for spraying and coating, closing the peristaltic pump after spraying, continuously rotating and drying for 6 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain the metformin hydrochloride sustained-release tablet, and discharging to obtain the metformin hydrochloride sustained-release tablet, wherein the weight of the coating.
Example 2:
a preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
1. pretreatment of a first guniting coating material: respectively crushing 5 parts of metformin hydrochloride, 2 parts of ethyl cellulose and 0.8 part of carbomer, and sieving with a 100-mesh sieve for later use; 0.6 part of silicon dioxide is taken and crushed to powder with the particle size of 60-100 mu m for standby; then putting metformin hydrochloride, ethyl cellulose, carbomer and silicon dioxide into a three-dimensional motion mixer, mixing for 25 minutes, and taking out to obtain mixed powder 1 for later use;
2. preparing a first guniting coating material: taking 65% volume fraction ethanol solution, placing in a tank with stirring, setting the stirring speed at 60 r/min, stirring, slowly adding the mixed powder 1 prepared in the step 1 under continuous stirring, after the addition is finished, continuing stirring for 1.5h to completely disperse the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a first-time guniting coating material for later use;
3. coating by spraying slurry for the first time: putting 13 parts of blank pellet cores into a coating pan, adjusting the rotating speed of a main machine to be 1.5rpm, rotating the coating pan, adjusting the height of a spray gun to be 130mm away from the hollow pellet cores, setting the temperature of hot air to be 70 ℃, adjusting the rotating speed of exhaust to be 50%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 30rpm when the outlet temperature reaches 28 ℃, keeping the liquid supply flow at 260g/min for spraying and coating, closing the peristaltic pump after spraying is finished, continuously rotating and drying for 7 minutes under the condition of coating temperature, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain coated sustained-release pellets, and discharging;
4. tabletting: placing the coated sustained-release pellets prepared in the step 3 into a rotary tablet press for tabletting, controlling the hardness to be 5-8 kg, and tabletting to obtain sustained-release tablet cores;
5. second guniting coating pretreatment: respectively crushing 25 parts of microcrystalline cellulose, 17 parts of hydroxypropyl methylcellulose sodium, 65 parts of hydroxypropyl methylcellulose and 5 parts of sodium metabisulfite, and sieving with a 100-mesh sieve for later use; putting 2008 parts of polyethylene glycol into 10 times of 70% ethanol solution by weight, and slightly heating to dissolve the polyethylene glycol to obtain a polyethylene glycol 200 ethanol solution for later use;
6. mixing: placing the sieved microcrystalline cellulose, sodium hydroxypropyl methylcellulose, hydroxypropyl methylcellulose and sodium metabisulfite in a three-dimensional motion mixer, mixing for 12 minutes, and taking out to obtain mixed powder 2 for later use;
7. preparing a second spraying coating solution: placing 65% by volume of ethanol solution in a stirring liquid storage tank, setting the stirring speed to be 60 r/min, stirring, slowly adding the ethanol solution of polyethylene glycol 200 in the step 5 under continuous stirring, continuously stirring for 4 minutes after the addition is finished, then slowly adding the mixed powder 2, continuously stirring for 1.5 hours after the addition is finished, completely dispersing the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a second guniting coating material for later use;
8. and (3) coating by spraying slurry for the second time: placing the sustained-release tablet core in a coating pan, adjusting the rotating speed of a main machine to be 2.2rpm, rotating the coating pan, adjusting the height of a spray gun to be 150mm away from the tablet bed, setting the temperature of hot air to be 70 ℃, the rotating speed of exhaust to be 50%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 22rpm when the outlet temperature reaches 28 ℃, keeping the liquid supply flow at 200g/min for spraying and coating, closing the peristaltic pump after spraying, continuously rotating and drying for 7 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain the metformin hydrochloride sustained-release tablet, and discharging to obtain the metformin hydrochloride sustained-release tablet, wherein the weight of the coating is increased.
Example 3:
a preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:
1. taking 8.8 parts of metformin hydrochloride, 2 parts of ethyl cellulose and 1.2 parts of carbomer, respectively crushing, and sieving with a 100-mesh sieve for later use; taking 1.2 parts of silicon dioxide, and crushing to powder with the particle size of 60-100 mu m for later use; then putting metformin hydrochloride, ethyl cellulose, carbomer and silicon dioxide into a three-dimensional motion mixer, mixing for 30 minutes, and taking out to obtain mixed powder 1 for later use;
2. preparing a first guniting coating material: taking an ethanol solution with the volume fraction of 70%, placing the ethanol solution in a tank with a stirrer, setting the stirring speed to 70 revolutions per minute, stirring, slowly adding the mixed powder 1 prepared in the step 1 under continuous stirring, continuing stirring for 2 hours after the addition is finished, completely dispersing the mixed powder, taking out, and sieving by a 100-mesh sieve to obtain a first-time guniting coating material for later use;
3. coating by spraying slurry for the first time: placing 26 parts of blank pellet cores into a coating pan, adjusting the rotating speed of a main machine to be 1.6rpm, rotating the coating pan, adjusting the height of a spray gun to be 150mm away from the hollow pellet cores, setting the hot air temperature to be 80 ℃ and the exhaust rotating speed to be 60%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 40rpm when the outlet temperature reaches 32 ℃, keeping the liquid supply flow at 280g/min for spraying and coating, closing the peristaltic pump after spraying is finished, continuously rotating and drying for 8 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain coated sustained-release pellets, and discharging;
4. tabletting: placing the coated sustained-release pellets prepared in the step 3 into a rotary tablet press for tabletting, controlling the hardness to be 5-8 kg, and tabletting to obtain sustained-release tablet cores;
5. second guniting coating pretreatment: respectively crushing 26 parts of microcrystalline cellulose, 18 parts of hydroxypropyl methylcellulose sodium, 67 parts of hydroxypropyl methylcellulose and 7 parts of sodium metabisulfite, and sieving with a 100-mesh sieve for later use; putting 2009 parts of polyethylene glycol into 12 times of 70% ethanol solution by weight, and slightly heating to dissolve to obtain 200 parts of polyethylene glycol ethanol solution for later use;
6. mixing: placing the sieved microcrystalline cellulose, sodium hydroxypropyl methylcellulose, hydroxypropyl methylcellulose and sodium metabisulfite into a three-dimensional motion mixer, mixing for 15 minutes, and taking out to obtain mixed powder 2 for later use;
7. preparing a second spraying coating solution: placing the ethanol solution with the volume fraction of 70% in a stirring liquid storage tank, setting the stirring speed to 70 r/min, stirring, slowly adding the ethanol solution of polyethylene glycol 200 in the step 5 under continuous stirring, continuously stirring for 5 minutes after the addition is finished, then slowly adding the mixed powder 2, continuously stirring for 2 hours after the addition is finished, completely dispersing the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a second guniting coating material for later use;
8. and (3) coating by spraying slurry for the second time: placing the sustained-release tablet core in a coating pan, adjusting the rotating speed of a main machine to be 2.5rpm, rotating the coating pan, adjusting the height of a spray gun to be 170mm away from the tablet bed, setting the temperature of hot air to be 80 ℃, the rotating speed of exhaust to be 60%, maintaining the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 40rpm when the outlet temperature reaches 32 ℃, keeping the liquid supply flow at 250g/min for spraying and coating, closing the peristaltic pump after spraying, continuously rotating and drying for 8 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain the metformin hydrochloride sustained-release tablet, and discharging to obtain the metformin hydrochloride sustained-release tablet, wherein the weight of the coating is increased.
Example 4: examples 1, 2, 3 and commercial product (NadaR) Release contrast experiment
And (3) release curve determination: according to a first method of standard operation procedures of a release degree inspection method, 1000ml of phosphate buffer solution with pH6.8 is used as a release medium, the rotation speed is 100 revolutions per minute, 5ml of solution is respectively taken and filtered after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours and 20 hours according to the method operation, and 5ml of the phosphate buffer solution with pH6.8 and the same temperature is immediately supplemented in a dissolution cup; accurately weighing 1ml of each of the subsequent filtrates, placing into a 100ml measuring flask, diluting with phosphate buffer solution with pH of 6.8 to scale, and shaking. The results of the measurements are shown in Table 1 below:
TABLE 1 Release Rate in 20h (per hour) for examples 1, 2, 3 and commercial products
The release rates (per hour) in 8h for examples 1, 2, 3 and the commercial product are shown in Table 2 below:
TABLE 2 Release Rate in 8h (per hour) of examples 1, 2, 3 and commercial products
| Time of day | Example 1 | Example 2 | Example 3 | Commercial product (Naida) |
| 1h | 8.30％ | 8.20％ | 8.60％ | 5.70％ |
| 2h | 8.50％ | 8.90％ | 8.30％ | 11.60％ |
| 3h | 8.80％ | 9.10％ | 9.40％ | 9.20％ |
| 4h | 7.80％ | 7.70％ | 7.40％ | 7.90％ |
| 5h | 8.50％ | 8.40％ | 8.80％ | 6.30％ |
| 6h | 7.70％ | 7.60％ | 7.80％ | 6.10％ |
| 7h | 7.70％ | 7.80％ | 8.10％ | 6.10％ |
| 8h | 7.90％ | 8.20％ | 7.90％ | 6.60％ |
As can be seen from the table above, the release rate within 8h of the commercial product is obviously different from that of the examples 1, 2 and 3, the release rate of the Nedar produced in Baiyang island is 5.7-11.6%, and the release rates of the examples are all within 7-10%, so that the release is more stable. As can be seen from figure 1, the comparative example has the phenomenon of uneven drug release, the sudden release phenomenon exists in 8-10 h, and the example releases the drug at a near constant speed within 10h and has no sudden release phenomenon.
Example 5: examples 1, 2, 3 stability during standing impurity changes
1. The test method comprises the following steps: refer to 2015 edition "Chinese pharmacopoeia" second part stability test investigation
2. The test conditions are as follows:
long-term test temperature: 25 +/-2 ℃; humidity of long-term test: RH 60% +/-10%
Long-term test investigation time: 0. 3, 6, 9, 12, 18, 24 months
Purpose of the experiment: and (5) observing the change condition of the total impurities after 24 months, and comparing with 0 month, judging whether the impurity increment meets the requirement or not.
| Time of day | Example 1 | Example 2 | Example 3 |
| 0 month | 0.034％ | 0.031％ | 0.029％ |
| 3 month | 0.037％ | 0.033％ | 0.031％ |
| 6 month | 0.039％ | 0.036％ | 0.034％ |
| 9 month | 0.041％ | 0.038％ | 0.037％ |
| 12 month | 0.042％ | 0.040％ | 0.039％ |
| 18 months | 0.045％ | 0.042％ | 0.042％ |
| 24 months | 0.048％ | 0.045％ | 0.044％ |
| Increment of impurities% | 0.014％ | 0.014％ | 0.015％ |
The results show that the products prepared by the invention in the examples 1, 2 and 3 have small impurity increment of only 0.015 percent after being placed for 24 months.
Example 6: examples 1, 2, 3 Change in Release Profile after Stable Placement
1. The test method comprises the following steps: refer to 2015 edition "Chinese pharmacopoeia" second part stability test investigation
2. The test conditions are as follows:
long-term test temperature: 25 +/-2 ℃; humidity of long-term test: RH 60% +/-10%
Long-term test investigation time: 0. 3, 6, 9, 12, 18, 24 months
Purpose of the experiment: whether the similarity meets the requirement or not is examined after 24 months when the release curve is compared with 0 month
And (3) release curve determination: according to a first method of standard operation procedures of a release degree inspection method, 1000ml of phosphate buffer solution with pH6.8 is used as a release medium, the rotation speed is 100 revolutions per minute, 5ml of solution is respectively taken and filtered after 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours and 20 hours according to the method operation, and 5ml of the phosphate buffer solution with pH6.8 and the same temperature is immediately supplemented in a dissolution cup; accurately weighing 1ml of each of the subsequent filtrates, placing into a 100ml measuring flask, diluting with phosphate buffer solution with pH of 6.8 to scale, and shaking. The results of the measurements are shown in Table 3 below:
table 3 comparative tables of release profiles at month 0 and month 24 for examples 1, 2 and 3
As can be seen from the above table, after 24 months of storage, the release performance is compared with 0 month, the release trend is almost unchanged, the similarity factor f2 is more than 80, and the in vitro release curve is proved to be compared with 0 month and similar after 24 months of storage.
Claims (10)
1. The metformin hydrochloride sustained release tablet comprises a tablet core and a coating layer, and is characterized in that the tablet core and the coating layer are prepared by two times of guniting coating, the tablet core is prepared by taking a blank pill core as a base mould and tabletting by the first time of guniting coating; the coating layer is prepared by spraying slurry for the second time on the basis of the tablet core.
2. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the first guniting coating comprises metformin hydrochloride, a sustained-release material and an anti-sticking agent as coating materials; the second guniting coating is a slow-release coating layer, and microcrystalline cellulose, hydroxypropyl methylcellulose sodium, hydroxypropyl methylcellulose and polyethylene glycol 200 are used as coating materials.
3. The metformin hydrochloride sustained release tablet according to claim 1, wherein the sustained release material is one or more of methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hypromellose, povidone, carbomer, and sodium alginate.
4. The metformin hydrochloride sustained release tablet according to claim 1, wherein the antisticking agent is one or more of silicon dioxide, talc, magnesium stearate and calcium stearate.
5. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the total mass ratio of the blank pellet core to the metformin hydrochloride, the sustained-release material and the anti-sticking agent is 1: 0.4-1.
6. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the sustained-release material comprises ethyl cellulose and carbomer, and the mass ratio of the ethyl cellulose to the carbomer is 1: 0.2 to 0.6.
7. The metformin hydrochloride sustained release tablet according to claim 2, wherein the anti-sticking agent is preferably silicon dioxide, wherein the particle size of the silicon dioxide is 60 to 100 μm; the mass ratio of the silicon dioxide to the carbomer is 1: 1.
8. The metformin hydrochloride sustained-release tablet according to claim 6, wherein the mass ratio of the metformin hydrochloride to the sustained-release material is 1: 0.4-0.8.
9. The metformin hydrochloride sustained-release tablet according to claim 3, wherein the sustained-release coating layer comprises 20 to 30 parts by weight of microcrystalline cellulose, 10 to 20 parts by weight of hydroxypropyl methylcellulose sodium, 50 to 80 parts by weight of hydroxypropyl methylcellulose and 2005 to 10 parts by weight of polyethylene glycol; the weight of the slow release coating layer is increased by 3-5% of the tablet, or 22-26 parts of microcrystalline cellulose, 15-18 parts of hydroxypropyl methylcellulose sodium, 62-67 parts of hydroxypropyl methylcellulose, 2007-9 parts of polyethylene glycol and 3-7 parts of sodium metabisulfite; the weight of the slow release coating layer is 3% -5% of the weight of the tablet.
10. A process for the preparation of a metformin hydrochloride sustained release tablet according to any one of claims 1 to 9, which comprises the steps of:
(1) pretreatment of a first guniting coating material: respectively crushing the metformin hydrochloride and the sustained-release material, and sieving with a 100-mesh sieve for later use; crushing the anti-sticking agent to powder with the particle size of 60-100 mu m for later use; then putting the metformin hydrochloride, the slow release material and the anti-sticking agent into a three-dimensional motion mixer, mixing for 20-30 minutes, and taking out to obtain mixed powder 1 for later use; the slow release material is one or more of methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, povidone, carbomer and sodium alginate; or the antisticking agent is one or more of silicon dioxide, talcum powder, magnesium stearate and calcium stearate or the slow-release material is ethyl cellulose and carbomer; the anti-sticking agent is silicon dioxide;
(2) preparing a first guniting coating material: placing an ethanol solution with the volume fraction of 60-70% in a tank with stirring, setting the stirring speed to be 50-70 r/min, stirring, slowly adding the mixed powder 1 prepared in the step (1) under continuous stirring, continuing stirring for 1-2 h after the addition is finished, completely dispersing the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a first-time guniting coating material for later use;
(3) coating by spraying slurry for the first time: placing a blank pellet core into a coating pan, adjusting the rotating speed of a main machine to be 1.3-1.6 rpm, rotating the coating pan, adjusting the height of a spray gun to be 120-150 mm away from the hollow pellet core, setting the temperature of hot air to be 60-80 ℃, setting the rotating speed of exhaust air to be 40% -60%, maintaining the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 16-40 rpm when the outlet temperature reaches 26-32 ℃, keeping the liquid supply flow at 200-280 g/min for guniting and coating, closing the peristaltic pump after guniting is finished, continuously rotating and drying for 6-8 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature to obtain coated sustained-release pellets, and discharging;
(4) tabletting: placing the coated sustained-release pellets prepared in the step 3 into a rotary tablet press for tabletting, controlling the hardness to be 5-8 kg, and tabletting to obtain sustained-release tablet cores;
(5) second guniting coating pretreatment: pulverizing the slow-release coating layer material and sieving with a 100-mesh sieve for later use; putting polyethylene glycol 200 into 10-12 times of 70% ethanol solution by weight, and slightly heating to dissolve to obtain polyethylene glycol 200 ethanol solution for later use; preferably, the slow-release coating layer material is one or more of microcrystalline cellulose, hydroxypropyl methylcellulose sodium, hydroxypropyl methylcellulose and sodium metabisulfite;
(6) mixing: placing the screened slow-release coating layer material into a three-dimensional motion mixer, mixing for 10-15 minutes, taking out to obtain mixed powder 2 for later use, preferably, the slow-release coating layer material is one or more of microcrystalline cellulose, hydroxypropyl methylcellulose sodium, hydroxypropyl methylcellulose and sodium metabisulfite;
(7) preparing a second spraying coating solution: placing 60-70% volume fraction ethanol solution in a stirring liquid storage tank, setting the stirring speed at 50-70 rpm, stirring, slowly adding the ethanol solution of polyethylene glycol 200 in the step 5 under continuous stirring, continuously stirring for 3-5 minutes after the addition is finished, slowly adding the mixed powder 2, continuously stirring for 1-2 hours after the addition is finished, completely dispersing the mixed powder, taking out, and sieving with a 100-mesh sieve to obtain a second guniting coating material for later use;
(8) and (3) coating by spraying slurry for the second time: placing the sustained-release tablet core into a coating pan, adjusting the rotating speed of a main machine to be 2.0-2.5 rpm, rotating the coating pan, adjusting the height of a spray gun to be 130-170 mm away from the tablet bed, setting the temperature of hot air to be 60-80 ℃, setting the exhaust rotating speed to be 40% -60%, keeping the negative pressure state in the pan, controlling the rotating speed of a peristaltic pump to be 16-40 rpm when the outlet temperature reaches 26-32 ℃, keeping the liquid supply flow at 180-250 g/min for spraying and coating, closing the peristaltic pump after spraying, continuously rotating and drying for 6-8 minutes under the coating temperature condition, closing the hot air, reducing the rotating speed, cooling to room temperature, obtaining the metformin hydrochloride sustained-release tablet, and discharging the coating, wherein the weight of the coating is increased by 3% -4%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010772830.1A CN111759818B (en) | 2020-08-04 | 2020-08-04 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010772830.1A CN111759818B (en) | 2020-08-04 | 2020-08-04 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111759818A true CN111759818A (en) | 2020-10-13 |
| CN111759818B CN111759818B (en) | 2021-10-01 |
Family
ID=72729321
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010772830.1A Active CN111759818B (en) | 2020-08-04 | 2020-08-04 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111759818B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022079287A1 (en) * | 2020-10-16 | 2022-04-21 | Zentiva K.S. | Pharmaceutical compositions with low amounts of nitrosamine impurities and methods for producing the same |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101374505A (en) * | 2006-01-27 | 2009-02-25 | Cj第一制糖株式会社 | Multiple unit type sustained release oral formulation and process for the preparation thereof |
| CN105832688A (en) * | 2016-05-30 | 2016-08-10 | 合肥合源药业有限公司 | Pellet compressing method |
| CN105832708A (en) * | 2016-05-26 | 2016-08-10 | 江西京通美联药业有限公司 | Sustained-release preparation for treating diabetes and preparation method thereof |
| CN106109431A (en) * | 2015-12-18 | 2016-11-16 | 上海奕利制药有限公司 | A kind of slow controlled release micro pill tablet and preparation method thereof |
| CN106727404A (en) * | 2017-03-27 | 2017-05-31 | 华益药业科技(安徽)有限公司 | Diabecron sustained-release tablet and preparation method thereof |
-
2020
- 2020-08-04 CN CN202010772830.1A patent/CN111759818B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101374505A (en) * | 2006-01-27 | 2009-02-25 | Cj第一制糖株式会社 | Multiple unit type sustained release oral formulation and process for the preparation thereof |
| CN106109431A (en) * | 2015-12-18 | 2016-11-16 | 上海奕利制药有限公司 | A kind of slow controlled release micro pill tablet and preparation method thereof |
| CN105832708A (en) * | 2016-05-26 | 2016-08-10 | 江西京通美联药业有限公司 | Sustained-release preparation for treating diabetes and preparation method thereof |
| CN105832688A (en) * | 2016-05-30 | 2016-08-10 | 合肥合源药业有限公司 | Pellet compressing method |
| CN106727404A (en) * | 2017-03-27 | 2017-05-31 | 华益药业科技(安徽)有限公司 | Diabecron sustained-release tablet and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| LI X等: "采用喷雾干燥法制备含硬脂酸的填充剂,以保护压片过程中包衣小丸的衣膜", 《中国医药工业杂志》 * |
| 胡孝国等: "盐酸二甲双胍肠溶微丸胶囊的制备及其释放度测定", 《武警医学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022079287A1 (en) * | 2020-10-16 | 2022-04-21 | Zentiva K.S. | Pharmaceutical compositions with low amounts of nitrosamine impurities and methods for producing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111759818B (en) | 2021-10-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2018177318A1 (en) | Metformin hydrochloride sustained-release tablets and preparation method therefor | |
| CN112190559B (en) | Controlled-release folic acid tablet and preparation method thereof | |
| CN112022825B (en) | Atorvastatin maleate tablet and preparation method thereof | |
| CN111450070B (en) | Extrusion 3D printing coating type sustained release preparation and preparation method thereof | |
| CN110279667B (en) | Valaciclovir hydrochloride tablet and preparation method thereof | |
| CN111759818B (en) | Metformin hydrochloride sustained release tablet and preparation method thereof | |
| CN110420192B (en) | Isosorbide mononitrate sustained-release tablet and preparation method thereof | |
| CN114010612B (en) | Sitagliptin and metformin double-layer sustained release tablet and preparation method thereof | |
| CN114344294B (en) | Telmisartan oral solid preparation with stable product performance and preparation method thereof | |
| CN105535018B (en) | A kind of calcium carbonate D3 particles and preparation method thereof | |
| WO2023040173A1 (en) | Pentoxifylline sustained-release tablet and preparation method therefor | |
| CN112137979A (en) | Terpontinib tablet and preparation method thereof | |
| CN109010298B (en) | Metformin and glipizide compound composition and preparation method thereof | |
| CN110585155A (en) | Gliclazide tablet (II) and preparation method thereof | |
| CN113304117B (en) | Preparation method of sodium valproate sustained release tablet | |
| CN111346064B (en) | Rivaroxaban tablet and preparation method thereof | |
| CN112370433A (en) | Indapamide sustained release tablet and preparation method thereof | |
| CN109771380A (en) | Desmethylvenlafaxine hydrochloride drug composition and preparation method thereof | |
| CN115531327A (en) | Irbesartan tablets and preparation method thereof | |
| CN111803456A (en) | Rapidly disintegrating composite auxiliary material and preparation method thereof | |
| CN114209668B (en) | Alfuzosin hydrochloride sustained release preparation and preparation method thereof | |
| CN112618502B (en) | High-dissolution clotrimazole vaginal tablet and preparation process thereof | |
| CN115252574B (en) | Telmisartan pellets, preparation method thereof and pharmaceutical preparation | |
| CN112516099B (en) | Gliclazide sustained release tablet and preparation method thereof | |
| CN111110645B (en) | Mosapride citrate sustained release tablet and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: No. 101, Jinyu Avenue, jingkaiyuan, North New District, Yubei District, Chongqing Applicant after: Chongqing kangkere Pharmaceutical Co., Ltd Address before: No. 101, Jinyu Avenue, jingkaiyuan, North New District, Yubei District, Chongqing Applicant before: CHONGQING CONQUER PHARMACEUTICAL Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |