CN111588701B

CN111588701B - Metformin hydrochloride sustained release tablet and preparation method thereof

Info

Publication number: CN111588701B
Application number: CN202010447301.4A
Authority: CN
Inventors: 张用杰
Original assignee: SHANGHAI PUKANG PHARMACEUTICAL CO Ltd
Current assignee: Hengchang (Guangzhou) new drug research Co.,Ltd.
Priority date: 2020-05-25
Filing date: 2020-05-25
Publication date: 2021-04-23
Anticipated expiration: 2040-05-25
Also published as: CN111588701A

Abstract

The invention discloses a metformin hydrochloride sustained-release tablet and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. The raw materials of the sustained-release tablet comprise metformin hydrochloride, sustained-release agent, adhesive, filler, glidant, lubricant and the like; wherein the sustained release agent is sodium carboxymethylcellulose and hydroxypropyl methylcellulose K100M; the adhesive is hydroxypropyl methylcellulose E5; the proportion of the metformin hydrochloride and the sustained release agent is as follows: 125: 80-120; the proportion of the adhesive is as follows: 125: 1.5-3.0; in the preparation process, granules obtained by mixing and granulating metformin hydrochloride and sodium carboxymethyl cellulose by water spraying are sprayed with water for the second time, and hydroxypropyl methyl cellulose K100M is added in two times. The method is suitable for industrial production, the product quality is stable, and the obtained metformin hydrochloride sustained-release tablets are uniformly and stably released.

Description

Metformin hydrochloride sustained release tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a metformin hydrochloride sustained-release tablet and a preparation method thereof.

Background

Metformin hydrochloride is a biguanide oral hypoglycemic agent, can be used for treating non-insulin-dependent diabetes mellitus, is a preferred type 2 diabetes for simple diet control and ineffective physical exercise treatment, and is particularly obese type 2 diabetes; for type 1 or type 2 diabetes, the product can be used together with insulin to increase blood sugar lowering effect of insulin, reduce insulin dosage, and prevent hypoglycemia. The product can also be used together with sulfonylureas oral hypoglycemic agents, and has synergistic effect.

According to the report of the literature, the product is a hypoglycemic agent. The product can reduce fasting and postprandial hyperglycemia of type II diabetes patients, HbAlc can be reduced by 1% -2%, and the mechanism of reducing blood sugar of the product is as follows: 1. increasing the sensitivity of the surrounding tissues to insulin, increasing insulin-mediated glucose utilization. 2. Increasing glucose utilization by non-insulin dependent tissues, such as brain, blood cells, renal medulla, intestinal tract, skin, etc. 3. Inhibiting liver gluconeogenesis and reducing hepatic glucose output. 4. Inhibit glucose uptake by intestinal wall cells. 5. Inhibit biosynthesis and storage of cholesterol, and reduce blood triglyceride and total cholesterol levels. Unlike insulin, the product has no fat synthesis promoting effect, no obvious blood sugar lowering effect on normal people and no hypoglycemia caused by independent application of type II diabetes.

In the chinese patent application CN1543937A (metformin hydrochloride sustained release tablet and its preparation method), the sustained release tablet is composed of metformin hydrochloride 46.5-70%, hydroxypropyl methylcellulose 13.5-33.0%, micro powder ethyl cellulose 10-14%, filler 1.3-9.4%, and lubricant 1.2-1.5%, and it is prepared by tabletting according to the conventional process. The use of the micro-powder ethyl cellulose with the particle size of less than 100 mu m can reduce the dosage of hydroxypropyl methyl cellulose and ethyl cellulose and realize the purpose of controlling the medicine to be stably released at a certain speed. In the Chinese patent application CN101283993A (application of metformin hydrochloride sustained release tablets in medicines for treating type 2 diabetes), the raw materials of the sustained release tablets comprise 42-60% of metformin hydrochloride, 34-50% of hydroxypropyl methylcellulose, 2-5% of sodium hydroxymethyl cellulose, 1-3% of microcrystalline cellulose and 2-4% of magnesium stearate. Microcrystalline cellulose is used as an auxiliary material, the dry powder is directly added into the granules to be mixed and then tableted, the processing is simple and convenient, the dosage of hydroxypropyl methylcellulose and sodium hydroxymethyl cellulose is reduced, and the medicine can be effectively controlled and released at a certain speed. In chinese patent application CN102440975A (a metformin hydrochloride sustained release tablet and a preparation method thereof), each 10000 tablet comprises the following raw materials: 5000g of metformin hydrochloride, 1750g of hydroxypropyl methylcellulose, 1750g of sodium carboxymethylcellulose, 180g of stearic acid, 200g of magnesium stearate and a proper amount of 75% ethanol. Firstly, 75% of ethanol is used for preparing hydroxypropyl methylcellulose with the mass percentage concentration of 0.5% and 10% of magnesium stearate solution; then adding the sieved metformin hydrochloride, hydroxypropyl methylcellulose and sodium carboxymethylcellulose into the hydroxypropyl methylcellulose solution for primary granulation, adding the magnesium stearate solution for secondary granulation, drying, sieving, granulating and tabletting. The granulation is carried out by adopting a method of adding slurry twice, so that the viscosity of the granules can be improved, the sustained release degree of the tablet can be increased, and the sustained release effect of the medicine can be obviously improved. In the chinese patent application CN103816130A (a metformin hydrochloride sustained release tablet), the sustained release tablet comprises the following raw materials: 600 parts of metformin hydrochloride, 30-60 parts of sodium carboxymethylcellulose, 250 parts of hypromellose 200, 220 parts of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion and 5-10 parts of magnesium stearate. The raw materials are screened, granulated, dried and granulated, and then tabletted, so that the metformin hydrochloride sustained-release tablet has good sustained-release performance, and the stability of the drug can reach 24 months under normal temperature storage. In the chinese patent application CN106176652A (a metformin hydrochloride sustained release tablet and a preparation method thereof), firstly, the absorption enhancer, metformin hydrochloride and the binder are mixed and granulated, and then mixed with hypromellose and pharmaceutic adjuvants, and tabletted. Wherein the absorption enhancer comprises chitosan and calcium dihydrogen phosphate, the binder comprises polyvidone and sodium carboxymethylcellulose, and the pharmaceutical adjuvant comprises microcrystalline cellulose and magnesium stearate. The obtained metformin hydrochloride sustained-release tablet can widen the absorption window of metformin hydrochloride, has high bioavailability, and can relatively stably maintain the blood concentration of metformin hydrochloride above a treatment level for a long time, thereby effectively treating the disease. In the chinese patent application CN110354090A (a metformin hydrochloride sustained release tablet and a preparation method thereof), the sustained release tablet is composed of sustained release granules, sustained release microcapsules and a lubricant, wherein the weight ratio of metformin hydrochloride contained in the sustained release granules and the sustained release microcapsules is 3:7-6:4, and the lubricant is selected from aerosil or magnesium stearate. The sustained-release granules are prepared by dry granulation, and the sustained-release granules consist of metformin hydrochloride, sustained-release materials and binders, wherein the sustained-release materials are hydroxypropyl methylcellulose, and the binders are selected from microcrystalline cellulose or copovidone; the sustained-release microcapsule is prepared by spray drying method, and comprises metformin hydrochloride and capsule wall material, wherein the capsule wall material is rhizoma bletilla polysaccharide, acacia, etc. The metformin hydrochloride sustained release tablet prepared by the method has the defects of unstable release, sudden release, complex preparation method, high difficulty in industrial production, unstable product quality and the like.

Disclosure of Invention

The invention aims to solve the technical problems that in the prior art, the metformin hydrochloride sustained release tablet is unstable in release, sudden release possibly exists, the production process is complex and the like.

In order to solve the technical problems, the invention discloses a preparation method of a metformin hydrochloride sustained release tablet, wherein the raw materials of the metformin hydrochloride sustained release tablet comprise metformin hydrochloride and a sustained release agent; the slow release agent comprises sodium carboxymethyl cellulose; in the preparation process, the metformin hydrochloride and the sodium carboxymethyl cellulose are subjected to water spraying, mixing and granulating, and then the granules obtained after mixing and granulating are subjected to secondary water spraying.

Further, the sustained release agent also comprises hydroxypropyl methyl cellulose; in the preparation process, a part of hydroxypropyl methylcellulose in the sustained-release agent is added into a granulator and is uniformly mixed with the granules after the water is sprayed for the second time; after finishing the granules, adding the rest hydroxypropyl methylcellulose in the sustained release preparation and other raw materials of the metformin hydrochloride sustained release tablets, uniformly mixing with the granules after finishing the granules, and tabletting.

And (4) granulating by using a glidant, wherein the glidant is silicon dioxide.

Wherein the mass of a part of hydroxypropyl methylcellulose in the sustained release preparation is 1/3 of the total mass of all hydroxypropyl methylcellulose in the sustained release preparation, namely the hydroxypropyl methylcellulose in the sustained release preparation is added twice, the first time is 1/3 of the total mass, and the second time is 2/3 of the rest. The slow release effect of the metformin hydrochloride diluent tablet can be optimized by adding the metformin hydrochloride diluent tablets in a plurality of times.

Further, in the second water spraying, the water spraying speed is higher than that in the mixing and granulating process, and the water spraying amount is lower than that in the mixing and granulating process. Furthermore, the amount of water sprayed is 1/4-1/2 of the amount of water sprayed during the mixing and granulating. The second water spray is mainly used for wetting the surface of the particles so that the particles can be well bonded with the hydroxypropyl methyl cellulose in the rest part of the sustained-release agent added later.

In the sustained release agent, the hydroxypropyl methyl cellulose is hydroxypropyl methyl cellulose K100M, the substitution degree of the hydroxypropyl methyl cellulose K100M is moderate, and the sustained release effect of the metformin hydrochloride sustained release tablet can be better improved when the hydroxypropyl methyl cellulose K100M is used as the sustained release agent.

The invention also claims a metformin hydrochloride sustained-release tablet prepared by the preparation method.

Further, other raw materials of the metformin hydrochloride sustained-release tablet comprise a binding agent, a filling agent and a lubricating agent.

Further, the mass ratio of the metformin hydrochloride to the sustained-release agent is 125: 80-120.

Further, the mass ratio of the metformin hydrochloride to the binder is 125: 1.5-3.0.

Further, the binder is selected from one or two of povidone K30 and hydroxypropyl methyl cellulose. Furthermore, the adhesive is hydroxypropyl methylcellulose, and the hydroxypropyl methylcellulose E5 is further selected as the hydroxypropyl methylcellulose, so that the hydroxypropyl methylcellulose has moderate viscosity and better adhesive effect.

Further, the filler is selected from one or two of lactose and microcrystalline cellulose. Still further, the filler is selected from microcrystalline cellulose.

Further, the lubricant is magnesium stearate.

In the invention, before preparing the metformin hydrochloride sustained-release tablets, the raw materials need to be processed, specifically, metformin hydrochloride, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose K100M, microcrystalline cellulose and hydroxypropyl methyl cellulose E5 in the raw materials need to be sieved.

In the raw materials, after being crushed, the metformin hydrochloride and the sodium carboxymethyl cellulose are sieved, and the mesh number of the sieved materials is larger than that of the sieved materials after the hydroxypropyl methyl cellulose K100M, the microcrystalline cellulose and the hydroxypropyl methyl cellulose E5 are crushed. This is because: the larger the mesh number of the screen, the finer the particle size of the sieved raw material, the fine particles are good in solubility but poor in flowability, and the coarse particles are poor in solubility but good in flowability. Metformin hydrochloride and sodium carboxymethyl cellulose are used as main medicinal components in the metformin hydrochloride sustained-release tablets and need to have higher solubility to better exert the medicinal effect, and hydroxypropyl methyl cellulose K100M, microcrystalline cellulose and hydroxypropyl methyl cellulose E5 are used as non-main medicinal components and need to have better fluidity to improve the operability of the medicinal tablet preparation process. Therefore, the required particle size of the raw material is different for different purposes.

Specifically, the preparation method of the metformin hydrochloride sustained release tablet comprises the following steps:

step 1: sieving hydroxypropyl methylcellulose K100M, microcrystalline cellulose and hydroxypropyl methylcellulose E5, and directly weighing the rest materials for later use;

step 2: adding the treated metformin hydrochloride and sodium carboxymethyl cellulose into a boiling drying granulator, and mixing;

and step 3: and spraying purified water into a boiling drying granulator, granulating and drying.

And 4, step 4: and (3) spraying water for the second time on the granules in the boiling drying granulator, and wetting:

and 5: hydroxypropyl methylcellulose K100M in the prescribed amount of 1/3 was added to a boiling drying granulator, mixed and dried.

Step 6: adding the silicon dioxide with the prescription amount into the material cabin, and granulating by using a lifting and turning granulator.

And 7: adding the rest prescription amount of hypromellose K100M, hypromellose E5, microcrystalline cellulose, and magnesium stearate into the material cabin, adding the granules, and pressing the mixing position button to start mixing. And (5) after mixing is finished, taking the intermediate for detection.

And 8: and (5) setting the weight of tablets to be pressed according to the content of the intermediate particles, and tabletting.

Wherein, the material in the step 1 is sieved, and the 60-80 meshes are preferred; more preferably 60 mesh.

Step 2, mixing materials in the fluidized drying granulator, wherein the frequency of a fan is set to be 35 Hz; mixing for 10-15 min; more preferably 10 min;

and 3, granulating, wherein the process parameters are set to that the frequency of a fan is 35Hz, the air inlet temperature is 80.0 ℃, the atomizing pressure is 0.35MPa at the inner layer and 0.30MPa at the outer layer, the liquid supply speed is 300r/min, water spraying granulation is started when the temperature of the material reaches 45 +/-5 ℃, and the granulation is promoted by 25r every 5 min. When the liquid supply frequency reaches 450r/min, the granulation is finished when the water spraying is finished and the temperature of the materials reaches 42.0 +/-2 ℃.

In the step 4, water is sprayed for the second time for wetting, and the frequency of a fan is 40 Hz; the liquid supply frequency is 400-; more preferably 500 r/min.

In the step 5, the mixing and drying time is 5-10 min;

before finishing, adding silicon dioxide into the material, wherein a finishing screen is 1.5 mm;

in the step 7, the mixing time is 20-30 min; more preferably 25 min; the mixing speed is 10 r/min;

tabletting in the step 8, wherein the mould is 19mm multiplied by 9 mm; the hardness of the tablet is controlled to be 150N-250N; more preferably 170N to 200N.

Compared with the prior art, the invention has the beneficial effects that:

1. the preparation method of the metformin hydrochloride sustained release tablet requires common equipment, has simple process, is suitable for large-scale commercial production, and has good reproducibility and stable quality.

2. The metformin hydrochloride sustained release tablet obtained by the invention has a more stable release curve, high similarity with a reference preparation, and a stable release curve after a long time.

3. The metformin hydrochloride sustained release tablet obtained by the invention is uniform in release and not easy to have burst release.

Drawings

FIG. 1: mean plasma concentrations (+/-SD) -time curves (linear coordinates) -PK concentration set curves for subjects in group T and group R.

FIG. 2: mean plasma concentrations (+/-SD) -time curves (semi-log coordinates) -PK concentration set curves for subjects in T and R groups.

Detailed Description

The technical solution of the present invention will be described in detail by the following specific examples.

The water used in the present invention is purified water.

The metformin hydrochloride sustained release tablet is prepared by the following method, which comprises the following steps:

step 1: sieving metformin hydrochloride, sodium carboxymethylcellulose, hydroxypropyl methylcellulose K100M, microcrystalline cellulose and hydroxypropyl methylcellulose E5, and then weighing the rest materials for later use;

step 2: adding the sieved metformin hydrochloride and sodium carboxymethylcellulose into a fluidized drying granulator, and mixing;

And 4, step 4: and (5) spraying water for the second time on the granules in the boiling drying granulator, and wetting.

And 5: hydroxypropyl methylcellulose K100M, in the prescribed amount of 1/3, was added to the boiling drying granulator, mixed and dried.

And 7: adding the rest prescription amount of hydroxypropyl methylcellulose K100M, and prescription amount of hydroxypropyl methylcellulose E5, microcrystalline cellulose, and magnesium stearate into the material cabin, adding the granules, and pressing the mixing position button to start mixing. And (5) after mixing is finished, taking the intermediate for detection.

Example 1

1) Pulverizing and sieving

Respectively crushing metformin hydrochloride and sodium carboxymethyl cellulose and sieving by a 80-mesh sieve before feeding and production; hydroxypropyl methylcellulose K100M, microcrystalline cellulose and hydroxypropyl methylcellulose E5 are sieved by a 60-mesh sieve, and the rest materials are directly weighed for standby.

2) Granulating

Mixing: adding the sieved metformin hydrochloride and sodium carboxymethylcellulose into a fluidized drying granulator, setting a fan at 35Hz, and mixing for 10min without heating.

And (3) granulating: setting the frequency of a fan to 35Hz, the air inlet temperature to 80.0 ℃, the atomizing pressure to be 0.35MPa at the inner layer and 0.30MPa at the outer layer (or the inner layer is larger than the outer layer by 0.05MPa, but the outer layer is not less than 0.2MPa), setting the liquid supply speed to be 300r/min, starting water spraying granulation when the temperature of the materials reaches 45 +/-5 ℃, and increasing the speed to be 25r every 5 min. When the liquid supply frequency reaches 450r/min, the materials fall into the pot to observe the granulation condition of the materials until the water spraying is finished and the temperature of the materials reaches 42.0 +/-2 ℃. The total amount of water sprayed during granulation was 85 kg.

Spraying water for the second time: the hot air is not started, the frequency of the fan is set to be 40Hz, and the liquid supply frequency is 500r/min to spray water to wet the materials. The fan frequency determines the drying speed, and the liquid supply frequency determines the water spray speed. The total amount of water sprayed in the second water spraying is 1/4-1/2 of the amount of water sprayed in the mixing granulation.

Mixing: adding the hydroxypropyl methyl cellulose K100M with the prescription amount of 1/3 into a boiling drying granulator by pumping, and mixing and drying for 5-10 min.

Straightening: adding the silicon dioxide of the prescription amount into a material cabin, granulating by using a lifting and overturning granulator, installing a 1.5mm screen on the granulator, pushing a bin of a fluidized dryer below a dry-method granulator, screwing 6 connecting screws of a connecting material barrel cover, and sealing; after the stock bin trolley is pushed away, the hoister is operated to turn the material barrel 180 degrees and lift the material barrel to a proper height. And (3) propelling a 1000L mixing tank to enable a discharge port of the mixing tank to be aligned with a feeding port of the dry-method granulator, aligning a discharge port of the dry-method granulator with the mixing tank port, fixing the discharge port of the dry-method granulator by using a hose, starting the granulator, setting the granulation rotating speed to be 10Hz, opening a discharge knob of a charging basket cover, granulating, closing the discharge knob of the charging basket cover after finishing granulation and discharge, and stopping the granulator.

3) Total mixing

Opening the hopper cover of the mixer, adding the rest of the hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose E5, microcrystalline cellulose and magnesium stearate into the material cabin, adding the granules, covering and tightening the hopper cover, setting the mixing time to be 25min and the mixing speed to be 10r/min, and pressing the button at the mixing position to start mixing. After mixing, the intermediate particles are inspected by sampling at the discharge port.

4) Tabletting

The tablet weight is determined according to the content of the intermediate particles, a special-shaped punch for the metformin hydrochloride sustained release tablet with the thickness of 19mm x 9mm is arranged for tabletting, the hardness of the tablet is controlled to be 170N-200N, and the friability of the tablet is not more than 0.8%.

5) Blister package

8/plate or 10/plate molds were selected for packaging. Taking the intermediate product, PVC and aluminum foil, installing a forming die, a heat sealing die, a printing die and a punching die, setting the air pressure of the full-automatic high-speed blister packaging machine to be 0.6-0.8 MPa, the temperature of the upper and lower forming dies to be 120-140 ℃, the heat sealing temperature to be 200-240 ℃ and the punching speed to be 20-45Hz, and packaging.

6) External packing

And carrying out carton packaging on the aluminum plastic of the tablet by aluminum plastic blister packaging, and finally carrying out carton packaging.

The kinds and amounts of the raw materials in the metformin hydrochloride sustained-release tablet in example 1 were as shown in table 1, and 25 ten thousand metformin hydrochloride sustained-release tablets were prepared and recorded as S1.

Examples 2 to 4

Metformin hydrochloride sustained-release tablets were prepared in the same manner as in example 1, and the types and amounts of the respective raw materials were as shown in table 1, and 25 ten thousand metformin hydrochloride sustained-release tablets, designated as S2-S4, were prepared.

Example 5

The types and the dosages of the raw materials are the same as those of S1, and the difference is that: the preparation method does not add the hydroxypropyl methyl cellulose K100M in a plurality of times, but adds the whole hydroxypropyl methyl cellulose K100M in the total mixing stage of the step 3). The types and the dosages of the raw materials are shown in table 1, and 25 ten thousand metformin hydrochloride sustained-release tablets are prepared and are marked as S5.

Comparative example 1

The types and the dosages of the raw materials are the same as those of S1, and the difference is that: the preparation method does not carry out secondary water spraying. The types and the dosages of the raw materials are shown in table 1, and 25 ten thousand metformin hydrochloride sustained-release tablets are prepared and are marked as B1.

Comparative example 2

The feed was similar to example 1 except that: the preparation method does not carry out the step of spraying water for the second time, and simultaneously, the sustained-release agent hydroxypropyl methyl cellulose K100M is not added for times, namely, all hydroxypropyl methyl cellulose K100M is added at the total mixing stage of the step 3) once. The types and the dosages of the raw materials are shown in table 1, and 25 ten thousand metformin hydrochloride sustained-release tablets are prepared and are marked as B2.

TABLE 1 kinds and amounts of raw materials for metformin hydrochloride sustained-release tablets in examples and comparative examples

The metformin hydrochloride sustained release tablets prepared by the method are subjected to performance test:

(1) in vitro dissolution profile

The test method comprises the following steps: taking the product, according to a determination method of dissolution rate and release rate (0931 first method of the general regulation of the Chinese pharmacopoeia 2015), taking 1000ml of phosphate buffer (pH6.8) as a dissolution medium, rotating at 100 revolutions per minute, operating according to the method, taking 5ml of solution respectively at 1 hour, 3 hours and 10 hours, filtering, instantly supplementing dissolution media with the same temperature and volume, precisely taking a proper amount of subsequent filtrate, quantitatively diluting with dissolution media to prepare a solution containing about 5 mu g of metformin hydrochloride in each 1ml, shaking up, and respectively determining absorbance at the wavelength of 233nm according to an ultraviolet-visible spectrophotometry (0401 of the general regulation of the Chinese pharmacopoeia 2015); taking a proper amount of metformin hydrochloride reference substance, precisely weighing, adding a dissolving medium to dissolve and quantitatively diluting to prepare a solution containing 5 mu g of metformin hydrochloride in each 1ml, measuring by the same method, and respectively calculating the dissolving amount of each tablet at different time. The dissolution amount of each tablet of the product in 1 hour, 3 hours and 10 hours is respectively 20-45%, 45-75% and more than 80% of the marked amount, and the dissolution amount meets the requirements. The release profiles in the hydrochloric acid solution pH1.2, acetate buffer pH4.0 and aqueous medium were also tested, respectively, as described above.

Sample source: examples 1 to 5, comparative examples 1 to 2; specification: 0.5 g.

Reference formulation: batch number HN0072, trade name:

XR; the manufacturer: Bristol-Myers Squibb Company; specification: 0.5 g.

The results of the measurements are shown in tables 2 to 5.

Table 2: results of comparison of dissolution curves of aqueous medium-evaluated preparation and reference preparation

Table 3: pH1.2 hydrochloric acid solution medium-dissolution curve similarity comparison result of evaluated preparation and reference preparation

Table 4: pH4.0 acetate buffer medium-the result of the comparison of the dissolution curves of the evaluated formulation and the reference formulation

Table 5: pH6.8 phosphate buffer medium-evaluated formulation and reference formulation dissolution curve similarity comparison results

The dissolution test results of the reference preparation and the preparation in the example under the condition of standard rotating speed (100 r/min) and the similar factors (f) of the dissolution curves of the preparation in the four media of pH1.2 hydrochloric acid solution, pH4.0 acetate buffer solution, pH6.8 phosphate buffer solution and water are calculated by taking the result of the HN0072 dissolution curve of the reference preparation as reference₂) The results are all greater than 50, indicating that the dissolution profiles in vitro are similar.

(2) Dose dumping test

In order to examine the possibility of sudden drug release in an in-vivo alcohol environment of the metformin hydrochloride sustained release tablet and possibly cause dose dumping by referring to technical guidance principle of chemical drug imitation pharmacy human bioequivalence research with pharmacokinetic parameters as end-point evaluation indexes issued by CFDA, 1 batch of reference preparation (batch number: HN0072) and examples 1-5 and comparative examples 1-2 are selected for dissolution curve determination. The results of the measurements are shown in tables 6 to 8.

Table 6: results of comparison of dissolution curves of 5% ethanol concentration hydrochloric acid solution-evaluated preparation and reference preparation

Table 7: results of comparison of dissolution curves of 20% ethanol concentration hydrochloric acid solution-evaluated preparation and reference preparation

Table 8: results of comparison of dissolution curves of hydrochloric acid solution of 40% ethanol concentration-evaluated preparation and reference preparation

The results show that the reference preparation and the preparation in example 1 do not have dosage dumping under severe conditions, and the safety can be ensured; calculating the dissolution curve similarity factor (f) of the evaluated preparation under corresponding conditions by taking the dissolution curve result of the reference preparation under each condition as reference₂) The results are all greater than 50, indicating that the dissolution profiles in vitro are similar. However, the samples of comparative example 1 and comparative example 2 have higher dissolution rate than those of examples 1-5 at each sampling point in ethanol solutions with different concentrations. The obtained sample has the risk of burst release when the secondary water spraying is not carried out, or the secondary water spraying is not carried out, and the hydroxypropyl methyl cellulose K100M is not added in a divided manner.

(3) Pharmacokinetic profile

PK concentration set 30 subjects were subjected to pharmacokinetic concentration analysis.

The sample from example 1 and the reference formulation (batch number: HN0072) were used for the pharmacokinetic experiments.

All the subjects after meal need to draw about 3mL of peripheral venous blood respectively at 19 blood sampling points of 0h (-1 h) before taking the medicine and 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 4.5h, 5.0h, 5.5h, 6.0h, 6.5h, 7.0h, 7.5h, 8.0h, 10.0h, 12.0h, 16.0h, 24.0h and 30.0h after taking the medicine in each cycle for detecting the blood concentration of the metformin.

And (3) determining the drug concentration of the metformin in the plasma by adopting a liquid chromatography mass spectrometry (LC-MS/MS) detection method. The lower limit of quantitation was 2.00 ng/mL.

And (3) carrying out estimation analysis on the pharmacokinetic parameters of the non-atrioventricular model on the blood concentration data by adopting Phoenix WinNonlin 8.1 software, and calculating the main pharmacokinetic parameters.

And when calculating pharmacokinetic parameters, calculating according to actual sampling time, and keeping two digits after the decimal point in the adjusted time.

All plasma concentration values below the lower limit of quantitation were processed as "0" before Tmax and after Tmax, were not involved in the calculation.

PK parameter set 30 subjects underwent pharmacokinetic parameter analysis.

Group T subjects took the example 1 sample; the subjects in group R took the reference formulation.

Mean plasma concentration (+/-SD) -time curve (linear coordinates) -PK concentration set curve, and mean plasma concentration (+/-SD) -time curve (semi-logarithmic coordinates) -PK concentration set curve for subjects in T group and R group are given in fig. 1 and 2, respectively. It can be seen that the metformin hydrochloride sustained release tablets prepared by the present invention can reach a peak value in a short time and maintain a stable concentration for a long period of 30 hours.

In the T group of subjects, the mean Cmax was 644.9. + -. 115.53ng/mL, and the coefficient of variation among individuals was 17.91%.

In the R group of subjects, the mean Cmax was 633.4 + -90.12 ng/mL, and the coefficient of variation among individuals was 14.23%.

In the T group of subjects, the mean AUC0-T was 7031.092. + -. 1357.5925h ng/mL, and the coefficient of variation between individuals was 19.31%.

In the subjects in the group R, the mean AUC0-t was 6960.412. + -. 1219.3524h ng/mL, and the coefficient of variation between individuals was 17.52%.

In the subjects in group T, the mean AUC0- ∞ was 7118.783. + -. 1368.9918h ng/mL, and the coefficient of variation among individuals was 19.23%.

In the subjects in group R, the mean AUC0- ∞ was 7052.991. + -. 1237.4619h ng/mL, and the coefficient of variation among individuals was 17.55%.

The median Tmax in the T group of subjects was 6.500h, ranging from 4.01 to 10.00 h.

The median Tmax in the subjects of group R was 6.000h, ranging from 4.00-8.00 h.

The metformin hydrochloride sustained release tablet prepared by the invention has stable in-vitro dissolution curve and has no obvious change in the period of validity. The metformin hydrochloride sustained release tablet prepared by the invention has a pharmacokinetic curve in human bodies similar to that of the original research, and has no obvious individual difference.

The above description is only for the preferred embodiments of the present invention, but these embodiments are only exemplary and do not limit the scope of the present invention. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.

Claims

1. A preparation method of the metformin hydrochloride sustained release tablet is characterized by comprising the following steps:

the components and the dosage are as follows: 125kg of metformin hydrochloride, 12.5kg of sodium carboxymethylcellulose, 17.5kg of microcrystalline cellulose, 100. 100M 82.5.5 kg of hydroxypropyl methyl cellulose, 5.0kg of silicon dioxide, and 5.0kg of magnesium stearate;

and step 3: spraying purified water into a fluidized drying granulator, granulating and drying;

and 4, step 4: carrying out secondary water spraying and wetting on the granules in the boiling drying granulator; the total amount of water spraying during the second water spraying is 1/4-1/2 of the water spraying amount during the mixing granulation;

and 5: adding 1/3 hydroxypropyl methylcellulose K100M into boiling drying granulator, mixing and drying;

step 6: adding the silicon dioxide with the prescription amount into a material cabin, and finishing granules by using a lifting and overturning granulator;

and 7: adding the rest hydroxypropyl methylcellulose K100M, and prescription amount of hydroxypropyl methylcellulose E5, microcrystalline cellulose, and magnesium stearate into the material cabin, adding the granules, and pressing the mixing position button to start mixing; after mixing, taking an intermediate for detection;

and 8: determining the weight of the tablet to be pressed according to the content of the intermediate particles, and tabletting;

and (3) sieving the material in the step (1) by using a 60-80-mesh sieve.

2. A metformin hydrochloride sustained-release tablet obtained by the production method according to claim 1.