CN106176652B - Metformin hydrochloride sustained release tablet and preparation method thereof - Google Patents

Abstract

The invention provides a metformin hydrochloride sustained-release tablet and a preparation method thereof, belonging to the field of pharmacy. The metformin hydrochloride sustained-release tablet comprises metformin hydrochloride, a binder, an absorption enhancer, hypromellose and pharmaceutical excipients, and the mass ratio of metformin hydrochloride to the binder and the absorption enhancer is 500:45-55:2.5- 3.5. The preparation method is as follows: firstly, the absorption enhancer, metformin hydrochloride and a binder are mixed and granulated, and then mixed with hypromellose and medicinal auxiliary materials, and pressed into tablets. The sustained-release tablet can widen the absorption window of metformin hydrochloride, has high bioavailability, and can keep the plasma concentration of metformin hydrochloride relatively stable at a therapeutic level for a long time, thereby effectively treating the disease. In the above preparation method, hypromellose is added after granulation, which greatly improves the sustained-release performance of the sustained-release tablet, thereby obtaining a better therapeutic effect.

Description

A kind of metformin hydrochloride sustained-release tablet and preparation method thereof

technical field

The invention relates to the field of pharmacy, in particular to a metformin hydrochloride sustained-release tablet and a preparation method thereof.

Background technique

Metformin hydrochloride, chemical name: 1,1-dimethyl biguanide hydrochloride, molecular formula: C ₄ H ₁₁ N ₅ ·HCl, molecular weight: 165.63, chemical structural formula is as follows:

Metformin hydrochloride is a biguanide oral hypoglycemic drug used for the treatment of non-insulin-dependent diabetes mellitus. It is an anti-diabetic drug that can control blood sugar levels and improve macrovascular complications. Metformin hydrochloride has a good hypoglycemic effect, and can reduce the risk of blood lipids and cardiovascular diseases. It has the advantages of long-term medication safety and high cost performance, and is widely recommended as the first-line drug for type 2 diabetes.

Metformin hydrochloride is a very water-soluble drug, and the half-life of ordinary oral preparations is short, requiring repeated use of large doses to maintain the effective blood drug concentration (3 times a day, 500 mg each time), which can easily cause large fluctuations in the blood drug concentration in the body and cause adverse effects. reaction. Therefore, in order to provide a lasting and stable blood concentration to better exert its hypoglycemic effect, people began to develop metformin hydrochloride sustained-release preparations to increase patient compliance.

"Chinese Pharmacopoeia" stipulates that sustained-release preparations refer to the slow and non-constant release of oral drugs in the specified release medium as required. 2 preparations.

With the development of polymer materials science, new polymers for medicinal use are increasing, and hydrophilic polymers are the most widely used. Such polymers can swell in water, and their specific structure can retain water and form swellable hydrogels to block drug release. The most common sustained-release dosage forms that use hydrophilic polymers as blocking agents are hydrophilic gel matrix tablets, and hypromellose (HPMC) matrix tablets are representative of this type of dosage form. Such skeletal sustained-release preparations can well solve the problem of drug "burst release" during the preparation of metformin hydrochloride sustained-release preparations. Therefore, existing metformin hydrochloride sustained-release tablets are generally prepared by such skeletal sustained-release preparations.

Metformin hydrochloride is inherently poorly permeable in the lower gastrointestinal tract, which results in its absorption almost exclusively in the upper gastrointestinal tract, and its oral bioavailability is only 40-60% and decreases with increasing dose, which Means it has some saturable absorption process, or permeation time limited absorption. The absorption of metformin hydrochloride is limited in the upper gastrointestinal tract and is poorly absorbed in the distal small intestine, large intestine, and colon. This limitation on absorption is called the "absorption window".

Chinese invention patent CN1295467A discloses a dual-phase controlled-release delivery system for highly water-soluble drugs, which comprises an inner solid particle phase and an outer solid continuous phase, wherein the particles of the inner solid particle phase are dispersed and embedded in the outer solid continuous phase. The inner solid particulate phase contains the drug with high water solubility and the sustained release material; the outer solid continuous phase contains the sustained release material. The patented technical solution realizes the prolongation of the gastric residence time of the drug without relying on the combined use of other drugs such as propylamine, thereby improving the bioavailability of the drug.

However, because metformin hydrochloride itself has a certain gastric irritation, some patients have adverse reactions of gastric discomfort. The above technology improves the bioavailability of metformin sustained-release tablets by increasing the residence time of the drug in the stomach, which will increase the time of gastric discomfort and adverse reactions to some extent, so it still has certain drawbacks.

SUMMARY OF THE INVENTION

The first object of the present invention is to provide a metformin hydrochloride sustained-release tablet, which can widen the absorption window of metformin hydrochloride, has high bioavailability, and can make the plasma concentration of metformin hydrochloride relatively in a relatively long period of time. Stable maintenance at therapeutic levels to effectively treat the disease.

The second object of the present invention is to provide a preparation method of the described metformin hydrochloride sustained-release tablet, the preparation method adds hypromellose after granulation, which greatly improves the sustained-release performance of the sustained-release tablet, resulting in a better treatment effect.

In order to realize the above-mentioned purpose of the present invention, the following technical solutions are specially adopted:

A metformin hydrochloride sustained-release tablet, the metformin hydrochloride sustained-release tablet comprises metformin hydrochloride, a binder, an absorption enhancer, hypromellose and pharmaceutical excipients, and the mass ratio of the metformin hydrochloride to the binder and the absorption enhancer is: 500:45-55:2.5-3.5.

A method for preparing metformin hydrochloride sustained-release tablets comprises first mixing an absorption enhancer, metformin hydrochloride and a binder into granules, then mixing them with hypromellose and pharmaceutical excipients, and pressing to obtain a tablet.

In general, the gastrointestinal tract of the human body has an absorption limitation, ie an absorption window, for metformin hydrochloride. However, although the oral sustained-release delivery system in the prior art can release the attached metformin hydrochloride for a long time after administration, it still has the problem of low bioavailability. This is mainly due to the common sustained-release preparations in the prior art, in the gastrointestinal tract region where metformin hydrochloride can be well absorbed, the sustained-release preparations have not completely released the contained metformin hydrochloride; In areas where metformin hydrochloride is poorly or not absorbed, such as the distal small intestine, large intestine, and colon, the sustained-release formulation still releases the metformin hydrochloride it contains, and a higher proportion of metformin hydrochloride is still waiting to be released. At this time, the absorption rate of metformin hydrochloride released is low or even not absorbed, resulting in low bioavailability of metformin hydrochloride, and the plasma concentration of metformin hydrochloride is lower than the therapeutic level in certain periods, and the disease cannot be effectively treated.

Compared with the prior art, the beneficial effects of the present invention are:

By controlling the ratio between metformin hydrochloride, the binder and the absorption enhancer, the sustained-release tablet can widen the absorption window of metformin hydrochloride, so that it can also maintain a certain absorption rate in the area where the absorption of metformin hydrochloride is weak. , thereby solving the problem of low bioavailability of metformin hydrochloride due to a narrow absorption window without increasing the reaction time of gastric discomfort. The high bioavailability of the sustained-release tablet enables the plasma concentration of metformin hydrochloride to be maintained at a therapeutic level relatively stably for a long period of time, thereby achieving an optimal level for treating the disease.

In addition, when preparing the sustained-release tablet, hypromellose is used as a matrix material, and the order of its addition has a significant impact on the release performance of the formulation. The inventor found through research that adding hypromellose after granulation can greatly improve the sustained-release performance of the sustained-release tablet compared to letting hypromellose directly participate in the granulation process. Specifically, the sustained-release tablet can quickly release the drug in a short period of time to make the blood drug concentration reach the therapeutic concentration, and then slow down the release speed, so that the blood drug concentration can be maintained at the therapeutic concentration for a long time, so as to obtain better treatment effect.

Detailed ways

The embodiments of the present invention will be described in detail below with reference to the examples, but those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. If the specific conditions are not indicated in the examples, it is carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used without the manufacturer's indication are conventional products that can be purchased from the market.

This embodiment provides a metformin hydrochloride sustained-release tablet, the sustained-release tablet includes metformin hydrochloride, a binder, an absorption enhancer, hypromellose and pharmaceutical excipients, and the mass ratio of metformin hydrochloride to the binder and the absorption enhancer It is 500:45-55:2.5-3.5, preferably 500:50:3.

By controlling the ratio between metformin hydrochloride, binder and absorption enhancer, the sustained-release tablet can widen the absorption window of metformin hydrochloride, so that it can also maintain a certain absorption rate in the area where the absorption of metformin hydrochloride is weak. , thereby solving the problem of low bioavailability of metformin hydrochloride due to a narrow absorption window without increasing the reaction time of gastric discomfort. The high bioavailability of the sustained-release tablet enables the plasma concentration of metformin hydrochloride to be maintained at a therapeutic level relatively stably for a long period of time, thereby achieving an optimal level for treating the disease.

The content of metformin hydrochloride in each sustained-release tablet is 450-550 mg, preferably 500 mg; the weight of each sustained-release tablet is 1.01-1.10 g, preferably 1.05 g.

Hypromellose is a sustained-release matrix material, preferably hypromellose with a viscosity of 4,000-100,000 cps.

In a preferred embodiment of the present invention, the mass ratio of the total mass of the above metformin hydrochloride, the binder and the absorption enhancer to the hypromellose is 11:7-8. By controlling the total mass of hypromellose, metformin hydrochloride, binder and absorption enhancer, the sustained-release performance of the sustained-release tablet can be greatly improved, so that the blood drug concentration can be maintained at a long time. Therapeutic concentration for better therapeutic effect.

Such binders include povidone and sodium carboxymethyl cellulose. Povidone is a kind of high-efficiency adhesive polymer, used as an adhesive in the present invention, preferably Povidone K30. Sodium carboxymethyl cellulose has binding and thickening properties. Preferably, the mass ratio of the above-mentioned povidone and sodium carboxymethylcellulose is 3:1.2-2, and most preferably, the mass ratio of the two is 3:2. After a large number of experiments, the inventor has confirmed that povidone and sodium carboxymethyl cellulose are mixed in this ratio as a binder, and the obtained sustained-release tablet has more sustained-release tablets than when they are used alone or when the two are mixed in other ratios. release performance.

The above-mentioned absorption enhancers include chitosan and dibasic calcium phosphate. Chitosan and calcium dihydrogen phosphate are used as absorption enhancers, which can promote the release amount of metformin hydrochloride contained in the sustained-release tablet in the upper part of the gastrointestinal tract. Preferably, the mass ratio of the above-mentioned chitosan and calcium dihydrogen phosphate is 1:2-3, and most preferably, the mass ratio of the two is 1:2. After a lot of experiments, the inventors have confirmed that the bioavailability of the prepared sustained-release tablet is higher when chitosan and calcium dihydrogen phosphate are mixed in this ratio than when they are used alone or when the two are mixed in other ratios.

The above-mentioned pharmaceutical excipients include microcrystalline cellulose and magnesium stearate. Microcrystalline cellulose acts as a diluent, binder, and corrosion inhibitor, as well as lubricating and disintegrating properties. Magnesium stearate is used as a glidant, which is conducive to the smooth progress of the tableting process.

Specifically, the raw materials of this sustained-release tablet include by weight:

50 parts of metformin hydrochloride, 2.8-3.7 parts of povidone, 1.4-2.1 parts of sodium carboxymethylcellulose, 0.08-0.11 parts of chitosan, 0.19-0.23 parts of calcium dihydrogen phosphate, 35-40 parts of hypromellose , 9-11 parts of microcrystalline cellulose, and 0.5-1.5 parts of magnesium stearate.

Wherein, the mass ratio of povidone and sodium carboxymethylcellulose is 3:1.2-2; the mass ratio of chitosan and calcium dihydrogen phosphate is 1:2-3.

Most preferably, the raw material of this sustained-release tablet comprises in parts by weight:

50 parts of metformin hydrochloride, 3 parts of povidone, 2 parts of sodium carboxymethyl cellulose, 0.1 parts of chitosan, 0.2 parts of calcium dihydrogen phosphate, 38 parts of hypromellose, microcrystalline fiber It is 10 parts, and magnesium stearate is 1 part.

The sustained-release tablet prepared by using the raw materials in this ratio has better sustained-release performance and higher bioavailability, and has the best therapeutic effect on non-insulin-dependent diabetes mellitus.

The present embodiment also provides a method for preparing the above-mentioned metformin hydrochloride sustained-release tablet, comprising:

a. The absorption enhancer, metformin hydrochloride and binder are mixed and granulated.

Specifically, the solution A is prepared with an absorption enhancer, and the concentration of the absorption enhancer in the solution A is 8-12%, preferably 10%; then the metformin hydrochloride and the binder are mixed uniformly, and then mixed with the solution A and wet granulated , dried and whole grained.

The above-mentioned absorption enhancers include chitosan and calcium dihydrogen phosphate; the above-mentioned binders include povidone and sodium carboxymethyl cellulose.

Preferably, chitosan and calcium dihydrogen phosphate are first prepared into solution A with water.

Preferably, metformin hydrochloride, povidone and sodium carboxymethyl cellulose are respectively passed through 60-100 mesh sieves, preferably 80 mesh sieves, before mixing, and then mixed with solution A, wet granulation, and After drying at 40-60°C, 15-17 mesh granules are dried, preferably 16 mesh granules are dried at 50°C.

b. The obtained granules are mixed with hypromellose and pharmaceutical excipients, and pressed into tablets.

In addition, when preparing the sustained-release tablet, hypromellose is used as a matrix material, and the order of its addition has a significant impact on the release performance of the formulation. The inventor found through research that adding hypromellose after granulation can greatly improve the sustained-release performance of the sustained-release tablet compared to letting hypromellose directly participate in the granulation process. Specifically, the sustained-release tablet can quickly release the drug in a short period of time to make the blood drug concentration reach the therapeutic concentration, and then slow down the release speed, so that the blood drug concentration can be maintained at the therapeutic concentration for a long time, so as to obtain better treatment effect.

The features and performance of the present invention are described in further detail below in conjunction with the embodiments:

Table 1. Raw materials of sustained-release tablets in Examples 1-5 and Comparative Examples 1-10

Example 1

The present embodiment provides a metformin hydrochloride sustained-release tablet, the raw material of the sustained-release tablet is shown in Table 1, and the preparation method of the sustained-release tablet is:

a. Solution A is prepared with chitosan and calcium dihydrogen phosphate, then metformin hydrochloride, povidone and sodium carboxymethyl cellulose are mixed uniformly, then mixed with solution A and wet granulated, dried and granulated.

b. Mix the prepared granules with hypromellose, microcrystalline cellulose and magnesium stearate, and press into tablets.

Example 2

The present embodiment provides a metformin hydrochloride sustained-release tablet, the raw material of the sustained-release tablet is shown in Table 1, and the preparation method of the sustained-release tablet is:

a. Mix chitosan and calcium dihydrogen phosphate with water into solution A with a concentration of 8%; then pass metformin hydrochloride, povidone and sodium carboxymethyl cellulose through a 100-mesh sieve respectively, and add solution A after mixing evenly. Wet granulation, and 15-mesh granulation after drying at 60°C to obtain granules.

b. Mix the prepared granules with hypromellose, microcrystalline cellulose and magnesium stearate, and press into tablets.

Example 3

The present embodiment provides a metformin hydrochloride sustained-release tablet, the raw material of the sustained-release tablet is shown in Table 1, and the preparation method of the sustained-release tablet is:

a. Mix chitosan and calcium dihydrogen phosphate with water into solution A with a concentration of 10%; then pass metformin hydrochloride, povidone and sodium carboxymethyl cellulose through an 80-mesh sieve respectively, and add solution A after mixing evenly. Wet granulation and 16 mesh granulation after drying at 50°C to obtain granules.

b. Mix the prepared granules with hypromellose, microcrystalline cellulose and magnesium stearate, and press into tablets.

Example 4

The present embodiment provides a metformin hydrochloride sustained-release tablet, the raw material of the sustained-release tablet is shown in Table 1, and the preparation method of the sustained-release tablet is:

a. Mix chitosan and calcium dihydrogen phosphate with water into solution A with a concentration of 12%; then pass metformin hydrochloride, povidone and sodium carboxymethyl cellulose through a 60-mesh sieve respectively, and add solution A after mixing evenly. Wet granulation and 17 mesh granulation after drying at 40°C to obtain granules.

b. Mix the prepared granules with hypromellose, microcrystalline cellulose and magnesium stearate, and press into tablets.

Example 5

This embodiment provides a metformin hydrochloride sustained-release tablet, the raw material of the sustained-release tablet is shown in Table 1, and the preparation method of the sustained-release tablet is the same as that of Example 3.

Comparative ratio

The raw materials of metformin hydrochloride sustained-release tablets provided in Comparative Examples 1-9 are shown in Table 1, and the preparation method thereof is the same as that in Example 3.

Comparative Example 10

This comparative example provides a metformin hydrochloride sustained-release tablet, the raw material of the sustained-release tablet is shown in Table 1, and the preparation method of the sustained-release tablet is:

a. Mix chitosan and calcium dihydrogen phosphate with water into solution A with a concentration of 10%; then pass metformin hydrochloride, povidone, sodium carboxymethyl cellulose and hypromellose through an 80-mesh sieve, respectively, and mix After homogenization, solution A was added, wet granulation, and dried at 50° C. and 16-mesh granules were obtained to obtain granules.

b. Mix the prepared granules with microcrystalline cellulose and magnesium stearate, and press into tablets.

Experimental example 1

In the following, the metformin hydrochloride sustained-release tablets provided in the embodiments of the present invention are evaluated in terms of release degree in combination with experiments.

Take Example 3, and the prepared Metformin Hydrochloride Sustained-Release Tablets from Comparative Examples 1-5 and Comparative Example 10, and measure their release rate according to the method for measuring the release rate (Appendix X D of the 2010 edition of the Chinese Pharmacopoeia). The second method in the dissolution assay method was used for the determination, and 1000 mL of phosphate buffer (pH 6.8) was used as the dissolution medium, and the rotation speed was 1000 rmp. Operate according to the law. When dissolving for 1h, 3h, 5h, 7h and 10h, take 10mL of each solution, filter and precisely measure 3mL, 1mL and 1mL of the subsequent filtrate, put them in 100mL, 50mL and 100mL volumetric flasks respectively, add phosphate Dilute the buffer solution (pH 6.8) to the mark, shake well, and use it as the test solution; accurately weigh an appropriate amount of metformin hydrochloride reference substance, add phosphate buffer (pH 6.8) to dissolve and quantitatively dilute to a solution containing 5μg per 1mL , as the reference solution. Finally, the absorbance of the test solution and the reference solution were measured at the wavelength of 232 nm by using ultraviolet-visible spectrophotometry (Appendix IVA of the 2010 edition of the Chinese Pharmacopoeia). cumulative release. The results are shown in Table 2:

Table 2. Release assay results

As can be seen from Table 2, the drug release of Example 3 in artificial intestinal fluid is stable, that is, within 1 hour, the drug release rate of this sustained-release tablet is faster, so that the blood concentration of metformin hydrochloride quickly reaches the therapeutic concentration in a short time. Then, the sustained-release tablet slowly and stably releases the drug, so that the blood drug concentration of metformin hydrochloride can be maintained at the therapeutic concentration for a long time, thereby improving the curative effect.

In contrast, the drug release properties of the sustained-release tablets prepared in Comparative Examples 1-5 were uneven, for example, the sustained-release tablets prepared in Comparative Examples 1 and 2 had a burst release within 1 hour; The sustained-release tablets prepared in Example 10 released less drug within 1 hour and did not reach the therapeutic concentration; while the sustained-release tablets prepared in Comparative Example 4 released slowly within 3-10 hours, and could not maintain the blood drug concentration at the therapeutic concentration. Difference.

It can be seen that when the mass ratio of povidone and carboxymethyl cellulose is 1:2-3, it is beneficial to make the prepared sustained-release tablets of metformin hydrochloride sustained-release tablets release stable, fast onset, long in action time, and Good curative effect. In addition, by comparing the release degrees of the sustained-release tablets prepared in Example 3 and Comparative Example 10, it can be found that whether hypromellose participates in granulation has a significant impact on the release properties of the final prepared sustained-release tablets. Experiments show that by the method provided by the present invention, after granulation and mixing with hypromellose, the prepared sustained-release tablet has the best sustained-release performance.

Test Example 2

The bioavailability of the metformin hydrochloride sustained-release tablets provided in the examples of the present invention is evaluated below in combination with tests.

XR格华止，注：其采用前述专利CN1295467A方法制备)作为参比制剂进行相对生物利用度试验研究。The products prepared by Example 3 and Comparative Examples 6-9 are test drugs, and the listed products (

XR Gehuazhi, Note: It was prepared by the method of the aforementioned patent CN1295467A) as a reference preparation to conduct a relative bioavailability test study.

120 healthy male subjects were selected, who did not take other drugs 2 weeks before and during the experiment. Randomly divided into 6 groups, using a double crossover design, washout period of 7 days. 20 subjects in each group were randomly divided into 2 groups, and subjects in each group were cross-administered the test drug and the reference preparation in different research periods. Subjects were deprived of water for 2 hours after taking the drug, and ate a uniform meal after fasting for 4 hours. During the test period, no alcohol, no caffeinated beverages, and strenuous exercise were avoided.

Blood collection time: Before taking the medicine and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24 hours after taking the medicine, blood was taken from the upper limb vein, 3.5 mL each time, centrifuged and frozen for testing.

XR格华止)的相对生物利用度。结果如表3所示：Taking the concentration of metformin in plasma as the measurement index (determined by HPLC-UV method), the trapezoidal integration method was used to calculate AUC _0-24 and AUC _SS , and the area method was used to estimate the relative value of each group of test drugs to the reference preparation (

The relative bioavailability of XR Glutathione). The results are shown in Table 3:

Table 3. Relative Bioavailability Assay Results

XR格华止)的生物利用度为112％，比该上市产品的生物利用度更高。而对比例6-9所制备的缓释片中盐酸二甲双胍的生物利用度(77-92％)，远低于实施例3。由此说明，壳聚糖和磷酸二氢钙的质量比为1：2-3时，能够提高所制备的缓释片中盐酸二甲双胍的生物利用度，从而提高药效。As can be seen from Table 2, in the sustained-release tablet prepared by Example 3, metformin hydrochloride is relative to the listed product (

The bioavailability of XR Gehuazhi) is 112%, which is higher than the bioavailability of the listed product. The bioavailability (77-92%) of metformin hydrochloride in the sustained-release tablets prepared in Comparative Examples 6-9 is much lower than that in Example 3. This shows that when the mass ratio of chitosan and calcium dihydrogen phosphate is 1:2-3, the bioavailability of metformin hydrochloride in the prepared sustained-release tablet can be improved, thereby improving the efficacy.

In addition, the release degree and bioavailability of the sustained-release tablets provided in Examples 1, 2, 4 and 5 of the present invention are similar to those in Example 3, so they are not listed one by one.

Although specific embodiments of the present invention have been illustrated and described, it should be understood that various other changes and modifications can be made without departing from the spirit and scope of the invention. Therefore, it is intended that all such changes and modifications as fall within the scope of this invention be included in the appended claims.

Claims (4)

1. The metformin hydrochloride sustained release tablet is characterized by comprising metformin hydrochloride, an adhesive, an absorption enhancer, hypromellose and pharmaceutic adjuvants, wherein the mass ratio of the metformin hydrochloride to the adhesive to the absorption enhancer is 500: 45-55: 2.5-3.5;

the adhesive is prepared from the following components in percentage by mass of 3: 1.2-2 of povidone and sodium carboxymethylcellulose;

the absorption enhancer comprises the following components in a mass ratio of 1: 2-3 of chitosan and monocalcium phosphate;

the mass ratio of the total mass of the metformin hydrochloride, the adhesive and the absorption enhancer to the hypromellose is 11: 7-8;

the pharmaceutical excipients comprise microcrystalline cellulose and magnesium stearate.

2. The metformin hydrochloride sustained-release tablet according to claim 1, wherein the sustained-release tablet comprises the following raw materials in parts by weight:

50 parts of metformin hydrochloride, 2.8-3.7 parts of povidone, 1.4-2.1 parts of sodium carboxymethylcellulose, 0.08-0.11 part of chitosan, 0.19-0.23 part of monocalcium phosphate, 35-40 parts of hypromellose, 9-11 parts of microcrystalline cellulose and 0.5-1.5 parts of magnesium stearate;

wherein the mass ratio of the povidone to the sodium carboxymethyl cellulose is 3: 1.2-2; the mass ratio of the chitosan to the monocalcium phosphate is 1: 2-3.

3. The preparation method of the metformin hydrochloride sustained release tablet according to any one of claims 1 to 2, wherein the absorption enhancer, the metformin hydrochloride and the binder are mixed and granulated, then mixed with the hypromellose and the pharmaceutical excipients, and tableted to obtain the metformin hydrochloride sustained release tablet.

4. The method for preparing the metformin hydrochloride sustained release tablet according to claim 3, wherein the mixing granulation comprises: preparing solution A by using the absorption enhancer, uniformly mixing the metformin hydrochloride and the binding agent, then mixing with the solution A, carrying out wet granulation, drying and finishing granules.