阅读说明：本技术 盐酸二甲双胍的精制方法、盐酸二甲双胍缓释片及其制备方法 (Refining method of metformin hydrochloride, metformin hydrochloride sustained-release tablet and preparation method thereof ) 是由 许丹青 余国新 耿亮 朱亚东 于 2021-01-05 设计创作，主要内容包括：本发明涉及药物制剂技术领域,尤其是盐酸二甲双胍的精制方法、盐酸二甲双胍缓释片及其制备方法。所述盐酸二甲双胍的精制方法包括如下步骤：将盐酸二甲双胍粗品溶于体积分数为65-70%乙醇水溶液中加热回流,然后冷却至室温,用浓盐酸调节pH值为2-3,降温结晶,分离、洗涤、干燥,即得。通过采用特定的体积分数为65-70%乙醇水溶液作为精制溶剂,结合用浓盐酸调节pH值为2-3,精制得到的盐酸二甲双胍产品的澄清度合格；由该精制方法精制得到的盐酸二甲双胍产品为原料制得的盐酸二甲双胍缓释片能够达到美国药典USP32标准中质量规定,24h内以一定速度平稳释放、维持平稳的血药浓度使之达到良好的治疗效果。(The invention relates to the technical field of pharmaceutical preparations, in particular to a method for refining metformin hydrochloride, a metformin hydrochloride sustained-release tablet and a preparation method thereof. The method for refining the metformin hydrochloride comprises the following steps: dissolving the metformin hydrochloride crude product in 65-70% ethanol water solution by volume fraction, heating and refluxing, cooling to room temperature, adjusting pH value to 2-3 with concentrated hydrochloric acid, cooling for crystallization, separating, washing and drying to obtain the metformin hydrochloride. The method comprises the steps of adopting a specific 65-70% ethanol water solution in volume fraction as a refining solvent, regulating the pH value to 2-3 by combining concentrated hydrochloric acid, and refining to obtain a metformin hydrochloride product with qualified clarity; the metformin hydrochloride sustained release tablet prepared by using the metformin hydrochloride product refined by the refining method as a raw material can reach the quality regulation in the USP32 standard, and can be stably released at a certain speed within 24h and maintain stable blood concentration so as to achieve good treatment effect.)

1. The method for refining the metformin hydrochloride is characterized by comprising the following steps: dissolving the metformin hydrochloride crude product in 65-70% ethanol water solution by volume fraction, heating and refluxing, cooling to room temperature, adjusting pH value to 2-3 with concentrated hydrochloric acid, cooling for crystallization, separating, washing and drying to obtain the metformin hydrochloride.

2. The method for refining metformin hydrochloride according to claim 1, wherein the mass ratio of the metformin hydrochloride crude product to the 65-70% ethanol aqueous solution by volume fraction is 1: 1.2-1.5.

3. The method for refining metformin hydrochloride according to claim 1 or 2, wherein the heating reflux time is 50 to 60 min;

the washing reagent is selected from absolute ethyl alcohol, and the mass ratio of the metformin hydrochloride crude product to the absolute ethyl alcohol is 1: 1.0-1.5;

the drying temperature is 45-50 ℃, and the drying time is 6-7 h.

4. Metformin hydrochloride obtained by the purification process of metformin hydrochloride according to any one of claims 1 to 3.

5. The metformin hydrochloride sustained release tablet is characterized by comprising the following raw materials in parts by weight:

45-65 parts of metformin hydrochloride, 40-50 parts of sustained release agent, 3-8 parts of lubricant and 2-6 parts of adhesive;

the metformin hydrochloride is obtained by refining the metformin hydrochloride according to any one of claims 1 to 3 by the refining method.

6. The metformin hydrochloride sustained-release tablet according to claim 5, wherein the sustained-release agent comprises hypromellose and ethylcellulose;

the adhesive is an ethanol solution of ethyl cellulose with the mass content of 5%.

7. The metformin hydrochloride sustained-release tablet according to claim 6, wherein the mass ratio of the hypromellose to the ethylcellulose is 1: 3-4.

8. The metformin hydrochloride sustained-release tablet according to any one of claims 5 to 7, wherein the lubricant is magnesium stearate.

9. The metformin hydrochloride sustained-release tablet according to claim 8, which comprises the following raw materials in parts by weight:

45-65 parts of metformin hydrochloride, 10 parts of hydroxypropyl methylcellulose, 30-40 parts of ethyl cellulose, 3-8 parts of magnesium stearate and 2-6 parts of ethyl cellulose ethanol solution with the mass content of 5%.

10. A process for the preparation of the metformin hydrochloride sustained release tablets according to any one of claims 5 to 9, comprising the steps of:

uniformly mixing metformin hydrochloride and the sustained-release agent according to the selected weight part, adding the adhesive, granulating, drying, adding the lubricant, uniformly mixing and tabletting to obtain the metformin hydrochloride sustained-release tablet.

Technical Field

The invention relates to the technical field of pharmaceutical preparations, in particular to a method for refining metformin hydrochloride, a metformin hydrochloride sustained-release tablet and a preparation method thereof.

Background

Metformin hydrochloride is an oral biguanide antihyperglycemic drug, in particular to a therapeutic drug for type II diabetes. The metformin hydrochloride has high solubility and low permeability in a human body, after a patient takes the metformin hydrochloride common tablet, the blood concentration fluctuation is large, gastrointestinal adverse reactions such as gastrectasia, diarrhea, nausea, abdominal discomfort and the like in different degrees are easy to occur, and the metformin hydrochloride sustained release tablet has a certain gastric retention effect, can improve the retention time of the medicament in the stomach, improve the bioavailability of the medicament, reduce the fluctuation range of the blood concentration, reduce the adverse reaction of the medicament, reduce the administration times and facilitate the administration of the patient. Therefore, the clinical application of the metformin hydrochloride sustained release tablets is becoming popular.

The existing metformin hydrochloride sustained release tablets have the phenomena of uneven drug release, easy occurrence of burst release or incomplete release, and sustained release indexes which do not reach the quality regulation in the United states pharmacopoeia USP32 standard: the medicine is controlled to release steadily at a certain speed within 24h and maintain steady blood concentration so as to achieve good treatment effect.

In order to overcome the defects, Chinese patent document CN107184559A discloses a metformin hydrochloride sustained release tablet and a preparation method thereof, and specifically, the metformin hydrochloride sustained release tablet is prepared by adding a certain stabilizing agent and a release regulator through a hot melt extrusion technology, so that the drug is released and dissolved without burst release. However, the sustained release index of the compound preparation still can not meet the quality regulation in the United states pharmacopoeia USP32 standard: the medicine is controlled to release steadily at a certain speed within 24h and maintain steady blood concentration.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for refining metformin hydrochloride, a metformin hydrochloride sustained-release tablet and a preparation method thereof, wherein the metformin hydrochloride sustained-release tablet can ensure that the sustained-release speed is stable within 24 hours and the stable blood concentration is maintained.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows:

a refining method of metformin hydrochloride comprises the following steps: dissolving the metformin hydrochloride crude product in 65-70% ethanol water solution by volume fraction, heating and refluxing, cooling to room temperature, adjusting pH value to 2-3 with concentrated hydrochloric acid, cooling for crystallization, separating, washing and drying to obtain the metformin hydrochloride.

The metformin hydrochloride crude product is prepared by any existing preparation method of metformin hydrochloride, such as a melting method, a solvent method and the like.

Optionally, the mass ratio of the crude metformin hydrochloride to 65-70% ethanol aqueous solution by volume fraction is 1 (1.2-1.5).

Optionally, the heating reflux time is 50-60 min;

the washing reagent is selected from absolute ethyl alcohol, and the mass ratio of the metformin hydrochloride crude product to the absolute ethyl alcohol is 1 (1.0-1.5);

the drying temperature is 45-50 ℃, and the drying time is 6-7 h.

The invention also provides the metformin hydrochloride refined by the refining method of the metformin hydrochloride.

The invention also provides a metformin hydrochloride sustained release tablet, which comprises the following raw materials in parts by weight:

45-65 parts of metformin hydrochloride, 40-50 parts of sustained release agent, 3-8 parts of lubricant and 2-6 parts of adhesive;

the metformin hydrochloride is refined by adopting the refining method of the metformin hydrochloride.

Optionally, the sustained release agent comprises hypromellose and ethylcellulose;

the adhesive is an ethanol solution of ethyl cellulose with the mass content of 5%.

Optionally, the mass ratio of the hydroxypropyl methylcellulose to the ethyl cellulose is 1 (3-4).

Optionally, the lubricant is magnesium stearate.

Optionally, the metformin hydrochloride sustained-release tablet comprises the following raw materials in parts by weight:

45-65 parts of metformin hydrochloride, 10 parts of hydroxypropyl methylcellulose, 30-40 parts of ethyl cellulose, 3-8 parts of magnesium stearate and 2-6 parts of ethyl cellulose ethanol solution with the mass content of 5%.

The invention also provides a preparation method of the metformin hydrochloride sustained release tablet, which comprises the following steps:

uniformly mixing metformin hydrochloride and the sustained-release agent according to the selected weight part, adding the adhesive, granulating, drying, adding the lubricant, uniformly mixing and tabletting to obtain the metformin hydrochloride sustained-release tablet.

Due to the adoption of the technical scheme, the invention has the technical progress that:

1. the existing method for refining the metformin hydrochloride is to refine the metformin hydrochloride product by using 80 to 95 percent ethanol or pure water by volume fraction.

The inventor finds that the metformin hydrochloride product refined by the existing refining method has unqualified clarity, directly influences the release speed of the metformin hydrochloride sustained release tablet, causes the release speed and blood concentration of the metformin hydrochloride sustained release tablet within 24 hours to be unstable, and is easy to have the phenomenon of burst release or incomplete release.

The invention provides a method for refining metformin hydrochloride, which adopts a specific 65-70% ethanol water solution in volume fraction as a refining solvent, combines concentrated hydrochloric acid to adjust the pH value to 2-3, and obtains a metformin hydrochloride product with qualified clarity; the metformin hydrochloride sustained release tablet prepared by using the metformin hydrochloride product refined by the refining method as a raw material can reach the quality regulation in the USP32 standard, and can be stably released at a certain speed within 24h and maintain stable blood concentration so as to achieve good treatment effect.

2. The invention provides a method for refining metformin hydrochloride, which is characterized in that the mass ratio of a metformin hydrochloride crude product to a 65-70% ethanol aqueous solution in volume fraction is limited to be 1: (1.2-1.5) and the pH adjusting step are combined, so that the clarity of the refined metformin hydrochloride can be further improved, and the stability of the release speed of the metformin hydrochloride sustained-release tablets prepared by taking the metformin hydrochloride product refined by the refining method as a raw material within 24 hours can be further obviously improved.

3. The metformin hydrochloride sustained release tablet provided by the invention adopts a specific 65-70% ethanol water solution in volume fraction as a refining solvent, combines concentrated hydrochloric acid to adjust the pH value to 2-3, and uses a metformin hydrochloride product obtained by refining as a raw material to prepare the metformin hydrochloride sustained release tablet which can reach the quality regulation in the USP32 standard of United states pharmacopoeia: the medicine is released steadily within 24h at a certain speed, and the steady blood concentration is maintained, so that the medicine achieves good treatment effect.

4. The metformin hydrochloride sustained release tablet provided by the invention has the advantages that the hydroxypropyl methylcellulose and the ethyl cellulose are used as sustained release agents, and the specific ethanol solution of the ethyl cellulose with the mass content of 5% is used as a binder, so that the stability of the release speed of the metformin hydrochloride sustained release tablet within 24 hours can be further improved.

5. The metformin hydrochloride sustained release tablet provided by the invention can further improve the stability of the release speed of the metformin hydrochloride sustained release tablet within 24h by further limiting the mass ratio of hydroxypropyl methylcellulose to ethyl cellulose in the sustained release agent to be 1 (3-4), so that the blood concentration stably reaches a good treatment effect.

6. The preparation method of the metformin hydrochloride sustained release tablet provided by the invention is simple and convenient, and easy to industrialize, and the prepared metformin hydrochloride sustained release tablet can reach the quality regulation in the USP32 standard, and can be stably released at a certain speed within 24h, and the stable blood concentration is maintained, so that a good treatment effect is achieved.

Detailed Description

The present invention will be described in further detail with reference to the following examples:

example 1

The embodiment provides a method for refining metformin hydrochloride, which comprises the following steps:

dissolving 10kg of metformin hydrochloride crude product in 15kg of ethanol water solution with volume fraction of 68%, heating and refluxing for 50min, naturally cooling to room temperature, adjusting the pH value of the system to 3 by using concentrated hydrochloric acid, then cooling to 2 ℃, crystallizing for 4h, filtering, washing a filter cake by using 15kg of absolute ethanol, and drying the washed filter cake for 7h at 48 ℃ to obtain the metformin hydrochloride product.

The metformin hydrochloride product was subjected to a clarity examination according to the first method (visual method) of the general rules of the clarity examination method of 0902 in accordance with the "chinese pharmacopoeia" on the 2015 edition, and the results showed that the aqueous solution of metformin hydrochloride was clear.

Example 2

The embodiment provides a method for refining metformin hydrochloride, which comprises the following steps:

dissolving 10kg of metformin hydrochloride crude product in 12kg of ethanol aqueous solution with volume fraction of 65%, heating and refluxing for 60min, naturally cooling to room temperature, adjusting the pH value of the system to be 2 by using concentrated hydrochloric acid, then cooling to 3 ℃, crystallizing for 5h, filtering, washing a filter cake by using 12kg of absolute ethanol, and drying the washed filter cake for 6h at 50 ℃ to obtain the metformin hydrochloride product.

The metformin hydrochloride product was checked for clarity by the first method (visual method) of the general rules of the clarity inspection method of 0902 in accordance with the "chinese pharmacopoeia" on the 2015 edition, and the results showed that the aqueous solution of metformin hydrochloride was clear.

Example 3

The embodiment provides a method for refining metformin hydrochloride, which comprises the following steps:

dissolving 10kg of metformin hydrochloride crude product in 13kg of 70% ethanol water solution with volume fraction, heating and refluxing for 55min, naturally cooling to room temperature, adjusting the pH value of the system to be 2 by using concentrated hydrochloric acid, then cooling to 0 ℃, crystallizing for 3h, filtering, washing a filter cake by using 10kg of absolute ethanol, and drying the washed filter cake for 6.5h at 45 ℃ to obtain the metformin hydrochloride product.

The metformin hydrochloride product was subjected to a clarity examination according to the first method (visual method) of the general rules of the clarity examination method of 0902 in accordance with the "chinese pharmacopoeia" on the 2015 edition, and the results showed that the aqueous solution of metformin hydrochloride was clear.

Example 4

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1, 100g of hydroxypropyl methylcellulose and 350g of ethyl cellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin hydrochloride sustained release tablet.

Example 5

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 650g of metformin hydrochloride prepared in example 2, 100g of hydroxypropyl methylcellulose and 400g of ethyl cellulose, adding 60g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 40 ℃ for 3h, taking out, granulating by using the 18-mesh sieve, adding 30g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin hydrochloride sustained release tablet.

Example 6

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 500g of metformin hydrochloride prepared in example 3, 100g of hydroxypropyl methylcellulose and 300g of ethyl cellulose, adding 20g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 60 ℃ for 1h, taking out, granulating by using the 18-mesh sieve, adding 50g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin hydrochloride sustained release tablet.

Example 7

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1, 100g of hydroxypropyl methylcellulose and 350g of ethyl cellulose, adding 40g of ethanol solution of povidone with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tablet press to obtain the metformin hydrochloride sustained release tablet.

Example 8

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1, 100g of hydroxypropyl methylcellulose and 350g of ethyl cellulose, adding 20g of povidone ethanol solution with the mass content of 5% and 20g of sodium carboxymethyl cellulose, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tablet press to obtain the metformin hydrochloride sustained release tablet.

Example 9

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1 and 450g of ethyl cellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin hydrochloride sustained release tablet.

Example 10

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1 and 450g of hypromellose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting to obtain the metformin hydrochloride sustained release tablet.

Example 11

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1 and 450g of sodium carboxymethylcellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin hydrochloride sustained-release tablet.

Example 12

The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in example 1, 200g of hydroxypropyl methylcellulose and 250g of ethyl cellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine to obtain the metformin hydrochloride sustained release tablet.

Comparative example 1

The comparative example provides a method for refining metformin hydrochloride, comprising the following steps:

dissolving 10kg of metformin hydrochloride crude product in 15kg of ethanol water solution with volume fraction of 80%, heating and refluxing for 50min, naturally cooling to room temperature, adjusting the pH value of the system to 3 by using concentrated hydrochloric acid, then cooling to 2 ℃, crystallizing for 4h, filtering, washing a filter cake by using 15kg of absolute ethanol, and drying the washed filter cake for 7h at 48 ℃ to obtain the metformin hydrochloride product.

The clarity of the metformin hydrochloride product was examined by the first method (visual method) of the general rules of the visibility examination method of 0902 in accordance with the general rules of "chinese pharmacopoeia" on the 2015 edition, and the results showed that the metformin hydrochloride aqueous solution contained insoluble substances and was not clarified.

Comparative example 2

The comparative example provides a method for refining metformin hydrochloride, comprising the following steps:

dissolving 10kg of metformin hydrochloride crude product in 15kg of ethanol water solution with volume fraction of 68%, heating and refluxing for 50min, naturally cooling to room temperature, then cooling to 2 ℃ for crystallization for 4h, filtering, washing a filter cake with 15kg of absolute ethanol, and drying the washed filter cake at 48 ℃ for 7h to obtain the metformin hydrochloride product.

The clarity of the metformin hydrochloride product was examined by the first method (visual method) of the general rules of the visibility examination method of 0902 in accordance with the general rules of "chinese pharmacopoeia" on the 2015 edition, and the results showed that the metformin hydrochloride aqueous solution contained insoluble substances and was not clarified.

Comparative example 3

The comparative example provides a method for refining metformin hydrochloride, comprising the following steps:

dissolving 10kg of metformin hydrochloride crude product in 15kg of ethanol water solution with volume fraction of 68%, heating and refluxing for 50min, naturally cooling to room temperature, adjusting the pH value of the system to 5 by using concentrated hydrochloric acid, then cooling to 2 ℃, crystallizing for 4h, filtering, washing a filter cake by using 15kg of absolute ethanol, and drying the washed filter cake for 7h at 48 ℃ to obtain the metformin hydrochloride product. The product metformin hydrochloride 1g was placed in 200mL of water and the clarity was off-specification.

Comparative example 4

The comparative example provides a metformin hydrochloride sustained release tablet, and the preparation method comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in the comparative example 1, 100g of hydroxypropyl methylcellulose and 350g of ethyl cellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tablet press to obtain the metformin hydrochloride sustained release tablet.

Comparative example 5

The comparative example provides a metformin hydrochloride sustained release tablet, and the preparation method comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in the comparative example 2, 100g of hydroxypropyl methylcellulose and 350g of ethyl cellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tablet press to obtain the metformin hydrochloride sustained release tablet.

Comparative example 6

The comparative example provides a metformin hydrochloride sustained release tablet, and the preparation method comprises the following steps:

uniformly mixing 450g of metformin hydrochloride prepared in the comparative example 3, 100g of hydroxypropyl methylcellulose and 350g of ethyl cellulose, adding 40g of ethyl cellulose ethanol solution with the mass content of 5%, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 80g of magnesium stearate, uniformly mixing, and tabletting by using a tablet press to obtain the metformin hydrochloride sustained release tablet.

Experimental example 1

The metformin hydrochloride sustained-release tablets obtained in examples 4 to 11 and comparative examples 4 to 6 were examined for identification reaction, related substances, difference in tablet weight and measurement of content, respectively, according to the relevant regulations in pharmacopoeia of the people's republic of China 2015 edition. Wherein, the identification reaction of the cyanide adopts 10 percent of sodium nitrosoferricyanide solution-sodium ferricyanide test solution-10 percent of sodium hydroxide solution; the related substances are checked by high performance liquid chromatography; the content determination adopts ultraviolet spectrophotometry to determine the content of the main drug in the metformin hydrochloride sustained release tablet. All the above items all meet the requirements of pharmacopoeia.

The metformin hydrochloride sustained-release tablets obtained in examples 4 to 11 and comparative examples 4 to 6 and the original preparation (Glucophage XR of Bristol-Myers-Squibb Company (BMS)) were subjected to dissolution examination, and the medium was selected from a hydrochloric acid solution having ph1.2, an acetate buffer solution having ph4.5, a phosphate buffer solution having ph6.8, and water (2015 version of chinese pharmacopoeia) 900mL, by a second method (paddle method) of dissolution measurement of 0931, which is a general rule of the four ministry of the national pharmacopoeia 2015, with a rotation speed set at 50rpm and a temperature set at 37 ℃, and dissolution was measured at different times. The results are shown in the following table.

TABLE 1 dissolution data (pH1.2 hydrochloric acid solution) for the time points

Time (h)	1	3	10	20	24
						Example 4	27.80％	50.03％	64.51％	83.41％	100.01％
Example 5	27.53％	49.76％	65.17％	84.21％	100.10％
						Example 6	28.31％	49.85％	64.89％	85.01％	100.06％
Example 7	23.67％	45.13％	60.57％	80.78％	99.98％
						Example 8	24.29％	46.82％	61.21％	81.26％	99.99％
Example 9	25.11％	46.81％	61.03％	81.14％	100.03％
						Example 10	23.76％	45.76％	60.38％	80.49％	99.76％
Example 11	24.82％	45.92％	60.97％	80.99％	99.89％
						Example 12	24.39％	46.41％	62.52％	83.48％	100.03％
Comparative example 4	69.81％	82.10％	99.01％	100.17％	--
						Comparative example 5	68.93％	83.02％	99.21％	100.26％	--
Comparative example 6	10.74％	40.32％	57.92％	69.87％	82.67％
						Original preparation	25.75％	51.31％	64.76％	83.42％	100.32％

TABLE 2 dissolution data (pH4.5 acetate buffer) for each time point

TABLE 3 dissolution data (pH6.8 phosphate buffer) at the time points

Table 4 dissolution data (water) at each time point

Time (h)	1	3	10	20	24
						Example 4	25.17％	48.96％	76.37％	100.21％	102.00％
Example 5	26.74％	47.56％	75.42％	100.06％	101.89％
						Example 6	25.65％	48.99％	75.96％	100.68％	102.31％
Example 7	22.92％	45.70％	70.24％	99.99％	101.11％
						Example 8	22.78％	45.61％	70.37％	99.96％	100.99％
Example 9	22.41％	45.93％	70.39％	99.89％	101.27％
						Example 10	21.47％	44.31％	69.88％	99.67％	101.35％
Example 11	21.80％	44.11％	69.45％	99.78％	101.21％
						Example 12	23.76％	45.13％	71.14％	100.37％	102.35％
Comparative example 4	96.74％	100.03％	--	--	--
						Comparative example 5	95.21％	100.29％	--	--	--
Comparative example 6	5.13％	12.94％	35.98％	43.28％	59.47％
						Original preparation	23.17％	47.94％	75.63％	100.26％	102.31％

The data in the table show that the metformin hydrochloride sustained release tablet provided by the invention has no phenomena of uneven drug release and burst release, and can reach the quality regulation in the United states pharmacopoeia USP32 standard: the medicine is released stably within 24h at a certain speed, so that the blood concentration is stable and a good treatment effect is achieved; completely meets the requirement of one-time administration for 24h in clinic; the quality and clinical curative effect of the traditional Chinese medicine preparation are consistent.

Experimental example 2

The metformin hydrochloride sustained release tablets prepared in examples 4 to 11 were subjected to a human bioavailability equivalence comparison test study of the metformin hydrochloride sustained release tablets by adopting a double-crossover design and using pharmacokinetic parameters (Cmax, AUC) as main analytical indexes. The reference drug was Glucophage XR from Bristol-Myers-Squibb Company (BMS).

Absorption: the metformin sustained release tablet is absorbed from stomach and intestine after being taken orally, and the average value of the peak reaching time of the blood concentration is 7 h. Metformin absorption can be increased by about 50% when taken with food, but has no effect on its Cmax and Tmax. The effect of the high-fat diet and the low-fat diet on the pharmacokinetic parameters of the metformin sustained release tablet was similar. When the metformin sustained-release tablet is taken for a plurality of times, the metformin can not accumulate in blood plasma.

Distribution: the binding rate of metformin to plasma proteins is negligible, corresponding to plasma protein binding rates of over 90% for sulfonylurea drugs. Metformin can enter erythrocytes and is most likely related to its duration of action. When the metformin sustained release tablet is taken at the clinical dose of 500 mg/time, the steady blood concentration reaches not less than 1 mug/mL within 24-48 h.

Metabolism and excretion: metformin is excreted in its original form from urine, without being metabolized by the liver, and also without being excreted by bile. Renal clearance is approximately 3.5 times that of creatinine, indicating that transtubular excretion is the major pathway for metformin clearance. After oral administration, about 90% of the absorbed drug is eliminated by the renal route within 24h, and the plasma elimination half-life is about 6.2 h. In blood, the elimination half-life of the drug is about 17.6 h.