CN112645845A - Purification method of metformin hydrochloride, metformin hydrochloride sustained-release tablet and preparation method thereof - Google Patents
Purification method of metformin hydrochloride, metformin hydrochloride sustained-release tablet and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a method for purifying metformin hydrochloride, a metformin hydrochloride sustained-release tablet and a preparation method thereof. The purification method of the metformin hydrochloride comprises the following steps: dissolving the metformin hydrochloride crude product in 70-75% ethanol water solution, adding activated carbon, adjusting pH to 3-5 with concentrated hydrochloric acid, heating and refluxing, filtering, cooling and crystallizing, separating, washing, and drying to obtain the final product. The specific ethanol water solution with the volume fraction of 70-75% is used as a purification solvent, and is combined with activated carbon to decolorize under the condition that the pH value is 3-5, so that the solution of the metformin hydrochloride product obtained by purification is qualified in color; the metformin hydrochloride sustained release tablet prepared from the metformin hydrochloride product has excellent stability, and can still keep stable release at a certain speed within 24 hours and maintain stable blood concentration after a stability acceleration test is carried out.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a method for purifying metformin hydrochloride, a metformin hydrochloride sustained-release tablet and a preparation method thereof.
Background
Metformin hydrochloride is a biguanide oral hypoglycemic agent, is used for treating non-insulin dependent diabetes mellitus, and is an antidiabetic agent which can control the blood sugar level and improve macrovascular complications. Metformin hydrochloride has good hypoglycemic effect, can reduce the risk of blood fat and cardiovascular diseases, has the advantages of long-term medication safety, high cost performance and the like, and is widely recommended to be first-line medication of type II diabetes.
Metformin hydrochloride is a very water-soluble drug, the half-life period of a common oral preparation is short, and a large amount of repeated medication is needed to maintain the effective blood concentration (3 times a day, 500mg each time), which very easily causes great fluctuation of the blood concentration in vivo and causes adverse reaction. Therefore, in order to provide a sustained and stable blood concentration to better exert its hypoglycemic effect, a sustained-release formulation of metformin hydrochloride has been developed to increase patient compliance.
The regulation of Chinese pharmacopoeia indicates that the slow-release preparation is a preparation which is slowly released by oral medicines in a regulated release medium according to a requirement and at a non-constant speed, and compared with other corresponding ordinary preparations, the frequency of taking medicines every 24 hours is reduced from 3-4 times to 1-2 times. However, the existing metformin hydrochloride sustained-release tablets have the defects of uneven drug release, easy occurrence of burst release or incomplete release, and incapability of maintaining stable blood concentration so as to achieve good treatment effect.
Aiming at the defects, the sustained-release material is tightly combined with metformin hydrochloride by adding a certain stabilizing agent and a release regulator and preparing the sustained-release material by a hot-melt extrusion technology in the prior art, so that the drug release and dissolution are smooth and have no burst release. However, the metformin hydrochloride sustained-release tablets prepared by the method have poor stability, and are easy to have burst release or incomplete release after a stability acceleration test is carried out according to the relevant requirements of pharmacopoeia of the people's republic of China 2015 edition.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the metformin hydrochloride sustained-release tablet with good stability and the preparation method thereof.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for purifying metformin hydrochloride comprises the following steps: dissolving the metformin hydrochloride crude product in 70-75% ethanol water solution, adding activated carbon, adjusting pH to 3-5 with concentrated hydrochloric acid, heating and refluxing, filtering, cooling and crystallizing, separating, washing, and drying to obtain the final product.
The metformin hydrochloride crude product is prepared by the 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 the ethanol aqueous solution with the volume fraction of 70-75% is 1: (1.7-2.0);
the mass ratio of the metformin hydrochloride crude product to the activated carbon is 1: (0.1-0.3).
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 metformin hydrochloride purified by the metformin hydrochloride purification method.
The invention also provides a metformin hydrochloride sustained release tablet, which comprises the following raw materials in parts by weight:
30-70 parts of metformin hydrochloride, 30-60 parts of sustained release agent, 1-10 parts of lubricant and 1-8 parts of adhesive;
the metformin hydrochloride is obtained by adopting the purification 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 (2-3).
Optionally, the lubricant is magnesium stearate.
Optionally, the metformin hydrochloride sustained-release tablet comprises the following raw materials in parts by weight:
30-70 parts of metformin hydrochloride, 10-15 parts of hydroxypropyl methylcellulose, 20-45 parts of ethyl cellulose, 1-10 parts of magnesium stearate and 1-8 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 solution refined by the existing refining method has unqualified color, 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 purifying metformin hydrochloride, which comprises the steps of adopting a specific ethanol water solution with the volume fraction of 70-75% as a purification solvent, decoloring by combining with activated carbon under the condition that the pH value is 3-5, and obtaining a metformin hydrochloride product through purification, wherein the solution color is qualified; the metformin hydrochloride sustained release tablet prepared by taking the metformin hydrochloride product purified by the purification method as a raw material has excellent stability, and can still keep stable release at a certain speed within 24h and maintain stable blood concentration to achieve good treatment effect after a stability acceleration test is carried out according to the related requirements of the pharmacopoeia of the people's republic of China 2015 edition.
2. The invention provides a method for purifying metformin hydrochloride, which is characterized in that the mass ratio of a metformin hydrochloride crude product to an ethanol aqueous solution with the volume fraction of 70-75% is limited to be 1: (1.7-2.0), and the addition of activated carbon and the pH adjustment step are combined, so that the color and yield of the solution of the metformin hydrochloride obtained by purification can be further improved, the stability of the release speed of the metformin hydrochloride sustained release tablet prepared by taking the metformin hydrochloride product obtained by purification by the purification method as a raw material within 24h is further remarkably improved, and particularly the stability of the release speed within 24h after a stability acceleration test is improved.
3. The metformin hydrochloride sustained release tablet provided by the invention is prepared by adopting a specific ethanol aqueous solution with the volume fraction of 70-75% as a purification solvent, decoloring by adding activated carbon under the condition of pH value of 3-5, and using a metformin hydrochloride product obtained by purification as a raw material, and has excellent stability, and can still keep stable release at a certain speed within 24h and maintain stable blood concentration to achieve good treatment effect after a stability acceleration test is carried out according to the related requirements of pharmacopoeia 2015 edition of the people's republic of China by combining the specific dosage of each raw material in the metformin hydrochloride sustained release tablet.
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 metformin hydrochloride sustained release tablet can be further improved.
5. The invention provides a metformin hydrochloride sustained release tablet, which is prepared by further limiting the mass ratio of hydroxypropyl methylcellulose to ethyl cellulose in a sustained release agent to be 1: (2-3), the stability of the metformin hydrochloride sustained release tablet can be further improved, and the stability of the release speed within 24 hours can be kept, so that the blood concentration is stable and a good treatment effect is achieved.
6. The preparation method of the metformin hydrochloride sustained release tablet provided by the invention is simple and convenient, is easy to industrialize, and the prepared metformin hydrochloride sustained release tablet has good stability, can reach the quality regulation in the USP32 standard, can be stably released at a certain speed within 24h, and can maintain stable blood concentration so as to achieve good treatment effect.
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 purifying metformin hydrochloride, which comprises the following steps:
dissolving 100kg of metformin hydrochloride crude product in 200kg of 70% ethanol water solution with volume fraction, adding 20kg of activated carbon, adjusting the pH value of the system to be 3 by concentrated hydrochloric acid, heating and refluxing for 50min, naturally cooling to room temperature, filtering, cooling the filtered filtrate to 2 ℃, crystallizing for 4h, filtering again, washing the filter cake by 150kg of absolute ethanol, and drying the washed filter cake for 7h at 50 ℃ to obtain the metformin hydrochloride product.
The metformin hydrochloride product is checked for clarity according to a first method (visual method) in the general rules of the 2015 version Chinese pharmacopoeia general rule 0902 clarity checking method, and the first method (visual method) in the 2015 version Chinese pharmacopoeia general rule 0901 solution color checking method is used for checking the solution color; the results showed that the aqueous solution of metformin hydrochloride was clear and colorless.
Example 2
The embodiment provides a method for purifying metformin hydrochloride, which comprises the following steps:
dissolving 100kg of metformin hydrochloride crude product in 180kg of 75% ethanol water solution with volume fraction, adding 30kg of activated carbon, adjusting the pH value of the system to be 5 by concentrated hydrochloric acid, heating and refluxing for 55min, naturally cooling to room temperature, filtering, cooling the filtered filtrate to 0 ℃, crystallizing for 4h, filtering again, washing the filter cake by 150kg of absolute ethanol, and drying the washed filter cake for 6h at 45 ℃ to obtain the metformin hydrochloride product.
The metformin hydrochloride product is checked for clarity according to a first method (visual method) in the general rules of the 2015 version Chinese pharmacopoeia general rule 0902 clarity checking method, and the first method (visual method) in the 2015 version Chinese pharmacopoeia general rule 0901 solution color checking method is used for checking the solution color; the results showed that the aqueous solution of metformin hydrochloride was clear and colorless.
Example 3
The embodiment provides a method for purifying metformin hydrochloride, which comprises the following steps:
dissolving 100kg of metformin hydrochloride crude product in 170kg of 73% ethanol water solution by volume fraction, adding 10kg of activated carbon, adjusting the pH value of the system to be 4 by concentrated hydrochloric acid, heating and refluxing for 60min, naturally cooling to room temperature, filtering, cooling the filtered filtrate to-5 ℃, crystallizing for 3h, filtering again, washing the filter cake by 150kg of absolute ethanol, and drying the washed filter cake for 7h at 48 ℃ to obtain the metformin hydrochloride product.
The metformin hydrochloride product is checked for clarity according to a first method (visual method) in the general rules of the 2015 version Chinese pharmacopoeia general rule 0902 clarity checking method, and the first method (visual method) in the 2015 version Chinese pharmacopoeia general rule 0901 solution color checking method is used for checking the solution color; the results showed that the aqueous solution of metformin hydrochloride was clear and colorless.
Example 4
The embodiment provides a metformin hydrochloride sustained release tablet, and the preparation method thereof comprises the following steps:
uniformly mixing 300g of metformin hydrochloride prepared in example 1, 100g of hydroxypropyl methylcellulose and 200g of ethyl cellulose, adding 80g 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 1000g 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 700g of metformin hydrochloride prepared in example 2, 150g of hydroxypropyl methylcellulose 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 40 ℃ for 3h, taking out, granulating by using the 18-mesh sieve, adding 10g 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, 120g of hydroxypropyl methylcellulose and 300g of ethyl cellulose, adding 10g 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 300g of metformin hydrochloride prepared in example 1, 100g of hydroxypropyl methylcellulose and 200g of ethyl cellulose, adding 80g 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 1000g 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 300g of metformin hydrochloride prepared in example 1, 100g of hydroxypropyl methylcellulose and 200g of ethyl cellulose, adding 20g of povidone ethanol solution with the mass content of 5% and 60g of sodium carboxymethylcellulose, uniformly mixing, granulating by using a 18-mesh sieve, drying at 50 ℃ for 2h, taking out, granulating by using the 18-mesh sieve, adding 1000g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine 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 300g of metformin hydrochloride prepared in example 1 and 300g of ethyl cellulose, adding 80g 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 1000g 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 300g of metformin hydrochloride prepared in example 1 with 300g of hypromellose, adding 80g 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 1000g of magnesium stearate, uniformly mixing, and tabletting by using a tabletting machine 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 300g of metformin hydrochloride prepared in example 1 with 300g of sodium carboxymethylcellulose, adding 80g 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 1000g 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 300g of metformin hydrochloride prepared in example 1, 150g of hydroxypropyl methylcellulose and 150g of ethyl cellulose, adding 80g 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 1000g 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 purifying metformin hydrochloride, comprising the following steps:
dissolving 10kg of metformin hydrochloride crude product in 20kg of ethanol water solution with volume fraction of 70%, adjusting the pH value of the system to 3 by concentrated hydrochloric acid, heating and refluxing for 50min, naturally cooling to room temperature, filtering, cooling the filtered filtrate to 2 ℃, crystallizing for 4h, filtering again, washing the filter cake by 15kg of absolute ethanol, and drying the washed filter cake at 50 ℃ for 7h to obtain the metformin hydrochloride product.
The metformin hydrochloride product is checked for clarity according to a first method (visual method) in the general rules of the 2015 version Chinese pharmacopoeia general rule 0902 clarity checking method, and the first method (visual method) in the 2015 version Chinese pharmacopoeia general rule 0901 solution color checking method is used for checking the solution color; the results show that the aqueous solution of metformin hydrochloride is not clear, darker in color and the solution is not acceptable in color compared to the control tube.
Comparative example 2
The comparative example provides a method for purifying metformin hydrochloride, comprising the following steps:
dissolving 10kg of metformin hydrochloride crude product in 20kg of ethanol water solution with volume fraction of 70%, then adding 2kg of activated carbon, heating and refluxing for 50min, naturally cooling to room temperature, filtering, cooling the filtered filtrate to 2 ℃, crystallizing for 4h, filtering again, washing the filter cake with 15kg of absolute ethanol, and drying the washed filter cake for 7h at 50 ℃ to obtain the metformin hydrochloride product.
The metformin hydrochloride product is checked for clarity according to a first method (visual method) in the general rules of the 2015 version Chinese pharmacopoeia general rule 0902 clarity checking method, and the first method (visual method) in the 2015 version Chinese pharmacopoeia general rule 0901 solution color checking method is used for checking the solution color; the results show that the aqueous solution of metformin hydrochloride is not clear, darker in color and the solution is not acceptable in color compared to the control tube.
Comparative example 3
The comparative example provides a method for purifying metformin hydrochloride, comprising the following steps:
dissolving 10kg of metformin hydrochloride crude product in 20kg of ethanol water solution with volume fraction of 70%, then adding 2kg of activated carbon, adjusting the pH value of the system to 1 by concentrated hydrochloric acid, heating and refluxing for 50min, naturally cooling to room temperature, filtering, cooling the filtered filtrate to 2 ℃, crystallizing for 4h, filtering again, washing the filter cake by 15kg of absolute ethanol, and drying the washed filter cake for 7h at 50 ℃ to obtain the metformin hydrochloride product.
The metformin hydrochloride product is checked for clarity according to a first method (visual method) in the general rules of the 2015 version Chinese pharmacopoeia general rule 0902 clarity checking method, and the first method (visual method) in the 2015 version Chinese pharmacopoeia general rule 0901 solution color checking method is used for checking the solution color; the results show that the aqueous solution of metformin hydrochloride is not clear, darker in color and the solution is not acceptable in color compared to the control tube.
Comparative example 4
The comparative example provides a metformin hydrochloride sustained release tablet, and the preparation method comprises the following steps:
uniformly mixing 300g of metformin hydrochloride prepared in the comparative example 1, 100g of hydroxypropyl methylcellulose and 200g of ethyl cellulose, adding 80g 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 1000g 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 300g of metformin hydrochloride prepared in the comparative example 2, 100g of hydroxypropyl methylcellulose and 200g of ethyl cellulose, adding 80g 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 1000g 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 300g of metformin hydrochloride prepared in the comparative example 3, 100g of hydroxypropyl methylcellulose and 200g of ethyl cellulose, adding 80g 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 1000g 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
TABLE 2 dissolution data (pH4.5 acetate buffer) for each time point
| Time (h) | 1 | 3 | 10 | 20 | 24 |
| Example 4 | 20.13％ | 44.56％ | 75.19％ | 96.59％ | 99.59％ |
| Example 5 | 21.54％ | 46.27％ | 77.37％ | 95.64％ | 100.06％ |
| Example 6 | 19.76％ | 45.91％ | 78.46％ | 96.18％ | 100.97％ |
| Example 7 | 15.37％ | 40.61％ | 71.03％ | 90.31％ | 98.86％ |
| Example 8 | 16.26％ | 41.59％ | 72.31％ | 91.24％ | 99.12％ |
| Example 9 | 15.31％ | 40.30％ | 71.27％ | 91.53％ | 99.60％ |
| Example 10 | 17.22％ | 42.81％ | 72.60％ | 91.61％ | 99.77％ |
| Example 11 | 16.35％ | 40.79％ | 71.44％ | 90.00％ | 99.00％ |
| Example 12 | 15.05％ | 39.12％ | 70.10％ | 89.61％ | 98.18％ |
| Comparative example 4 | 99.12％ | 102.37％ | -- | -- | -- |
| Comparative example 5 | 68.79％ | 96.84％ | 102.19％ | -- | -- |
| Comparative example 6 | 6.40％ | 16.82％ | 26.37％ | 56.44％ | 71.02％ |
| Original preparation | 19.21％ | 45.34％ | 76.41％ | 98.81％ | 100.53％ |
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 | 20.73％ | 42.57％ | 76.19％ | 99.34％ | 101.68％ |
| Example 5 | 23.25％ | 43.31％ | 77.60％ | 100.92％ | 103.73％ |
| Example 6 | 21.61％ | 42.20％ | 75.73％ | 99.49％ | 102.52％ |
| Example 7 | 19.12％ | 39.92％ | 71.01％ | 95.10％ | 100.31％ |
| Example 8 | 18.94％ | 38.45％ | 70.32％ | 94.07％ | 99.49％ |
| Example 9 | 17.36％ | 38.08％ | 72.70％ | 96.33％ | 100.07％ |
| Example 10 | 16.47％ | 37.74％ | 70.19％ | 94.68％ | 98.24％ |
| Example 11 | 18.08％ | 40.53％ | 72.55％ | 95.94％ | 101.67％ |
| Example 12 | 15.42％ | 37.84％ | 70.05％ | 93.41％ | 99.94％ |
| Comparative example 4 | 74.14％ | 96.61％ | 102.33％ | -- | -- |
| Comparative example 5 | 86.07％ | 100.37％ | -- | -- | - |
| Comparative example 6 | 10.39％ | 21.61％ | 38.92％ | 46.78％ | 68.50％ |
| Original preparation | 22.96％ | 47.46％ | 74.88％ | 100.07％ | 102.12％ |
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 and reaches the quality and the clinical curative effect consistent with the original preparation.
Experimental example 2
According to the relevant regulations in pharmacopoeia of the people's republic of China 2015 edition, the stability of the metformin hydrochloride sustained release tablets prepared in examples 4-11 and comparative examples 4-6 is researched, items such as 60 ℃, strong light (4500Lx) irradiation, accelerated test (simulating that packages on the market are placed at 40 ℃), room stability sample observation and the like are investigated, and degradation products, content and the like are measured. The experimental results show that: after the stability test, the metformin hydrochloride sustained release tablets prepared in the embodiments 4 to 11 of the invention have no obvious change in various investigation indexes compared with those before placement.
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 heating at 60 ℃ for 10 days and strong light (4500Lx) irradiation for 10 days, and then dissolution was examined by selecting 900mL of a hydrochloric acid solution having a ph of 1.2, an acetate buffer having a ph of 4.5, a phosphate buffer having a ph of 6.8, and water (2015 version of chinese pharmacopoeia) in the medium according to the second method for dissolution measurement (paddle method) of 0931 by the four-part general rule of the 2015 version of chinese pharmacopoeia, wherein the rotation speed was set to 50rpm, the temperature was set to 37 ℃, and dissolution rates at different times were measured. The results are shown in the following table.
TABLE 560 dissolution data (pH1.2 hydrochloric acid solution) at each time point after 10 days of heating at 560 ℃ and 10 days of intense light (4500Lx) irradiation
TABLE 660 degree of dissolution data (pH4.5 acetate buffer) at various time points after 10 days of heating at 660 ℃ and 10 days of intense light (4500Lx) irradiation
| Time (h) | 1 | 3 | 10 | 20 | 24 |
| Example 4 | 15.34％ | 40.51％ | 74.86％ | 95.42％ | 99.76％ |
| Example 5 | 17.21％ | 39.70％ | 75.05％ | 98.54％ | 101.30％ |
| Example 6 | 18.59％ | 44.34％ | 76.17％ | 97.09％ | 100.51％ |
| Example 7 | 14.24％ | 40.49％ | 71.03％ | 94.12％ | 99.53％ |
| Example 8 | 15.53％ | 38.31％ | 70.57％ | 93.95％ | 98.19％ |
| Example 9 | 14.71％ | 37.25％ | 69.91％ | 92.34％ | 98.87％ |
| Example 10 | 16.48％ | 39.17％ | 69.04％ | 92.11％ | 99.10％ |
| Example 11 | 15.90％ | 38.66％ | 70.26％ | 93.80％ | 100.63％ |
| Example 12 | 15.76％ | 37.51％ | 71.47％ | 94.38％ | 101.06％ |
| Comparative example 4 | 79.84％ | 100.17％ | -- | -- | -- |
| Comparative example 5 | 70.52％ | 90.34％ | 100.77％ | -- | -- |
| Comparative example 6 | 5.35％ | 18.66％ | 31.42％ | 57.25％ | 69.58％ |
| Original preparation | 16.6％ | 42.76％ | 75.68％ | 96.22％ | 100.03％ |
TABLE 760 ℃ dissolution data (pH6.8 phosphate buffer) at various time points after 10 days of heating at 760 ℃ and 10 days of intense light (4500Lx) irradiation
TABLE 860 deg.C 10 days, 10 days after intense light (4500Lx) irradiation dissolution data (water) at each time point
| Time (h) | 1 | 3 | 10 | 20 | 24 |
| Example 4 | 21.37％ | 43.50％ | 68.12％ | 98.71％ | 100.57％ |
| Example 5 | 19.29％ | 42.16％ | 67.83％ | 99.36％ | 102.33％ |
| Example 6 | 22.71％ | 45.49％ | 69.08％ | 100.64％ | 101.94％ |
| Example 7 | 16.13％ | 42.35％ | 64.31％ | 95.21％ | 101.47％ |
| Example 8 | 16.47％ | 41.27％ | 61.50％ | 93.91％ | 99.96％ |
| Example 9 | 17.50％ | 43.63％ | 62.44％ | 92.53％ | 100.61％ |
| Example 10 | 15.09％ | 40.71％ | 60.73％ | 90.40％ | 98.70％ |
| Example 11 | 18.82％ | 44.89％ | 63.26％ | 91.09％ | 101.09％ |
| Example 12 | 19.38％ | 40.83％ | 64.67％ | 92.87％ | 101.64％ |
| Comparative example 4 | 70.93％ | 103.59％ | -- | -- | -- |
| Comparative example 5 | 65.13％ | 83.42％ | 102.19％ | -- | -- |
| Comparative example 6 | 6.79％ | 21.89％ | 49.72％ | 63.01％ | 76.28％ |
| Original preparation | 20.51％ | 44.39％ | 69.46％ | 99.88％ | 101.11％ |
The data in the table show that the metformin hydrochloride sustained release tablet provided by the invention has excellent stability, and after being heated at 60 ℃ for 10 days and irradiated by strong light (4500Lx) for 10 days, the metformin hydrochloride sustained release tablet has no phenomena of uneven drug release or burst release, and can still reach the quality regulation in the 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 and reaches the quality and the clinical curative effect consistent with the original preparation.
Claims (10)
1. The method for purifying the metformin hydrochloride is characterized by comprising the following steps: dissolving the metformin hydrochloride crude product in 70-75% ethanol water solution, adding activated carbon, adjusting pH to 3-5 with concentrated hydrochloric acid, heating and refluxing, filtering, cooling and crystallizing, separating, washing, and drying to obtain the final product.
2. The method for refining metformin hydrochloride according to claim 1, wherein the mass ratio of the crude metformin hydrochloride to the 70-75% ethanol aqueous solution by volume fraction is 1: 1.7-2.0;
the mass ratio of the metformin hydrochloride crude product to the activated carbon is 1: 0.1-0.3.
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: 1-1.5;
the drying temperature is 45-50 ℃, and the drying time is 6-7 h.
4. Metformin hydrochloride purified by the method for purifying 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:
30-70 parts of metformin hydrochloride, 30-60 parts of sustained release agent, 1-10 parts of lubricant and 1-8 parts of adhesive;
the metformin hydrochloride is purified by the method for purifying metformin hydrochloride according to any one of claims 1 to 3.
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: 2-3.
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:
30-70 parts of metformin hydrochloride, 10-15 parts of hydroxypropyl methylcellulose, 20-45 parts of ethyl cellulose, 1-10 parts of magnesium stearate and 1-8 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.
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