WO2022148053A1 - 盐酸二甲双胍的纯化方法、盐酸二甲双胍缓释片及其制备方法 - Google Patents

盐酸二甲双胍的纯化方法、盐酸二甲双胍缓释片及其制备方法 Download PDF

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WO2022148053A1
WO2022148053A1 PCT/CN2021/118204 CN2021118204W WO2022148053A1 WO 2022148053 A1 WO2022148053 A1 WO 2022148053A1 CN 2021118204 W CN2021118204 W CN 2021118204W WO 2022148053 A1 WO2022148053 A1 WO 2022148053A1
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metformin hydrochloride
sustained
release
parts
release tablet
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PCT/CN2021/118204
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English (en)
French (fr)
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许丹青
余国新
耿亮
朱亚东
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海南海力制药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, in particular to a purification method of metformin hydrochloride, a metformin hydrochloride sustained-release tablet and a preparation method thereof.
  • 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.
  • sustained-release preparations refer to the slow and non-constant release of oral drugs in the specified release medium as required. 2 preparations.
  • metformin hydrochloride sustained-release tablet has uneven drug release, is prone to sudden release or incomplete release, and cannot maintain a stable blood drug concentration to achieve a good therapeutic effect.
  • the prior art by adding certain stabilizers and release regulators, it is prepared by hot-melt extrusion technology, so that the sustained-release material is closely combined with metformin hydrochloride, so that the drug release is dissolved without burst and more smoothly.
  • metformin hydrochloride sustained-release tablet prepared by this method has poor stability. According to the relevant requirements of the 2015 edition of the Pharmacopoeia of the People's Republic of China, after an accelerated stability test, it is prone to sudden release or incomplete release.
  • the technical problem to be solved by the present invention is to provide a stable metformin hydrochloride sustained-release tablet and a preparation method thereof.
  • the technical scheme adopted in the present invention is:
  • a method for purifying metformin hydrochloride comprising the following steps: dissolving a crude metformin hydrochloride in an aqueous ethanol solution with a volume fraction of 70-75%, adding activated carbon, adjusting the pH to 3-5 with concentrated hydrochloric acid, heating under reflux, filtering The obtained filtrate is crystallized by cooling, separated, washed and dried.
  • the metformin hydrochloride crude product is prepared by the existing metformin hydrochloride preparation method, such as a melting method, a solvent method and the like.
  • 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 crude metformin hydrochloride to the activated carbon is 1:(0.1-0.3).
  • the time for the heating and refluxing is 50-60min;
  • the reagent for washing is selected from absolute ethanol, and the mass ratio of the crude metformin hydrochloride to absolute ethanol is 1: (1.0-1.5);
  • the drying temperature is 45-50° C., and the drying time is 6-7 h.
  • the present invention also provides metformin hydrochloride purified by the above-mentioned purification method of metformin hydrochloride.
  • the present invention also provides a metformin hydrochloride sustained-release tablet, comprising the following raw materials in parts by weight:
  • metformin hydrochloride is purified by the above-mentioned purification method of metformin hydrochloride.
  • the sustained release agent includes hypromellose and ethyl cellulose
  • the binder is an ethanol solution of ethyl cellulose with a mass content of 5%.
  • the mass ratio of hypromellose to ethyl cellulose is 1:(2-3).
  • the lubricant is magnesium stearate.
  • metformin hydrochloride sustained-release tablet includes the following raw materials by weight:
  • metformin hydrochloride 30-70 parts of metformin hydrochloride, 10-15 parts of hypromellose, 20-45 parts of ethyl cellulose, 1-10 parts of magnesium stearate and 5% ethanol solution of ethyl cellulose 1- 8 servings.
  • the present invention also provides the above-mentioned preparation method of metformin hydrochloride sustained-release tablet, comprising the following steps:
  • a binder is added to granulate, dried, and then a lubricant is added, and the mixture is uniformly pressed to obtain a tablet.
  • the existing method for purifying metformin hydrochloride is to use ethanol or pure water with a volume fraction of 80-95% to obtain a metformin hydrochloride product.
  • the method for purifying metformin hydrochloride uses a specific volume fraction of 70-75% ethanol aqueous solution as a purification solvent, combined with activated carbon to decolorize under the condition of pH 3-5, and purifies the obtained solution of metformin hydrochloride product
  • the color is qualified; the metformin hydrochloride sustained-release tablet obtained from the metformin hydrochloride product purified by this purification method as the raw material has excellent stability. To maintain a stable release at a certain speed within 24h and maintain a stable blood concentration to achieve a good therapeutic effect.
  • the purification method of metformin hydrochloride provided by the present invention, by limiting the mass ratio of crude metformin hydrochloride to 70-75% ethanol aqueous solution with a volume fraction of 1:(1.7-2.0), and combining with the steps of adding activated carbon and pH adjustment, can further Improve the solution color and yield of the purified metformin hydrochloride, and then significantly improve the stability of the release rate within 24 hours of the metformin hydrochloride sustained-release tablet prepared from the metformin hydrochloride product purified by the purification method, especially the stability is improved The stability of the release rate within 24h after the accelerated test.
  • the metformin hydrochloride sustained-release tablet provided by the present invention is purified by using a specific volume fraction of 70-75% ethanol aqueous solution as a purification solvent, combined with adding activated carbon to decolorize under the condition of pH 3-5, and purifying the obtained metformin hydrochloride product
  • the metformin hydrochloride sustained-release tablets prepared as raw materials have excellent stability. Combined with the specific dosage of each raw material in the metformin hydrochloride sustained-release tablets, according to the relevant requirements of the "Pharmacopoeia of the People's Republic of China" 2015 edition, after the accelerated stability test, it can still be To maintain a stable release at a certain speed within 24h and maintain a stable blood concentration to achieve a good therapeutic effect.
  • the metformin hydrochloride sustained-release tablet provided by the present invention adopts hypromellose and ethyl cellulose as sustained-release agents, combined with a specific mass content of 5% ethyl cellulose ethanol solution as a binder, The stability of metformin hydrochloride sustained-release tablets can be further improved.
  • the metformin hydrochloride sustained-release tablet provided by the present invention, by further limiting the mass ratio of hypromellose to ethylcellulose in the sustained-release agent to be 1:(2-3), the metformin hydrochloride sustained-release tablet can be further improved. It is stable, and can maintain the stability of the release rate within 24 hours, so that the blood drug concentration is stable and achieves a good therapeutic effect.
  • the preparation method of the metformin hydrochloride sustained-release tablet provided by the present invention is simple and convenient, easy to industrialize, and the prepared metformin hydrochloride sustained-release tablet has good stability, can meet the quality requirements in the USP32 standard, and is stable at a certain speed within 24 hours. Release and maintain a stable blood drug concentration to achieve a good therapeutic effect.
  • the present embodiment provides a method for purifying metformin hydrochloride, comprising the following steps:
  • the metformin hydrochloride product is checked for clarity according to the first method (visual method) in the general rule 0902 of the 2015 edition of the "Chinese Pharmacopoeia” general rule of the clarity inspection method, and the first method in the 2015 edition of the "Chinese Pharmacopoeia” general rule 0901 solution color inspection method.
  • One method was used to check the color of the solution; the results showed that the aqueous solution of metformin hydrochloride was clear and colorless.
  • the present embodiment provides a method for purifying metformin hydrochloride, comprising the following steps:
  • the metformin hydrochloride product is checked for clarity according to the first method (visual method) in the general rule 0902 of the 2015 edition of the "Chinese Pharmacopoeia” general rule of the clarity inspection method, and the first method in the 2015 edition of the "Chinese Pharmacopoeia” general rule 0901 solution color inspection method.
  • One method was used to check the color of the solution; the results showed that the aqueous solution of metformin hydrochloride was clear and colorless.
  • the present embodiment provides a method for purifying metformin hydrochloride, comprising the following steps:
  • the metformin hydrochloride product is checked for clarity according to the first method (visual method) in the general rule 0902 of the 2015 edition of the "Chinese Pharmacopoeia” general rule of the clarity inspection method, and the first method in the 2015 edition of the "Chinese Pharmacopoeia” general rule 0901 solution color inspection method.
  • One method was used to check the color of the solution; the results showed that the aqueous solution of metformin hydrochloride was clear and colorless.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 was mixed with 100 g of hypromellose and 200 g of ethyl cellulose, 80 g of an ethyl cellulose solution with a mass content of 5% was added. After sieving and granulating, drying at 50°C for 2 hours, taking it out, granulating with an 18-mesh sieve, then adding 1000 g of magnesium stearate, mixing evenly, and pressing with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 2 was mixed with 150 g of hypromellose and 450 g of ethyl cellulose, 40 g of an ethanol solution of 5% ethyl cellulose was added, and the mixture was homogeneously mixed with an 18-mesh sieve. Granulated, dried at 40°C for 3 hours, taken out, granulated with an 18-mesh sieve, then added with 10 g of magnesium stearate, mixed and compressed with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 3 was mixed with 120 g of hypromellose and 300 g of ethyl cellulose, 10 g of an ethanol solution of 5% ethyl cellulose was added, and the mixture was homogeneously mixed with an 18-mesh sieve. After granulation, drying at 60°C for 1 hour, take out, granulate with an 18-mesh sieve, then add 50 g of magnesium stearate, mix evenly, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 was mixed with 100 g of hypromellose and 200 g of ethyl cellulose, 80 g of an ethanol solution of povidone with a mass content of 5% was added, and the mixture was homogeneously sieved with 18 meshes. After drying at 50°C for 2 hours, take it out, use an 18-mesh sieve to granulate, then add 1000 g of magnesium stearate, mix evenly, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 was mixed with 100 g of hypromellose and 200 g of ethyl cellulose, 20 g of an ethanol solution of 5% povidone was added and mixed with 60 g of sodium carboxymethyl cellulose. After homogeneous, granulate with an 18-mesh sieve, dry at 50°C for 2 hours, take out, granulate with an 18-mesh sieve, then add 1000 g of magnesium stearate, mix well, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 After mixing 300 g of metformin hydrochloride prepared in Example 1 with 300 g of ethyl cellulose, add 80 g of an ethanol solution of ethyl cellulose with a mass content of 5%, mix evenly, granulate with an 18-mesh sieve, and dry at 50° C. Then take it out, use an 18-mesh sieve to granulate, and then add 1000 g of magnesium stearate, mix it evenly, and press it with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 was mixed with 300 g of hypromellose, 80 g of an ethanol solution of 5% ethyl cellulose was added, and after mixing, granulated with an 18-mesh sieve and dried at 50°C. Take out after 2 hours, granulate with an 18-mesh sieve, then add 1000 g of magnesium stearate, mix evenly, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 was mixed with 300 g of sodium carboxymethyl cellulose, 80 g of an ethanol solution of ethyl cellulose with a mass content of 5% was added. After drying for 2 hours, take it out, use an 18-mesh sieve to granulate, then add 1000 g of magnesium stearate, mix evenly, and press it with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present embodiment provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Example 1 was mixed with 150 g of hypromellose and 150 g of ethyl cellulose, 80 g of an ethanol solution of ethyl cellulose with a mass content of 5% was added. After sieving and granulating, drying at 50°C for 2 hours, taking it out, granulating with an 18-mesh sieve, then adding 1000 g of magnesium stearate, mixing evenly, and pressing with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the present comparative example provides a method for purifying metformin hydrochloride, comprising the following steps:
  • the metformin hydrochloride product is checked for clarity according to the first method (visual method) in the general rule 0902 of the 2015 edition of the "Chinese Pharmacopoeia” general rule of the clarity inspection method, and the first method in the 2015 edition of the "Chinese Pharmacopoeia” general rule 0901 solution color inspection method.
  • the first method (visual method) is to check the color of the solution; the result shows that the aqueous solution of metformin hydrochloride is not clear, and compared with the control tube, the color is darker, and the color of the solution is unqualified.
  • the present comparative example provides a method for purifying metformin hydrochloride, comprising the following steps:
  • the metformin hydrochloride product is checked for clarity according to the first method (visual method) in the general rule 0902 of the 2015 edition of the "Chinese Pharmacopoeia” general rule of the clarity inspection method, and the first method in the 2015 edition of the "Chinese Pharmacopoeia” general rule 0901 solution color inspection method.
  • the first method (visual method) is to check the color of the solution; the result shows that the aqueous solution of metformin hydrochloride is not clear, and compared with the control tube, the color is darker, and the color of the solution is unqualified.
  • the present comparative example provides a method for purifying metformin hydrochloride, comprising the following steps:
  • the metformin hydrochloride product is checked for clarity according to the first method (visual method) in the general rule 0902 of the 2015 edition of the "Chinese Pharmacopoeia” general rule of the clarity inspection method, and the first method in the 2015 edition of the "Chinese Pharmacopoeia” general rule 0901 solution color inspection method.
  • the first method (visual method) is to check the color of the solution; the result shows that the aqueous solution of metformin hydrochloride is not clear, and compared with the control tube, the color is darker, and the color of the solution is unqualified.
  • This comparative example provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Comparative Example 1 After mixing 300 g of metformin hydrochloride prepared in Comparative Example 1 with 100 g of hypromellose and 200 g of ethyl cellulose, add 80 g of an ethanol solution of 5% ethyl cellulose to make the mixture uniform, and then use an 18-mesh sieve. After granulation, drying at 50°C for 2 hours, take out, granulate with an 18-mesh sieve, then add 1000 g of magnesium stearate, mix well, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • This comparative example provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Comparative Example 2 was mixed with 100 g of hypromellose and 200 g of ethyl cellulose, 80 g of an ethanol solution of ethyl cellulose with a mass content of 5% was added. After granulation, drying at 50°C for 2 hours, take out, granulate with an 18-mesh sieve, then add 1000 g of magnesium stearate, mix evenly, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • This comparative example provides a metformin hydrochloride sustained-release tablet, and its preparation method is as follows:
  • metformin hydrochloride prepared in Comparative Example 3 was mixed with 100 g of hypromellose and 200 g of ethyl cellulose, 80 g of an ethanol solution of ethyl cellulose with a mass content of 5% was added. After granulation, drying at 50°C for 2 hours, take out, granulate with an 18-mesh sieve, then add 1000 g of magnesium stearate, mix evenly, and press with a tablet machine to obtain metformin hydrochloride sustained-release tablets.
  • the metformin hydrochloride sustained-release tablets prepared in Example 4-11 and Comparative Example 4-6 were respectively subjected to identification reaction, related substances, differences in tablet weight and content determination.
  • the identification reaction of cyanide adopts 10% sodium nitroferricyanide solution-sodium ferricyanide test solution-10% sodium hydroxide solution; the inspection of related substances adopts high performance liquid chromatography; the content determination adopts ultraviolet spectrophotometry Content of main drug in metformin hydrochloride sustained-release tablets. All of the above are in compliance with pharmacopoeia requirements.
  • the metformin hydrochloride sustained-release tablets prepared in Example 4-11 and Comparative Example 4-6 and the original preparation (Glucophage XR from Bristol-Myers-Squibb Company (BMS)) were respectively investigated for dissolution, and the medium was selected as pH 1.2.
  • Hydrochloric acid solution, pH4.5 acetate buffer, pH6.8 phosphate buffer and water (Chinese Pharmacopoeia 2015 edition) 900mL, the method adopts "Chinese Pharmacopoeia” 2015 edition four general rules 0931 Dissolution Determination Method II (paddle method) ), the rotational speed was set to 50 rpm, and the temperature was set to 37 °C, and the dissolution rates at different times were measured. The results are shown in the table below.
  • Example 6 1 3 10 20 twenty four Example 4 24.76% 50.86% 63.93% 82.39% 99.57% Example 5 25.39% 51.28% 64.19% 83.40% 99.99%
  • Example 6 24.52% 51.60% 64.10% 85.55% 100.06%
  • Example 7 20.13% 46.06% 60.89% 81.18% 99.96%
  • Example 8 19.28% 45.31% 59.07% 81.64% 99.88%
  • Example 9 20.71% 46.02% 60.62% 82.16% 98.76%
  • Example 10 19.34% 44.48% 58.05% 83.34% 99.52%
  • Example 11 20.44% 46.96% 60.76% 82.21% 99.91%
  • Example 12 19.02% 40.90% 58.69% 81.03% 98.01% Comparative Example 4 76.21% 89.37% 100.03% -- -- Comparative Example 5 83.45% 90.40% 100.03% -- -- Comparative Example 6 13.23% 26.39% 40.67% 52.23% 61.32%
  • Example 4 1 3 10 20 twenty four 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%
  • Example 11 28.18% 55.03% 71.05% 93.51% 101.63%
  • Example 12 25.60% 53.45% 69.99% 90.82% 100.52%
  • Comparative Example 4 79.86% 99.03% 103.62% -- -- Comparative Example 5 69.86% 98.16% 102.83% -- -- Comparative Example 6 13.75% 36.81% 51.10% 76.16% 80.27% original preparation 35.66% 62.99% 77.02% 97.79% 100.03%
  • the metformin hydrochloride sustained-release tablet provided by the present invention does not have the phenomenon of uneven drug release and sudden release, and can meet the quality regulations in the USP32 standard of the United States Pharmacopoeia: within 24h, it is released stably at a certain speed, so that blood is released.
  • the drug concentration is stable and achieves a good therapeutic effect; it fully meets the clinical requirements of once 24h administration, and is consistent with the quality and clinical efficacy of the original preparation.
  • the stability of the metformin hydrochloride sustained-release tablets prepared in Example 4-11 and Comparative Example 4-6 was studied.
  • irradiation, accelerated test (simulating marketed packaging placed at 40°C), inspection of room-stabilized samples, etc., and the degradation products, content, etc. were determined.
  • the experimental results show that: the metformin hydrochloride sustained-release tablets prepared in Examples 4-11 of the present invention have no obvious change in the above-mentioned stability test compared with those before placement.
  • Example 4 1 3 10 20 twenty four Example 4 25.16% 48.31% 65.25% 82.07% 100.03% Example 5 23.53% 47.87% 63.66% 81.34% 99.19% Example 6 21.49% 45.61% 62.07% 79.32% 98.28% Example 7 20.34% 44.90% 60.36% 78.19% 98.37% Example 8 19.42% 42.28% 59.15% 77.84% 97.21% Example 9 21.16% 43.41% 62.07% 80.03% 100.79% Example 10 18.75% 42.02% 63.23% 81.81% 99.24% Example 11 20.90% 46.91% 64.44% 81.99% 101.60% Example 12 20.13% 47.64% 63.35% 80.65% 99.99%
  • Comparative Example 4 69.31% 88.14% 100.50% -- -- Comparative Example 5 60.57% 86.92% 99.08% 101.28% -- Comparative Example 6 12.55% 19.64% 42.19% 66.81% 79.42% original preparation 20.59% 46.78% 63.27% 80.19% 99.98%
  • 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 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 8 20.22% 52.37% 71.72% 84.71% 99.43%
  • Example 9 19.15% 50.09% 73.16% 87.53% 100.28%
  • Example 10 20.03% 55.48% 70.52% 83.24% 99.99%
  • Example 11 18.26% 53.14% 72.67% 82.70% 98.21%
  • Example 12 17.17% 55.26% 73.51% 84.27% 99.98% Comparative
  • Example 4 80.56% 103.64% -- -- -- Comparative Example 5 72.61% 95.83% 102.04% -- -- Comparative Example 6 9.67% 19.50% 47.15% 60.03% 72.82% original preparation 26.71% 59.37% 76.16% 89.67% 99.67%
  • Table 8 Dissolution data (water) at each time point after heating at 60°C for 10 days and strong light (4500Lx) irradiation for 10 days
  • the metformin hydrochloride sustained-release tablet provided by the present invention has excellent stability, and after being heated at 60° C. for 10 days and irradiated with strong light (4500Lx) for 10 days, there is no uneven drug release or sudden release phenomenon, and It can still meet the quality requirements in the USP32 standard of the United States Pharmacopoeia: stable release at a certain speed within 24 hours, so that the blood drug concentration is stable, and a good therapeutic effect is achieved; it fully meets the clinical requirements of one administration in 24 hours, and achieves the same quality and clinical efficacy as the original formulation. The effect is the same.

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Abstract

本发明涉及药物制剂技术领域，尤其是一种盐酸二甲双胍的纯化方法、盐酸二甲双胍缓释片及其制备方法。盐酸二甲双胍的纯化方法包括如下步骤：将盐酸二甲双胍粗品溶于体积分数为70-75％的乙醇水溶液中，加入活性炭，用浓盐酸调节pH值为3-5后，加热回流、过滤后的滤液经冷却结晶、分离、洗涤、干燥，即得。通过采用特定的体积分数为70-75％的乙醇水溶液作为纯化溶剂，结合活性炭在pH值为3-5的条件下脱色，纯化得到的盐酸二甲双胍产品的溶液颜色合格；且由该盐酸二甲双胍产品制得的盐酸二甲双胍缓释片稳定性优异，在进行稳定性加速试验后，依然能够保持24h内以一定速度平稳释放、维持平稳的血药浓度。

Description

盐酸二甲双胍的纯化方法、盐酸二甲双胍缓释片及其制备方法 技术领域
本发明涉及药物制剂技术领域，尤其是一种盐酸二甲双胍的纯化方法、盐酸二甲双胍缓释片及其制备方法。
背景技术
盐酸二甲双胍为双胍类口服降糖药，用于非胰岛素依赖型糖尿病的治疗，是一种既能控制血糖水平、又能改善大血管并发症的抗糖尿病药物。盐酸二甲双胍的降糖作用好，同时能够降低血脂和心血管疾病发生的风险，具有长期用药安全和性价比较高等优点，被广泛推荐为Ⅱ型糖尿病的一线用药。
盐酸二甲双胍为极易水溶性药物，普通口服制剂半衰期短，需要大剂量反复用药以维持有效血药浓度(每日3次，每次500mg)，这极易造成体内血药浓度波动大，引起不良反应。因此，为了提供持久稳定的血药浓度以更好地发挥其降糖作用，人们开始研制盐酸二甲双胍缓释制剂以增加患者顺应性。
《中国药典》规定，缓释制剂系指口服药物在规定释放介质中，按要求缓慢的非恒速释放，与其他相应的普通制剂相比，每24h用药次数应从3-4次减少至1-2次的制剂。但是，现有的盐酸二甲双胍缓释片存在释药不均，易出现突释或释放不完全的现象，不能维持平稳的血药浓度使之达到良好的治疗效果。
针对上述缺陷，现有技术中通过添加一定的稳定剂和释放调节剂，经热熔挤压技术进行制备，使缓释材料与盐酸二甲双胍紧密结合，使药物释放溶出无突释且更加平缓。但是该方法制得的盐酸二甲双胍缓释片稳定性差，根据《中华人民共和国药典》2015版的相关要求，在进行稳定性加速试验后，其易出现突释或释放不完全的现象。
发明内容
本发明需要解决的技术问题是提供一种稳定性好的盐酸二甲双胍缓释片及其制备方法。
为解决上述技术问题，本发明所采用的技术方案是：
一种盐酸二甲双胍的纯化方法，包括如下步骤：将盐酸二甲双胍粗品溶于体积分数为70-75％的乙醇水溶液中，加入活性炭，用浓盐酸调节pH值为3-5后，加热回流、过滤后的滤液经冷却结晶、分离、洗涤、干燥，即得。
所述盐酸二甲双胍粗品为现有盐酸二甲双胍的制备方法制得，例如熔融法、溶媒法等。
可选地，盐酸二甲双胍粗品与体积分数为70-75％乙醇水溶液的质量比为1：(1.7-2.0)；
所述盐酸二甲双胍粗品与活性炭的质量比为1：(0.1-0.3)。
可选地，所述加热回流的时间为50-60min；
洗涤的试剂选自无水乙醇，所述盐酸二甲双胍粗品与无水乙醇的质量比为1：(1.0-1.5)；
所述干燥的温度为45-50℃，所述干燥的时间为6-7h。
本发明还提供了上述的盐酸二甲双胍的纯化方法纯化得到的盐酸二甲双胍。
本发明还提供了一种盐酸二甲双胍缓释片，包括如下重量份数的原料：
盐酸二甲双胍30-70份，缓释剂30-60份，润滑剂1-10份和粘合剂1-8份；
所述盐酸二甲双胍是采用上述的盐酸二甲双胍的纯化方法纯化得到。
可选地，所述缓释剂包括羟丙甲纤维素和乙基纤维素；
所述粘合剂为质量含量为5％的乙基纤维素的乙醇溶液。
可选地，羟丙甲纤维素与乙基纤维素的质量比为1:(2-3)。
可选地，所述润滑剂为硬脂酸镁。
可选地，所述盐酸二甲双胍缓释片包括如下重量份的原料：
盐酸二甲双胍30-70份，羟丙甲纤维素10-15份，乙基纤维素20-45份， 硬脂酸镁1-10份和质量含量为5％的乙基纤维素的乙醇溶液1-8份。
本发明还提供了上述的盐酸二甲双胍缓释片的制备方法，包括如下步骤：
按选定的重量份数将盐酸二甲双胍与缓释剂混匀后，加入粘合剂制粒、干燥，然后加入润滑剂，混匀后压片即得。
由于采用了上述技术方案，本发明取得的技术进步是：
1、现有的盐酸二甲双胍的精制方法是用体积分数为80-95％的乙醇或纯水精制得到盐酸二甲双胍产品。
发明人经研究发现，现有的精制方法精制得到的盐酸二甲双胍产品溶液颜色不合格，直接影响了盐酸二甲双胍缓释片的释放速度，导致盐酸二甲双胍缓释片24h内的释放速度及血药浓度不平稳，易出现突释或释放不完全的现象。
本发明提供的盐酸二甲双胍的纯化方法，通过采用特定的体积分数为70-75％的乙醇水溶液作为纯化溶剂，结合活性炭在pH值为3-5的条件下脱色，纯化得到的盐酸二甲双胍产品的溶液颜色合格；由该纯化方法纯化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稳定性优异，根据《中华人民共和国药典》2015版的相关要求，在进行稳定性加速试验后，依然能够保持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。
2、本发明提供的盐酸二甲双胍的纯化方法，通过限定盐酸二甲双胍粗品与体积分数为70-75％乙醇水溶液的质量比为1：(1.7-2.0)，并结合添加活性炭及pH调节步骤，可进一步提高纯化得到的盐酸二甲双胍的溶液颜色及产率，进而显著提高由该纯化方法纯化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24h内释放速度的平稳性，尤其是提高了稳定性加速试验后，24h内释放速度的平稳性。
3、本发明提供的盐酸二甲双胍缓释片，通过采用特定的体积分数为70-75％乙醇水溶液作为纯化溶剂，结合添加活性炭在pH值为3-5的条件下脱色，纯化得到的盐酸二甲双胍产品作为原料制得的盐酸二甲双胍缓释片稳定性 优异，结合盐酸二甲双胍缓释片中各原料的特定用量，根据《中华人民共和国药典》2015版的相关要求，在进行稳定性加速试验后，依然能够保持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。
4、本发明提供的盐酸二甲双胍缓释片，通过采用羟丙甲纤维素和乙基纤维素作为缓释剂，结合特定的质量含量为5％的乙基纤维素的乙醇溶液作为粘结剂，可进一步提高盐酸二甲双胍缓释片的稳定性。
5、本发明提供的盐酸二甲双胍缓释片，通过进一步限定缓释剂中羟丙甲纤维素与乙基纤维素的质量比为1：(2-3)，可进一步提高盐酸二甲双胍缓释片的稳定性，并能够保持24h内释放速度的平稳性，使得血药浓度平稳达到良好的治疗效果。
6、本发明提供的盐酸二甲双胍缓释片的制备方法，简单方便，易于工业化，且制备得到的盐酸二甲双胍缓释片稳定性好，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。
具体实施方式
下面结合实施例对本发明做进一步详细说明：
实施例1
本实施例提供一种盐酸二甲双胍的纯化方法，包括如下步骤：
将100kg盐酸二甲双胍粗品溶于200kg体积分数为70％乙醇水溶液中，然后加入20kg的活性炭，用浓盐酸调节体系pH值为3，加热回流50min后，自然冷却至室温，过滤，过滤后的滤液降温至2℃结晶4h，再次过滤,并用150kg无水乙醇洗涤滤饼，将洗涤后的滤饼于50℃干燥7h，即得盐酸二甲双胍产品。
将该盐酸二甲双胍产品按照2015版《中国药典》通则0902澄清度检查法通则中的第一法(目视法)进行澄清度的检查，2015版《中国药典》通则0901溶液颜色检查法中的第一法(目视法)进行溶液颜色的检查；结果显示盐酸二 甲双胍的水溶液澄清，无色。
实施例2
本实施例提供一种盐酸二甲双胍的纯化方法，包括如下步骤：
将100kg盐酸二甲双胍粗品溶于180kg体积分数为75％乙醇水溶液中，然后加入30kg的活性炭，用浓盐酸调节体系pH值为5，加热回流55min后，自然冷却至室温，过滤，过滤后的滤液降温至0℃结晶4h，再次过滤,并用150kg无水乙醇洗涤滤饼，将洗涤后的滤饼于45℃干燥6h，即得盐酸二甲双胍产品。
将该盐酸二甲双胍产品按照2015版《中国药典》通则0902澄清度检查法通则中的第一法(目视法)进行澄清度的检查，2015版《中国药典》通则0901溶液颜色检查法中的第一法(目视法)进行溶液颜色的检查；结果显示盐酸二甲双胍的水溶液澄清，无色。
实施例3
本实施例提供一种盐酸二甲双胍的纯化方法，包括如下步骤：
将100kg盐酸二甲双胍粗品溶于170kg体积分数为73％乙醇水溶液中，然后加入10kg的活性炭，用浓盐酸调节体系pH值为4，加热回流60min后，自然冷却至室温，过滤，过滤后的滤液降温至-5℃结晶3h，再次过滤,并用150kg无水乙醇洗涤滤饼，将洗涤后的滤饼于48℃干燥7h，即得盐酸二甲双胍产品。
将该盐酸二甲双胍产品按照2015版《中国药典》通则0902澄清度检查法通则中的第一法(目视法)进行澄清度的检查，2015版《中国药典》通则0901溶液颜色检查法中的第一法(目视法)进行溶液颜色的检查；结果显示盐酸二甲双胍的水溶液澄清，无色。
实施例4
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与100g羟丙甲纤维素、200g乙基纤维素混匀后，再加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均 匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例5
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将700g实施例2制得的盐酸二甲双胍与150g羟丙甲纤维素、450g乙基纤维素混匀后，加入40g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、40℃干燥3h后取出，用18目筛整粒，然后加入10g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例6
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将500g实施例3制得的盐酸二甲双胍与120g羟丙甲纤维素、300g乙基纤维素混匀后，加入10g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、60℃干燥1h后取出，用18目筛整粒，然后加入50g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例7
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与100g羟丙甲纤维素、200g乙基纤维素混匀后，加入80g质量含量为5％的聚维酮的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例8
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与100g羟丙甲纤维素、200g乙基纤维素混匀后，加入20g质量含量为5％的聚维酮的乙醇溶液和60g羧甲基纤维素钠混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然 后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例9
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与300g乙基纤维素混匀后，加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例10
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与300g羟丙甲纤维素混匀后，加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例11
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与300g羧甲基纤维素钠混匀后，加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实施例12
本实施例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g实施例1制得的盐酸二甲双胍与150g羟丙甲纤维素、150g乙基纤维素混匀后，再加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
对比例1
本对比例提供一种盐酸二甲双胍的纯化方法，包括如下步骤：
将10kg盐酸二甲双胍粗品溶于20kg体积分数为70％乙醇水溶液中，用浓盐酸调节体系pH值为3，加热回流50min后，自然冷却至室温，过滤，过滤后的滤液降温至2℃结晶4h，再次过滤,并用15kg无水乙醇洗涤滤饼，将洗涤后的滤饼于50℃干燥7h，即得盐酸二甲双胍产品。
将该盐酸二甲双胍产品按照2015版《中国药典》通则0902澄清度检查法通则中的第一法(目视法)进行澄清度的检查，2015版《中国药典》通则0901溶液颜色检查法中的第一法(目视法)进行溶液颜色的检查；结果显示盐酸二甲双胍的水溶液不澄清，与对照管相比，颜色更深，溶液颜色不合格。
对比例2
本对比例提供一种盐酸二甲双胍的纯化方法，包括如下步骤：
将10kg盐酸二甲双胍粗品溶于20kg体积分数为70％乙醇水溶液中，然后加入2kg的活性炭，加热回流50min后，自然冷却至室温，过滤，过滤后的滤液降温至2℃结晶4h，再次过滤,并用15kg无水乙醇洗涤滤饼，将洗涤后的滤饼于50℃干燥7h，即得盐酸二甲双胍产品。
将该盐酸二甲双胍产品按照2015版《中国药典》通则0902澄清度检查法通则中的第一法(目视法)进行澄清度的检查，2015版《中国药典》通则0901溶液颜色检查法中的第一法(目视法)进行溶液颜色的检查；结果显示盐酸二甲双胍的水溶液不澄清，与对照管相比，颜色更深，溶液颜色不合格。
对比例3
本对比例提供一种盐酸二甲双胍的纯化方法，包括如下步骤：
将10kg盐酸二甲双胍粗品溶于20kg体积分数为70％乙醇水溶液中，然后加入2kg的活性炭，用浓盐酸调节体系pH值为1，加热回流50min后，自然冷却至室温，过滤，过滤后的滤液降温至2℃结晶4h，再次过滤,并用15kg无水 乙醇洗涤滤饼，将洗涤后的滤饼于50℃干燥7h，即得盐酸二甲双胍产品。
将该盐酸二甲双胍产品按照2015版《中国药典》通则0902澄清度检查法通则中的第一法(目视法)进行澄清度的检查，2015版《中国药典》通则0901溶液颜色检查法中的第一法(目视法)进行溶液颜色的检查；结果显示盐酸二甲双胍的水溶液不澄清，与对照管相比，颜色更深，溶液颜色不合格。
对比例4
本对比例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g对比例1制得的盐酸二甲双胍与100g羟丙甲纤维素、200g乙基纤维素混匀后，加入80g质量含量为5％的乙基纤维素的乙醇溶液制混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
对比例5
本对比例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g对比例2制得的盐酸二甲双胍与100g羟丙甲纤维素、200g乙基纤维素混匀后，加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
对比例6
本对比例提供一种盐酸二甲双胍缓释片，其制备方法如下：
将300g对比例3制得的盐酸二甲双胍与100g羟丙甲纤维素、200g乙基纤维素混匀后，加入80g质量含量为5％的乙基纤维素的乙醇溶液，混合均匀后用18目筛制粒、50℃干燥2h后取出，用18目筛整粒，然后加入1000g硬脂酸镁，混匀后用压片机压片即得盐酸二甲双胍缓释片。
实验例1
根据《中华人民共和国药典》2015版中的相关规定，将实施例4-11和对 比例4-6制得的盐酸二甲双胍缓释片分别进行鉴别反应、有关物质、片重差异及含量测定的检查。其中氰化物的鉴别反应采用10％亚硝基铁氰化钠溶液-铁氰化钠试液-10％氢氧化钠溶液；有关物质检查采用高效液相色谱法；含量测定采用紫外分光光度法测定盐酸二甲双胍缓释片中主药含量。以上各项均符合药典要求。
将实施例4-11和对比例4-6制得的盐酸二甲双胍缓释片及原研制剂(Bristol-Myers-Squibb Company(BMS)公司的Glucophage XR)分别进行溶出度的考察，介质选择pH1.2盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液和水(中国药典2015版)900mL，方法采用《中国药典》2015年版四部通则0931溶出度测定法第二法(桨法)，转速设定为50rpm，温度设定为37℃，分别测定不同时间的溶出度。结果如下表所示。
表1 各时间点的溶出度数据(pH1.2盐酸溶液)
时间(h) 1 3 10 20 24
实施例4 24.76％ 50.86％ 63.93％ 82.39％ 99.57％
实施例5 25.39％ 51.28％ 64.19％ 83.40％ 99.99％
实施例6 24.52％ 51.60％ 64.10％ 85.55％ 100.06％
实施例7 20.13％ 46.06％ 60.89％ 81.18％ 99.96％
实施例8 19.28％ 45.31％ 59.07％ 81.64％ 99.88％
实施例9 20.71％ 46.02％ 60.62％ 82.16％ 98.76％
实施例10 19.34％ 44.48％ 58.05％ 83.34％ 99.52％
实施例11 20.44％ 46.96％ 60.76％ 82.21％ 99.91％
实施例12 19.02％ 40.90％ 58.69％ 81.03％ 98.01％
对比例4 76.21％ 89.37％ 100.03％ -- --
对比例5 83.45％ 90.40％ 100.03％ -- --
对比例6 13.23％ 26.39％ 40.67％ 52.23％ 61.32％
原研制剂 25.9％ 51.68％ 64.39％ 83.17％ 100.61％
表2 各时间点的溶出度数据(pH4.5醋酸盐缓冲液)
时间(h) 1 3 10 20 24
实施例4 20.13％ 44.56％ 75.19％ 96.59％ 99.59％
实施例5 21.54％ 46.27％ 77.37％ 95.64％ 100.06％
实施例6 19.76％ 45.91％ 78.46％ 96.18％ 100.97％
实施例7 15.37％ 40.61％ 71.03％ 90.31％ 98.86％
实施例8 16.26％ 41.59％ 72.31％ 91.24％ 99.12％
实施例9 15.31％ 40.30％ 71.27％ 91.53％ 99.60％
实施例10 17.22％ 42.81％ 72.60％ 91.61％ 99.77％
实施例11 16.35％ 40.79％ 71.44％ 90.00％ 99.00％
实施例12 15.05％ 39.12％ 70.10％ 89.61％ 98.18％
对比例4 99.12％ 102.37％ -- -- --
对比例5 68.79％ 96.84％ 102.19％ -- --
对比例6 6.40％ 16.82％ 26.37％ 56.44％ 71.02％
原研制剂 19.21％ 45.34％ 76.41％ 98.81％ 100.53％
表3 各时间点的溶出度数据(pH6.8磷酸盐缓冲液)
时间(h) 1 3 10 20 24
实施例4 36.12％ 60.24％ 76.34％ 95.07％ 100.13％
实施例5 35.57％ 63.31％ 78.50％ 94.48％ 99.76％
实施例6 34.49％ 61.62％ 77.12％ 97.13％ 101.30％
实施例7 30.11％ 57.56％ 71.29％ 90.62％ 99.30％
实施例8 31.19％ 58.31％ 73.87％ 92.13％ 101.53％
实施例9 30.30％ 57.27％ 72.94％ 91.20％ 100.10％
实施例10 29.44％ 56.10％ 73.90％ 92.47％ 102.91％
实施例11 28.18％ 55.03％ 71.05％ 93.51％ 101.63％
实施例12 25.60％ 53.45％ 69.99％ 90.82％ 100.52％
对比例4 79.86％ 99.03％ 103.62％ -- --
对比例5 69.86％ 98.16％ 102.83％ -- --
对比例6 13.75％ 36.81％ 51.10％ 76.16％ 80.27％
原研制剂 35.66％ 62.99％ 77.02％ 97.79％ 100.03％
表4 各时间点的溶出度数据(水)
时间(h) 1 3 10 20 24
实施例4 20.73％ 42.57％ 76.19％ 99.34％ 101.68％
实施例5 23.25％ 43.31％ 77.60％ 100.92％ 103.73％
实施例6 21.61％ 42.20％ 75.73％ 99.49％ 102.52％
实施例7 19.12％ 39.92％ 71.01％ 95.10％ 100.31％
实施例8 18.94％ 38.45％ 70.32％ 94.07％ 99.49％
实施例9 17.36％ 38.08％ 72.70％ 96.33％ 100.07％
实施例10 16.47％ 37.74％ 70.19％ 94.68％ 98.24％
实施例11 18.08％ 40.53％ 72.55％ 95.94％ 101.67％
实施例12 15.42％ 37.84％ 70.05％ 93.41％ 99.94％
对比例4 74.14％ 96.61％ 102.33％ -- --
对比例5 86.07％ 100.37％ -- -- -
对比例6 10.39％ 21.61％ 38.92％ 46.78％ 68.50％
原研制剂 22.96％ 47.46％ 74.88％ 100.07％ 102.12％
由上表中的数据可知，本发明提供的盐酸二甲双胍缓释片不存在释药不均，突释的现象，且能够达到美国药典USP32标准中质量规定：24h内以一定速度平稳释放，使得血药浓度平稳，达到良好的治疗效果；完全满足了临床上24h给药一次的要求，达到与原研制剂质量和临床疗效一致。
实验例2
根据《中华人民共和国药典》2015版中的相关规定，对实施例4-11和对比例4-6制得的盐酸二甲双胍缓释片的稳定性进行了研究，考察了60℃、强光(4500Lx)照射、加速试验(模拟上市包装在40℃条件下放置)、室稳留样考察等项目，测定了降解产物、含量等。实验结果表明：本发明实施例4-11制得的盐酸二甲双胍缓释片经上述的稳定性试验后各项考察指标与放置前比较均未见明显变化。
将实施例4-11和对比例4-6制得的盐酸二甲双胍缓释片及原研制剂(Bristol-Myers-Squibb Company(BMS)公司的Glucophage XR)依次经60℃加热10天、强光(4500Lx)照射10天后分别进行溶出度的考察，介质选择pH1.2盐酸溶液、pH4.5醋酸盐缓冲液、pH6.8磷酸盐缓冲液和水(中国药典2015版)900mL，方法采用《中国药典》2015年版四部通则0931溶出度测定法第二法(桨法)，转速设定为50rpm，温度设定为37℃，分别测定不同时间的溶出度。结果如下表所示。
表5 60℃加热10天、强光(4500Lx)照射10天后各时间点的溶出度数据(pH1.2盐酸溶液)
时间(h) 1 3 10 20 24
实施例4 25.16％ 48.31％ 65.25％ 82.07％ 100.03％
实施例5 23.53％ 47.87％ 63.66％ 81.34％ 99.19％
实施例6 21.49％ 45.61％ 62.07％ 79.32％ 98.28％
实施例7 20.34％ 44.90％ 60.36％ 78.19％ 98.37％
实施例8 19.42％ 42.28％ 59.15％ 77.84％ 97.21％
实施例9 21.16％ 43.41％ 62.07％ 80.03％ 100.79％
实施例10 18.75％ 42.02％ 63.23％ 81.81％ 99.24％
实施例11 20.90％ 46.91％ 64.44％ 81.99％ 101.60％
实施例12 20.13％ 47.64％ 63.35％ 80.65％ 99.99％
对比例4 69.31％ 88.14％ 100.50％ -- --
对比例5 60.57％ 86.92％ 99.08％ 101.28％ --
对比例6 12.55％ 19.64％ 42.19％ 66.81％ 79.42％
原研制剂 20.59％ 46.78％ 63.27％ 80.19％ 99.98％
表6 60℃加热10天、强光(4500Lx)照射10天后各时间点的溶出度数据(pH4.5醋酸盐缓冲液)
时间(h) 1 3 10 20 24
实施例4 15.34％ 40.51％ 74.86％ 95.42％ 99.76％
实施例5 17.21％ 39.70％ 75.05％ 98.54％ 101.30％
实施例6 18.59％ 44.34％ 76.17％ 97.09％ 100.51％
实施例7 14.24％ 40.49％ 71.03％ 94.12％ 99.53％
实施例8 15.53％ 38.31％ 70.57％ 93.95％ 98.19％
实施例9 14.71％ 37.25％ 69.91％ 92.34％ 98.87％
实施例10 16.48％ 39.17％ 69.04％ 92.11％ 99.10％
实施例11 15.90％ 38.66％ 70.26％ 93.80％ 100.63％
实施例12 15.76％ 37.51％ 71.47％ 94.38％ 101.06％
对比例4 79.84％ 100.17％ -- -- --
对比例5 70.52％ 90.34％ 100.77％ -- --
对比例6 5.35％ 18.66％ 31.42％ 57.25％ 69.58％
原研制剂 16.6％ 42.76％ 75.68％ 96.22％ 100.03％
表7 60℃加热10天、强光(4500Lx)照射10天后各时间点的溶出度数据(pH6.8磷酸盐缓冲液)
时间(h) 1 3 10 20 24
实施例4 27.12％ 58.40％ 77.96％ 90.27％ 101.35％
实施例5 26.59％ 61.18％ 75.50％ 87.36％ 100.54％
实施例6 25.37％ 57.34％ 76.73％ 92.01％ 102.03％
实施例7 21.20％ 51.48％ 72.60％ 86.39％ 100.19％
实施例8 20.22％ 52.37％ 71.72％ 84.71％ 99.43％
实施例9 19.15％ 50.09％ 73.16％ 87.53％ 100.28％
实施例10 20.03％ 55.48％ 70.52％ 83.24％ 99.99％
实施例11 18.26％ 53.14％ 72.67％ 82.70％ 98.21％
实施例12 17.17％ 55.26％ 73.51％ 84.27％ 99.98％
对比例4 80.56％ 103.64％ -- -- --
对比例5 72.61％ 95.83％ 102.04％ -- --
对比例6 9.67％ 19.50％ 47.15％ 60.03％ 72.82％
原研制剂 26.71％ 59.37％ 76.16％ 89.67％ 99.67％
表8 60℃加热10天、强光(4500Lx)照射10天后各时间点的溶出度数据(水)
时间(h) 1 3 10 20 24
实施例4 21.37％ 43.50％ 68.12％ 98.71％ 100.57％
实施例5 19.29％ 42.16％ 67.83％ 99.36％ 102.33％
实施例6 22.71％ 45.49％ 69.08％ 100.64％ 101.94％
实施例7 16.13％ 42.35％ 64.31％ 95.21％ 101.47％
实施例8 16.47％ 41.27％ 61.50％ 93.91％ 99.96％
实施例9 17.50％ 43.63％ 62.44％ 92.53％ 100.61％
实施例10 15.09％ 40.71％ 60.73％ 90.40％ 98.70％
实施例11 18.82％ 44.89％ 63.26％ 91.09％ 101.09％
实施例12 19.38％ 40.83％ 64.67％ 92.87％ 101.64％
对比例4 70.93％ 103.59％ -- -- --
对比例5 65.13％ 83.42％ 102.19％ -- --
对比例6 6.79％ 21.89％ 49.72％ 63.01％ 76.28％
原研制剂 20.51％ 44.39％ 69.46％ 99.88％ 101.11％
由上表中的数据可知，本发明提供的盐酸二甲双胍缓释片稳定性优异，经 60℃加热10天、强光(4500Lx)照射10天后，没有出现释药不均或突释的现象，且依然能够达到美国药典USP32标准中质量规定：24h内以一定速度平稳释放，使得血药浓度平稳，达到良好的治疗效果；完全满足了临床上24h给药一次的要求，达到与原研制剂质量和临床疗效一致。

Claims (10)

  1. 一种盐酸二甲双胍的纯化方法，其特征在于，包括如下步骤：将盐酸二甲双胍粗品溶于体积分数为70-75％的乙醇水溶液中，加入活性炭，用浓盐酸调节pH值为3-5后，加热回流、过滤后的滤液经冷却结晶、分离、洗涤、干燥，即得。
  2. 根据权利要求1所述的盐酸二甲双胍的精制方法，其特征在于，盐酸二甲双胍粗品与体积分数为70-75％乙醇水溶液的质量比为1：1.7-2.0；
    所述盐酸二甲双胍粗品与活性炭的质量比为1：0.1-0.3。
  3. 根据权利要求1或2所述的盐酸二甲双胍的精制方法，其特征在于，所述加热回流的时间为50-60min；
    洗涤的试剂选自无水乙醇，所述盐酸二甲双胍粗品与无水乙醇的质量比为1：1-1.5；
    所述干燥的温度为45-50℃，所述干燥的时间为6-7h。
  4. 权利要求1-3任一项所述的盐酸二甲双胍的纯化方法纯化得到的盐酸二甲双胍。
  5. 一种盐酸二甲双胍缓释片，其特征在于，包括如下重量份数的原料：
    盐酸二甲双胍30-70份，缓释剂30-60份，润滑剂1-10份和粘合剂1-8份；
    所述盐酸二甲双胍是采用权利要求1-3任一项所述的盐酸二甲双胍的纯化方法纯化得到。
  6. 根据权利要求5所述的盐酸二甲双胍缓释片，其特征在于，所述缓释剂包括羟丙甲纤维素和乙基纤维素；
    所述粘合剂为质量含量为5％的乙基纤维素的乙醇溶液。
  7. 根据权利要求6所述的盐酸二甲双胍缓释片，其特征在于，羟丙甲纤维素与乙基纤维素的质量比为1:2-3。
  8. 根据权利要求5-7任一项所述的盐酸二甲双胍缓释片，其特征在于，所 述润滑剂为硬脂酸镁。
  9. 根据权利要求8所述的盐酸二甲双胍缓释片，其特征在于，包括如下重量份的原料：
    盐酸二甲双胍30-70份，羟丙甲纤维素10-15份，乙基纤维素20-45份，硬脂酸镁1-10份和质量含量为5％的乙基纤维素的乙醇溶液1-8份。
  10. 一种权利要求5-9任一项所述的盐酸二甲双胍缓释片的制备方法，其特征在于，包括如下步骤：
    按选定的重量份数将盐酸二甲双胍与缓释剂混匀后，加入粘合剂制粒、干燥，然后加入润滑剂，混匀后压片即得。
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