Methotrexate tablet and preparation method thereof

Abstract

The invention discloses a methotrexate tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, and the preparation method comprises the following steps: step 1, respectively sieving a diluent and an adhesive through a shaking screen provided with a screen mesh to obtain an auxiliary material; the preparation method comprises the following steps: 1, preparing a methotrexate raw material medicine, 2, dissolving sodium carbonate in purified water to obtain a sodium carbonate solution, adding the methotrexate raw material medicine into the sodium carbonate solution, and carrying out a reaction on methotrexate and sodium carbonate to obtain a methotrexate disodium salt solution, and 3, mixing the methotrexate disodium salt solution and auxiliary materials, carrying out granulation, and carrying out drying treatment to obtain medicine particles. And 4, uniformly mixing the medicine particles with a lubricant, and tabletting to obtain the methotrexate tablets. The methotrexate disodium salt is prepared through reaction of methotrexate and sodium carbonate, the methotrexate tablet is prepared through wet granulation, and experiments prove that the improved methotrexate tablet is good in storage stability, few in impurities, high in drug solubility, high in dissolution rate, high in drug absorbance and capable of reducing side effects of drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a methotrexate tablet and a preparation method thereof. Background Art

[0002] In 2022, there will be 20 million new cancer cases and about 9.7 million deaths worldwide. Among them, China has 4.82 million new cancer cases, accounting for 24.1% of the global cases, and 2.57 million cancer deaths, accounting for 26.5% of the total number of cancer deaths. The number of new cancer cases and cancer deaths far exceeds that of other countries in the world, ranking first in the world. Among them, the top five cancer incidence rates are lung cancer, colorectal cancer, thyroid cancer, liver cancer and breast cancer, accounting for 57.5% of all new cancers2. The top five mortality rates are lung cancer, liver cancer, gastric cancer, colorectal cancer and esophageal cancer, and the total number of deaths accounts for 67.5% of the total number of cancer deaths. Among them, the incidence and mortality rates of men are much higher than those of women. Methotrexate tablets are a drug with multiple therapeutic effects. It belongs to the anti-folate tumor drug. It mainly inhibits the biological activity of thymidylate synthase and hinders the synthesis of tumor cells, thereby achieving anti-cancer effects. The drug is widely used to treat various acute leukemias, especially acute lymphocytic leukemia, as well as malignant lymphomas, lung cancer, various soft tissue sarcomas, breast cancer, ovarian cancer, cervical cancer, malignant hydatidiform mole, choriocarcinoma, testicular cancer and other malignant tumors. Methotrexate tablets are also an immunosuppressant that can regulate the body's immune function and enhance the body's resistance to disease. It mainly inhibits dihydrofolate reductase and limits its reduction to active tetrahydrofolate, thereby inhibiting synovial cell proliferation and inducing apoptosis, reducing inflammatory activity and slowing bone damage. Methotrexate tablets are a basic drug for the treatment of rheumatoid arthritis, which can control inflammation, delay disease progression, and improve patients' quality of life.

[0003] Methotrexate, English name: Methotrexate, chemical name: L-(+)-N-[4-[[(2,4-diamino-6-pteridinyl]methyl]methylamino]benzoyl)glutamic acid, English chemical name: (2S)-2-[(4-{[(4-amino-2-imino-2,3-dihydropteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioic acid, CAS number: 59-05-2, molecular formula: C 20 H 22 N8O5, molecular weight: 454.44, chemical structure is as follows:

[0004] Although methotrexate tablets are widely used in clinical practice, their preparations have certain defects in production process and use. Most of the existing production processes are to mix methotrexate raw materials with starch and dextrin, and then add 10% starch paste at one time for mixed granulation. The granules after granulation are uneven in size, the powder particles are large and hard, and the properties are unstable. The tableting is not good, the tablets are soft and small, the surface is not smooth and the appearance is low. During storage and use, methotrexate is easily affected by environmental factors such as light, temperature and humidity, which leads to reduced drug efficacy and affects human absorption, thereby affecting the efficacy.

[0005] In response to these problems, researchers have been exploring and improving the preparation method of methotrexate tablets. For example: Japanese patent application CN109475557B discloses a methotrexate tablet, which contains iron oxide in the film coating layer and the uncoated tablet, thereby inhibiting the reduction of the content of methotrexate as an active ingredient due to light and the generation of analogs, but the preparation process of the coated tablet is relatively complicated, which increases the preparation cost. Chinese patent application CN118806711A discloses a methotrexate tablet and a preparation method thereof, which adopts starch emulsion wet granulation to prepare methotrexate tablets, with many auxiliary materials and complicated processes: it contains lecithin, microcrystalline cellulose, β-cyclodextrin, magnesium stearate calcium pantothenate, fumed silica, sorbitol, calcium bicarbonate, starch emulsion and other auxiliary materials. Chinese patent application CN118845682A discloses a dry granulation method for methotrexate tablets, wherein methotrexate is mixed with excipients by a geometric dilution method, and the methotrexate tablets are prepared by roller compaction and direct tableting. The preparation process is complex and the cost is high, and the stability of the drug preparation components is improved by coating. Summary of the invention

[0006] The purpose of the present invention is to provide a paper tube hanging device for vertical hanging in view of the problems and shortcomings described in the background technology.

[0007] The present invention is used to solve the problems of methotrexate tablets being easily degraded by light, having low bioavailability, and having a complicated production process. The present invention prepares methotrexate tablets by wet granulation through reacting methotrexate with sodium carbonate to produce methotrexate disodium salt, thereby achieving the effects of good stability, high bioavailability, and simple production process.

[0008] A method for preparing methotrexate tablets comprises the following steps:

[0009] Step 1: sieving the diluent and the binder through an oscillating sieve equipped with a sieve to obtain auxiliary materials;

[0010] Step 2: dissolving sodium carbonate in purified water to obtain a sodium carbonate solution, adding the methotrexate API to the sodium carbonate solution, reacting the methotrexate with the sodium carbonate to obtain a methotrexate disodium salt solution, the structural formula of the methotrexate disodium salt is shown below;

[0011]

[0012] Step 3: Mixing the methotrexate disodium salt solution with the auxiliary materials to prepare granules, and drying the granules to obtain drug granules;

[0013] Step 4: Mix the drug particles and lubricant evenly, and press into tablets to obtain methotrexate tablets.

[0014] Preferably, the binder may be one or more of pregelatinized starch, corn starch, povidone, and hydroxypropyl methylcellulose, but is not limited thereto.

[0015] Preferably, the diluent may be one or more of lactose, corn starch, mannitol, and microcrystalline cellulose, but is not limited thereto.

[0016] Preferably, the lubricant may be one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate, but is not limited thereto.

[0017] Preferably, the diluent is lactose and corn starch, the binder is pregelatinized starch, and the lubricant is magnesium stearate;

[0018] The mass ratio of methotrexate, lactose, corn starch, pregelatinized starch, sodium carbonate and magnesium stearate is: 1.0-10: 30-50: 30-60: 3.0-15: 0.9-7.0: 0.9-7.0.

[0019] Preferably, in step three: granulation is performed by a wet granulator, with a stirring speed of 25 Hz, a knife cutting speed of 35 Hz, and a granulation time of 1 min.

[0020] Preferably, in step three: drying treatment refers to: drying by fluidized bed, with air inlet temperature of 30-50°C, air inlet volume of 45-55HZ, and drug particle drying loss ≤4.0%.

[0021] Preferably, in step 4: the drug particles and magnesium stearate are mixed by a square cone mixer, the rotation speed of the square cone mixer is 15 to 30 rpm, and the mixing time is 20 to 30 min.

[0022] Preferably, in step 4: tabletting is performed by a rotary tablet press, the rotation speed of the rotary tablet press is 25-45 rpm, the main pressing thickness is 1.00-2.00 mm, and the mold is a shallow concave notch die with a diameter of φ8.5 mm.

[0023] Preferably, the unit tablet weight of the methotrexate tablet in step 4 is 100 mg.

[0024] A methotrexate tablet is prepared by applying the preparation method of the methotrexate tablet.

[0025] Beneficial effects of the present invention:

[0026] The invention prepares methotrexate disodium salt by reacting methotrexate with sodium carbonate, and prepares methotrexate tablets by wet granulation. Experiments show that the improved methotrexate tablets have good storage stability, less impurities, improved drug solubility, faster dissolution, improved drug absorption, and reduced drug side effects.

[0027] The methotrexate tablets prepared by the method maintain stable properties under light (5000Lx) for 30 days: (1) impurity B ≤ 0.5%, impurity C ≤ 0.5%, impurity E ≤ 0.3%, impurity H ≤ 0.2%, impurity I ≤ 0.2%, other single impurities ≤ 0.2%, and total impurities ≤ 1.0% except for impurities B, C and E; (2) in the dissolution test, the dissolution rate of the methotrexate tablets prepared by the method reaches 101.1.4%. After 30 days of illumination, the solubility of the reference preparation (GW1078) in simulated gastric fluid is 98.9%, and it can reach 83.7% after 30 days of illumination. Under the same conditions, the solubility of the comparative drug is significantly improved; (3) In the content determination of the methotrexate tablets prepared by this method, the content of the methotrexate tablets can reach 101.44%, and it can still reach 94.54% after 30 days of illumination; the content of the reference preparation is 101.5%, and the content after 30 days of illumination is only 79.20%. After multiple tests and comparisons, the methotrexate tablets of the present invention have less impurities, good stability, and high content;

[0028] The invention adopts drugs such as lactose, corn starch, pregelatinized starch, magnesium stearate, etc. as auxiliary materials, so that the particles are uniform, there are no large particles, the adhesiveness is improved, the tablets are uniform in size, smooth and beautiful, the edges are complete, the color is uniform, the properties are stable, and it is easy to store for a long time.

[0029] The present invention adopts the method of dissolving the methotrexate raw material medicine in the aqueous solution of sodium carbonate, reducing the dust pollution in the production process during the wet granulation process, and the raw material medicine is added in the form of liquid, thereby reducing the risk of uneven mixing. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explanation of the present invention and are not used to limit the invention.

[0031] Test method:

[0032] 1. High performance liquid chromatography detection method

[0033] Content: Take 10 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount (equivalent to 2.5 mg of methotrexate), place in a 25 ml volumetric bottle, add 20 ml of diluent, ultrasonically dissolve methotrexate, cool, dilute to scale with diluent, shake well, filter, and take the filtrate. Use octadecylsilane bonded silica gel as filler (C184.6mm×250mm, 5μm or other chromatographic columns with equivalent performance); use buffer (take 4.2g of anhydrous disodium hydrogen phosphate and 1.8g of citric acid, add 1000ml of water to dissolve, pH value is about 6.0)-acetonitrile (90:10) as mobile phase, flow rate is 1.2ml per minute; column temperature is 25℃; detection wavelength is 302nm; injection volume is 10μl.

[0034] Related substances: Take an appropriate amount of fine powder of this product (equivalent to approximately 10 mg of methotrexate), accurately weigh it, place it in a 25 ml volumetric flask, add an appropriate amount of diluent, sonicate to dissolve the methotrexate, dilute to the scale with the diluent, shake well, filter, and take the filtrate. Octadecylsilane bonded silica gel was used as filler (C18 4.6 mm × 250 mm, 5 μm or other chromatographic columns with equivalent performance); 0.03 mol / L phosphate buffer (4.2 g of anhydrous disodium hydrogen phosphate was dissolved in 1000 ml of water, and the pH value was adjusted to 6.0 with phosphoric acid)-acetonitrile (95:5) was used as mobile phase A, and 0.03 mol / L phosphate buffer (4.2 g of anhydrous disodium hydrogen phosphate was dissolved in 1000 ml of water, and the pH value was adjusted to 6.0 with phosphoric acid)-acetonitrile (50:50) was used as mobile phase B. Linear gradient elution was performed according to Table 1; the flow rate was 1.5 ml per minute; the column temperature was 25°C; the detection wavelength was 280 nm; the injection volume was 20 μl.

[0035] Table 1

[0036] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 10 100 0 20 95 5 35 50 50 45 50 50 45.1 100 0 55 100 0

[0037] 2. Light stability:

[0038] The drug to be tested was placed in an open state in a drug strong light irradiation test box under an illumination of 5000Lx for 10 days and 30 days, and high performance liquid chromatography was used to detect the relevant substances and content in the drug to be tested.

[0039] 3. High humidity stability:

[0040] The drug to be tested is placed in a drug stability test chamber at 25°C and RH92.5% for 10 days and 30 days, and the relevant substances and contents in the drug to be tested are detected by high performance liquid chromatography.

[0041] 4. High temperature stability:

[0042] The drug to be tested was placed in a drug stability test chamber at 60°C for 10 days and 30 days, and high performance liquid chromatography was used to detect the relevant substances and content in the drug to be tested.

[0043] 5. Dissolution:

[0044] The dissolution and release method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Pulp Method) was used to detect the dissolution of the drug to be tested (1 tablet, effective concentration of methotrexate is 2.5 mg), with purified water as the dissolution medium, the rotation speed is 50 rpm, and the sampling time is 45 minutes. Liquid chromatography (high performance liquid chromatography) was used to detect the dissolution of the drug to be tested.

[0045] Dissolution (%) = liquid phase detection concentration / effective concentration of the drug to be tested

[0046] Raw materials used in homemade products:

[0047] Methotrexate: CAS 59-05-2;

[0048] Lactose: purchased from Jiangxi Daoning Pharmaceutical Co., Ltd.;

[0049] Corn starch: purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.;

[0050] Pregelatinized starch: purchased from Shanghai Colorcon Coating Technology Co., Ltd.;

[0051] Magnesium stearate: purchased from Shandong Liujia Pharmaceutical Excipients Co., Ltd.

[0052] Granulation: Use a high-efficiency mixing granulator with a stirring speed of 20-40Hz and a cutting speed of 30-60Hz;

[0053] Drying: Use one-step granulator, air inlet temperature 30-50℃, air inlet volume 45-55HZ;

[0054] Mixing: Use a square cone mixer, mixing speed 15-30rpm, mixing time 20-30 minutes;

[0055] Tabletting: It is carried out by a rotary tablet press with a rotation speed of 25 to 45 rpm, a main pressing thickness of 1.00 to 2.00 mm, and a shallow concave notch die with a diameter of φ8.5 mm.

[0056] Example 1 of the present invention (preparation of 2.5 mg methotrexate tablets)

[0057] prescription

[0058] Serial number name Unit (mg / tablet) 100kg batch 1 Methotrexate 2.50 2.50 2 lactose 57.78 57.78 3 Corn starch 34.70 34.70 4 Pregelatinized starch 4.00 4.00 5 Anhydrous sodium carbonate 0.52 0.52 6 Magnesium Stearate 0.50 0.50 7 total 100.00 100.00g

[0059] 57.78 kg of lactose, 34.70 kg of corn starch and 4.00 kg of pregelatinized starch were added to a wet granulator, with a stirring speed of 20-40 Hz, a cutting speed of 30-60 Hz, and a mixing time of 1-4 min. Then 0.52 kg of anhydrous sodium carbonate was weighed and added to an appropriate amount of purified water, stirred and dissolved, and then 2.50 kg of methotrexate API was added to the aqueous solution of sodium carbonate, stirred and dissolved, and added to the wet granulator after complete dissolution. During the liquid addition process, the wet granulator was turned on for stirring and cutting, with a stirring speed of 20-40 Hz and a cutting speed of 30-60 Hz. After the liquid addition was completed, granulation was performed for 1-4 minutes to obtain wet granules.

[0060] The wet granules are slowly pumped into a one-step granulator, the inlet air temperature range is set to 30°C to 50°C, the inlet air volume frequency is set to 45 to 55HZ, and the granules are dried to a moisture content of ≤4.0%.

[0061] The dry granules were granulated at a frequency of 700±200 rpm.

[0062] 0.50 kg of magnesium stearate and the granules after granulation are added to a square cone mixer and mixed at 15-30 rpm for 20-30 minutes. The total mixed granules are pressed on a rotary tablet press using a Ø8.5 mm die to obtain tablets with an average target weight of 100 mg ± 5% and an average target hardness of 15-75 N.

[0063] Light stability:

[0064] Table 2

[0065]

[0066] According to Example 1, 2.5 mg methotrexate tablets were prepared under 5000 lx light conditions. The content of the reference preparation was reduced from 101.44% to 95.54%, and the content of the reference preparation was reduced from 101.50% to 79.20%. The downward trend of the content was significantly better than that of the reference preparation. At the same time, the growth trend of the related substances was smaller than that of the reference preparation.

[0067] High humidity stability:

[0068] Table 3

[0069]

[0070] According to Example 1, 2.5 mg methotrexate tablets were prepared under 92.5% RH high humidity conditions. Compared with day 0, there was no significant difference in properties and content, and the related substances increased slightly. The reference preparation under 92.5% RH high humidity conditions, compared with day 0, the related substances increased slightly, the content showed a downward trend, and there was no significant difference in properties.

[0071] High temperature stability:

[0072] Table 4

[0073]

[0074]

[0075] The 2.5 mg methotrexate tablets prepared according to Example 1 were significantly better in quality than the reference preparation under high temperature (60° C.).

[0076] Dissolution:

[0077] Table 5

[0078] batch number Dissolution (%) Example 1 99.8、99.7、101.1、99.7、101.1、101.1 Reference preparation GW1078 96.5、96.3、95.3、97.2、97.6、98.9

[0079] The dissolution rate of 2.5 mg methotrexate tablets prepared according to Example 1 is not lower than that of the reference preparation.

[0080] The self-made product of the present invention is described above, but it is not used to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Many forms can also be made without departing from the scope of protection of the purpose of the present invention and the claims, all of which are protected by the present invention.

Claims

1. A method for preparing methotrexate tablets, characterized in that: The following steps are involved: Step 1: sieving the diluent and the binder through an oscillating sieve equipped with a sieve to obtain auxiliary materials; Step 2: dissolving sodium carbonate in purified water to obtain a sodium carbonate solution, adding the methotrexate API to the sodium carbonate solution, reacting the methotrexate with the sodium carbonate to obtain a methotrexate disodium salt solution, the structural formula of the methotrexate disodium salt is shown below; Step 3: Mixing the methotrexate disodium salt solution with the auxiliary materials to prepare granules, and drying the granules to obtain drug granules; Step 4: Mix the drug particles and lubricant evenly, and press into tablets to obtain methotrexate tablets.

2. The method for preparing a methotrexate tablet according to claim 1, characterized in that: The adhesive is selected from one or more of pregelatinized starch, corn starch, povidone, and hypromellose.

3. The method for preparing a methotrexate tablet according to claim 1, characterized in that: The diluent is selected from one or more of lactose, corn starch, mannitol and microcrystalline cellulose.

4. The method for preparing a methotrexate tablet according to claim 1, characterized in that: The lubricant is selected from one or more of magnesium stearate, stearic acid, and sodium stearyl fumarate.

5. The method for preparing a methotrexate tablet according to claim 1, characterized in that: The diluent is lactose and corn starch, the binder is pregelatinized starch, and the lubricant is magnesium stearate; The mass ratio of methotrexate, lactose, corn starch, pregelatinized starch, sodium carbonate and magnesium stearate is: 1.0-10: 30-50: 30-60: 3.0-15: 0.9-7.0: 0.9-7.

0.

6. The method for preparing a methotrexate tablet according to claim 1, characterized in that: In the step 3, granulation is performed by a wet granulator, with a stirring speed of 25 Hz, a knife cutting speed of 35 Hz, and a granulation time of 1 min.

7. The method for preparing a methotrexate tablet according to claim 1, characterized in that: In the step 3, drying treatment refers to drying by fluidized bed, with air inlet temperature of 30-50° C., air inlet volume of 45-55 Hz, and drug particle drying loss of ≤4.0%.

8. The method for preparing a methotrexate tablet according to claim 1, characterized in that: In the step 4, the drug particles and magnesium stearate are mixed by a square cone mixer, the rotation speed of the square cone mixer is 15 to 30 rpm, and the mixing time is 20 to 30 min.

9. The method for preparing a methotrexate tablet according to claim 1, characterized in that: In the step 4, tabletting is performed by a rotary tablet press, the rotation speed of the rotary tablet press is 25-45 rpm, the main pressing thickness is 1.00-2.00 mm, and the mold is a shallow concave notch die with a diameter of φ8.5 mm.

10. A methotrexate tablet, characterized in that: The methotrexate tablet is prepared by using the above-mentioned preparation method of the methotrexate tablet.

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