A method for preparing a pharmaceutical composition containing fluorouracil

Abstract

The present invention provides a method for preparing a pharmaceutical composition containing fluorouracil. 5-fluorouracil and salicylic acid are mixed to prepare the pharmaceutical composition, methanol and water are used as solvents, the mixture is refluxed at 50-55°C for 30-50 minutes to fully dissolve the mixture, and the mixture is allowed to stand for 8-12 hours to produce a finished product. The method for preparing the pharmaceutical composition containing fluorouracil can improve the stability of 5-fluorouracil and prolong the blood concentration of 5-fluorouracil in the systemic circulation.

Description

Technical Field

[0001] The present invention relates to the technical field of fluorouracil preparation, and in particular to a method for preparing a pharmaceutical composition containing fluorouracil. Background Art

[0002] Pyrimidine drugs are widely used in various medical fields, including anti-inflammatory, antipyretic, antifungal, antiviral, antioxidant, and anti-tumor drugs. Pyrimidine compounds have become a key discovery in the 21st century in anti-tumor drugs and represent a potential and effective lead in cancer treatment. The presence of multiple interchangeable substitution sites on the pyrimidine ring provides pyrimidines with diverse variations and targets.

[0003] 5-Fluorouracil is a homologue of uracil, a uracil with a fluorine atom substituent. Its mechanism of action is that, after being absorbed by cancer cells, it can interfere with DNA synthesis within the cancer cells, thereby affecting RNA production, ultimately preventing protein production and disrupting several physiological processes within the cancer cells. Ultimately, this can lead to cancer cell death due to insufficient nutrient supply. Studies have shown that intravenous injection of 5-fluorouracil can lead to a rapid drop in blood concentration and significant side effects. When formulated into capsules and tablets, 5-fluorouracil is preferentially broken down and absorbed in gastric fluid, resulting in reduced therapeutic efficacy for colorectal cancer patients. Prior art studies have investigated the preparation and sustained-release properties of 5-fluorouracil-modified attapulgite, leveraging the adsorption properties of attapulgite to achieve sustained-release properties. However, these technologies do not address the significant side effects associated with 5-fluorouracil. In clinical use, 5-fluorouracil can cause nausea, loss of appetite, and vomiting. Some patients experience leukopenia, and combined with cancer cell interference, adverse reactions such as thrombosis can occur. Therefore, a method for preparing a pharmaceutical composition containing fluorouracil is proposed to solve the above problems. Summary of the Invention

[0004] In view of this, the present invention proposes a method for preparing a pharmaceutical composition containing fluorouracil to solve the above problems.

[0005] The technical solution of the present invention is achieved as follows:

[0006] A method for preparing a pharmaceutical composition containing fluorouracil comprises the following steps: adding 5-fluorouracil and salicylic acid into a solvent, mixing, standing, and drying to obtain a finished product.

[0007] Furthermore, the molar ratio of 5-fluorouracil to salicylic acid is 1:1.7-2.2.

[0008] Furthermore, the solvent is methanol and water.

[0009] Furthermore, the solvent is methanol and water in a mass ratio of 1:3-7.

[0010] In the present invention, methanol and water are used as solvents, which can fully dissolve 5-fluorouracil and salicylic acid and are conducive to the formation of precipitation.

[0011] Furthermore, the mass ratio of the 5-fluorouracil to the solvent is 1:8-12.

[0012] Furthermore, the mixing is performed by adding 5-fluorouracil and salicylic acid into a solvent, heating to 50-55° C., and refluxing for 30-50 minutes.

[0013] Furthermore, the standing is standing at 30-35° C. for 8-12 hours.

[0014] Furthermore, the drying is to collect the crystals and dry them at 85-100° C. for 7-10 hours.

[0015] Furthermore, the heating rate is 2-4°C / min.

[0016] According to the present invention, 5-fluorouracil and salicylic acid are added to a solvent, heated to 50-55° C., and refluxed for 30-50 minutes, thereby promoting the mixing of 5-fluorouracil and salicylic acid. In the present invention, the heating rate is further controlled to be 2-4° C. / min, thereby effectively preventing the adverse reaction of increased by-products caused by the thermal decomposition of salicylic acid.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] The present invention utilizes a mixture of 5-fluorouracil and salicylic acid to prepare a pharmaceutical composition containing fluorouracil, which improves the stability of 5-fluorouracil and prolongs its blood concentration in the systemic circulation. In clinical use, 5-fluorouracil can cause symptoms such as nausea, loss of appetite, and vomiting. Some patients also experience leukopenia, and combined with cancer cell interference, it can cause adverse reactions such as thrombosis. Research in the present invention has found that salicylic acid can not only be mixed with 5-fluorouracil, but also, through its own properties, can reduce the likelihood of adverse reactions such as thrombosis. DETAILED DESCRIPTION

[0019] In order to better understand the technical content of the present invention, specific examples are provided below to further illustrate the present invention.

[0020] Unless otherwise specified, the experimental methods used in the examples of the present invention are all conventional methods.

[0021] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0022] Example 1

[0023] 5-Fluorouracil and salicylic acid in a molar ratio of 1:2 were added to a solvent consisting of methanol and water in a mass ratio of 1:5, the mass ratio of 5-fluorouracil to the solvent was 1:10, and the mixture was heated to 53°C at 3°C / min, refluxed for 40 minutes, allowed to stand at 33°C for 10 hours, the precipitate was collected, and dried at 95°C for 8.5 hours to obtain the finished product.

[0024] Example 2

[0025] 5-Fluorouracil and salicylic acid in a molar ratio of 1:1.7 were added to a solvent consisting of methanol and water in a mass ratio of 1:3, the mass ratio of 5-fluorouracil to the solvent was 1:10, and the mixture was heated to 50°C at 2°C / min, refluxed for 30 minutes, allowed to stand at 30°C for 8 hours, the precipitate was collected, and dried at 85°C for 7 hours to obtain the finished product.

[0026] Example 3

[0027] 5-Fluorouracil and salicylic acid in a molar ratio of 1:2.2 were added to a solvent consisting of methanol and water in a mass ratio of 1:7, the mass ratio of 5-fluorouracil to the solvent was 1:10, and the mixture was heated to 55°C at 4°C / min, refluxed for 50 minutes, allowed to stand at 35°C for 12 hours, the precipitate was collected, and dried at 100°C for 10 hours to obtain the finished product.

[0028] Comparative Example 1

[0029] 5-Fluorouracil and salicylic acid in a molar ratio of 1:1.5 were added to a solvent consisting of methanol and water in a mass ratio of 1:5, the mass ratio of 5-fluorouracil to the solvent was 1:10, and the mixture was heated to 53°C at 3°C / min, refluxed for 40 minutes, allowed to stand at 33°C for 10 hours, the precipitate was collected, and dried at 95°C for 8.5 hours to obtain the finished product.

[0030] Comparative Example 2

[0031] 5-Fluorouracil and salicylic acid in a molar ratio of 1:2 were added to a solvent consisting of methanol and water in a mass ratio of 1:15, the mass ratio of 5-fluorouracil to the solvent was 1:10, and the mixture was heated to 53°C at 3°C / min, refluxed for 40 minutes, allowed to stand at 33°C for 10 hours, the precipitate was collected, and dried at 95°C for 8.5 hours to obtain the finished product.

[0032] Comparative Example 3

[0033] 5-Fluorouracil and salicylic acid in a molar ratio of 1:2 were added to a solvent consisting of methanol and water in a mass ratio of 1:5, and the mass ratio of 5-fluorouracil to the solvent was 1:10. The mixture was directly heated to 53°C, refluxed for 40 minutes, and allowed to stand at 33°C for 10 hours. The precipitate was collected and dried at 95°C for 8.5 hours to obtain the finished product.

[0034] Comparative Example 4

[0035] 5-Fluorouracil and salicylic acid in a molar ratio of 1:2 were added to an aqueous solution with a pH value of 8.5, and the mixture was heated to 53°C at a rate of 3°C / min, with a mass ratio of 5-fluorouracil to solvent of 1:10. The mixture was refluxed for 40 minutes, allowed to stand at 33°C for 10 hours, the precipitate was collected, and dried at 95°C for 8.5 hours to obtain the finished product.

[0036] Comparative Example 5

[0037] 5-Fluorouracil and salicylic acid in a molar ratio of 1:2 were added to a solvent consisting of methanol and water in a mass ratio of 1:5, the mass ratio of 5-fluorouracil to the solvent was 1:10, and the mixture was heated to 70°C at 3°C / min, refluxed for 40 minutes, allowed to stand at 33°C for 10 hours, the precipitate was collected, and dried at 95°C for 8.5 hours to obtain the finished product.

[0038] Recovery statistics of Test Example 1

[0039] Recovery rate (%) = finished product weight / total weight of 5-fluorouracil and salicylic acid × 100

[0040] name Recovery rate (%) Example 1 95.8 Example 2 94.2 Example 3 94.9 Comparative Example 1 95.3 Comparative Example 2 93.7 Comparative Example 3 87.3 Comparative Example 4 90.6 Comparative Example 5 85.1

[0041] The experimental results show that the preparation method of the pharmaceutical composition containing fluorouracil of the present invention can improve the recovery rate. In comparative example 1, the ratio of 5-fluorouracil and salicylic acid is adjusted, resulting in poor mixing effect and decreased dissolution effect of salicylic acid in the solvent. In comparative example 2, the solvent ratio is adjusted, resulting in poor dissolution effect of 5-fluorouracil and salicylic acid, and salicylic acid is precipitated during the crystallization process. In comparative example 3, the heating rate is not controlled, resulting in rapid decomposition of salicylic acid, failure to react completely with 5-fluorouracil, and decreased recovery rate. In comparative example 4, the solvent is adjusted, and the solution effect of 5-fluorouracil in an aqueous solution with a pH value of 8.5 is good. Salicylic acid is heated and decomposed, and mixed with alkali solution, resulting in changes in the color of the finished product, resulting in a significant decrease in the recovery rate. In comparative example 5, the reflux temperature is adjusted, and the temperature is too high, resulting in a decrease in the recovery rate. In the present invention, by reasonably proportioning the raw materials and adjusting the reaction temperature, 5-fluorouracil and salicylic acid are fully dissolved, which is conducive to the preparation of the finished product.

[0042] Test Example 2

[0043] A phosphate buffer solution with a pH value of 7.4 and a hydrochloric acid solution with a pH value of 2 were prepared, and the release rates of 5-fluorouracil and the fluorouracil prepared in Example 1 in the phosphate buffer solution with a pH value of 7.4 and the hydrochloric acid solution with a pH value of 2 were detected using an ultraviolet spectrophotometer.

[0044] Preparation of standard curve: Using phosphate buffer solution with pH 7.4 and hydrochloric acid solution with pH 2 as solvents, prepare 5-fluorouracil standard solutions of 0.02, 0.04, 0.06, 0.08 and 0.1 mg / ml, respectively. Use ultraviolet spectrophotometer to measure the absorbance at 265 nm to draw the standard curve.

[0045] Experimental procedure: 20 mg of 5-fluorouracil and fluorouracil prepared in Example 1 were added to the medium respectively, shaken at 37° C., and the absorbance was measured every 1 h. The absorbance was substituted into the standard curve to calculate the release rate (%).

[0046] name pH 7.4 (4h) pH 7.4 (6h) pH2(4h) pH2(6h) 5-Fluorouracil release rate (%) 5.03 5.19 3.74 3.92 Example 1 Release rate (%) 9.72 12.87 7.88 8.36

[0047] The experimental results show that the pharmaceutical composition containing fluorouracil prepared by the present invention is more conducive to maintaining the blood drug concentration than 5-fluorouracil.

[0048] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a pharmaceutical composition containing fluorouracil, characterized in that: The preparation method comprises the following steps: adding 5-fluorouracil and salicylic acid in a molar ratio of 1:1.7-2.2 to a mixed solvent of methanol and water in a mass ratio of 1:3-7, wherein the mass ratio of 5-fluorouracil to the solvent is 1:8-12; mixing the mixture; heating the mixture to 50-55°C at a heating rate of 2-4°C / min; reflux for 30-50 minutes; standing the mixture; and drying the mixture to obtain a finished product.

2. The method for preparing a pharmaceutical composition containing fluorouracil according to claim 1, wherein: The standing is standing at 30-35° C. for 8-12 hours.

3. The method for preparing the pharmaceutical composition containing fluorouracil according to claim 1, wherein: The drying step is to collect the crystals and dry them at 85-100° C. for 7-10 hours.