1, 3-bis [4-(trifluoromethyl) phenyl] urea solid dispersion and preparation method and application thereof

Abstract

The invention discloses a 1, 3-bis [4-(trifluoromethyl) phenyl] urea solid dispersion and a preparation method and application thereof, the solid dispersion comprises a drug and a carrier, the drug is 1, 3-bis [4-(trifluoromethyl) phenyl] urea, the carrier is a mixture of polyvinylpyrrolidone and a solubilizer, and the solid dispersion can be applied to preparation of drugs for treating inflammatory bowel diseases. The 1, 3-bis [4-(trifluoromethyl) phenyl] urea solid dispersion is prepared by adopting a mixed carrier of polyvinylpyrrolidone and sodium dodecyl sulfate, changing a drug into an amorphous state by using polyvinylpyrrolidone and simultaneously increasing the solubility of the drug by using the solubilizing effect of sodium dodecyl sulfate, and the solid dispersion can improve the solubility of the drug and improve the bioavailability of the drug. In the treatment of the inflammatory bowel disease, an excellent treatment effect is achieved.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion, a preparation method and an application thereof. Background Art

[0002] Ulcerative colitis (UC) is a chronic, nonspecific colorectal inflammation, a type of inflammatory bowel inflammation. The main clinical manifestations are pathological intestinal mucosal damage, diarrhea, bloody stools, and weight loss. In recent years, the incidence of the disease has increased significantly, and it has become a global disease, bringing a huge economic burden to the healthcare system. Due to the complexity of the pathogenesis of UC, there is still a lack of specific cure drugs in clinical practice. Commonly used quality drugs in clinical practice include aminosalicylic acids, immunosuppressants, glucocorticoids, and biologics. The above-mentioned drugs mainly reduce inflammation by inhibiting abnormal immune responses, and have disadvantages such as obvious side effects, high recurrence rate, and high price. Therefore, there is an urgent need to develop new safe and effective drugs for the treatment of UC.

[0003] Studies have shown that activation of Mas-related G-protein-coupled receptor member X2 (MrgX2) on mast cells is associated with UC inflammation, suggesting that MrgX2 could be a new therapeutic target for UC. 1,3-Bis[4-(trifluoromethyl)phenyl]urea has been confirmed to be an MrgX2 antagonist that can inhibit MrgX2-mediated mast cell activation and could be used as a potential drug for the treatment of UC; however, its poor solubility and low bioavailability limit its application. Summary of the invention

[0004] In order to solve the problems of poor solubility and low bioavailability of 1,3-bis[4-(trifluoromethyl)phenyl]urea in the prior art, the present invention aims to provide a 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion, a preparation method and an application thereof. The dispersant can improve the solubility of 1,3-bis[4-(trifluoromethyl)phenyl]urea, thereby increasing the bioavailability.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] A 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion comprises a drug and a carrier, wherein the drug is 1,3-bis[4-(trifluoromethyl)phenyl]urea and the carrier is a mixture of polyvinyl pyrrolidone and a solubilizer.

[0007] A further improvement of the present invention is that the solubilizing agent is dodecyl sulfonic acid.

[0008] A further improvement of the present invention is that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecylsulfonate is 1:3-9:3-9.

[0009] A method for preparing a 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion comprises the following steps:

[0010] 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and a solubilizing agent are dissolved in a solvent, dispersed uniformly, dried, crushed and sieved to obtain a solid dispersion.

[0011] A further improvement of the present invention is that the solubilizing agent is dodecyl sulfonic acid.

[0012] A further improvement of the present invention is that when 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfonate are dissolved in a solvent, the mass ratio of the 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfonate is 1:3-9:3-9.

[0013] A further improvement of the present invention is that the solvent is ethanol; the drying method is reduced pressure drying; and the sieving is a 80-mesh sieve.

[0014] A pharmaceutical composition comprising a solid dispersion and at least one intragranular excipient.

[0015] A further improvement of the present invention is that the pharmaceutical composition is a tablet, capsule, granule, sustained-release preparation or controlled-release preparation.

[0016] A 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion is used in the preparation of a drug for treating inflammatory bowel disease.

[0017] A further improvement of the present invention is that the inflammatory bowel disease is ulcerative colitis.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] In the present invention, polyvinyl pyrrolidone can improve the solubility and bioavailability of poorly soluble drugs through hydrogen bonding or complexation; sodium dodecyl sulfate is a surfactant, and its solubilization effect can significantly improve the solubility of poorly soluble drugs, and is also used to prepare amorphous solid dispersions. The present invention uses a mixed carrier of polyvinyl pyrrolidone and sodium dodecyl sulfate, and uses polyvinyl pyrrolidone to make the drug into an amorphous state. At the same time, the solubilization effect of sodium dodecyl sulfate increases the solubility of the drug, thereby preparing a 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion, which can improve the solubility of the drug and improve the bioavailability.

[0020] Furthermore, when the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinylpyrrolidone and sodium dodecylsulfonate is 1:9:9, the prepared 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion has the highest solubility. Activity tests have shown that 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion can significantly inhibit the occurrence and development of experimental colitis and effectively alleviate colitis-related symptoms. It can not only alleviate the symptoms of experimental animals caused by colitis, such as weight loss, increased disease activity index (DAI), colon and spleen enlargement, etc., so as to achieve the purpose of preventing and treating colitis.

[0021] The 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion of the present invention improves the bioavailability of poorly soluble drugs, can be applied to the treatment of inflammatory bowel disease, and achieves excellent therapeutic effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The solubility diagram of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion in water within 6 hours with different ratios; wherein a is 1:9:3-9, b is 1:6:3-9, and c is 1:3:3-9;

[0023] Figure 2 This is a line graph showing the average weight changes of the four groups of mice in Example 1;

[0024] Figure 3 This is a statistical diagram of the average DAI of the four groups of mice in Example 1;

[0025] Figure 4 The macroscopic images of spleen and colon of four groups of mice in Example 1 and the average colon weight and length ratio; wherein (a) is the colon length and (b) is the average colon weight;

[0026] Figure 5 is the average spleen weight to mouse body weight ratio of the four groups of mice in Example 1;

[0027] Figure 6 This is a graph showing the average FITC-dextran detection results of the three groups of mice in Example 1. DETAILED DESCRIPTION

[0028] In order to facilitate the understanding of the present invention, the present invention will be described more fully below with reference to the relevant drawings. The preferred embodiments of the present invention are given in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly and comprehensively understood.

[0029] The 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion of the present invention comprises a drug and a carrier, wherein the drug is 1,3-bis[4-(trifluoromethyl)phenyl]urea and the carrier is a mixture of polyvinyl pyrrolidone and sodium dodecyl sulfate.

[0030] The mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfonate is 1:3 to 9:3 to 9. When the carrier is polyvinyl pyrrolidone, the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea to polyvinyl pyrrolidone is 1:3 to 11.

[0031] A method for preparing a 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion of the present invention comprises the following steps:

[0032] 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfonate are dissolved in a solvent, or 1,3-bis[4-(trifluoromethyl)phenyl]urea and polyvinyl pyrrolidone are dissolved in a solvent, dispersed uniformly, the solvent is removed, and the mixture is dried under reduced pressure at 25-50° C., crushed, and passed through an 80-mesh sieve to obtain a solid dispersion.

[0033] A pharmaceutical composition of the present invention comprises a solid dispersion and at least one intragranular excipient.

[0034] Furthermore, the pharmaceutical composition is a tablet, capsule, granule, sustained-release preparation or controlled-release preparation formed by compressing the solid dispersion with an intra-granular excipient.

[0035] The invention discloses an application of the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion in the preparation of a drug for treating inflammatory bowel disease.

[0036] Furthermore, the inflammatory bowel disease is ulcerative colitis.

[0037] Example 1

[0038] The preparation method of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion in this embodiment comprises the following steps:

[0039] 1,3-Bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate were dissolved in ethanol, stirred and dispersed for 30 minutes, the solvent was removed, and the mixture was dried under reduced pressure at 37° C., crushed, and passed through an 80-mesh sieve to obtain a solid dispersion.

[0040] Wherein, the mass ratio of the 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:9:9.

[0041] Example 2

[0042] The preparation method of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion in this embodiment comprises the following steps:

[0043] 1,3-Bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate were dissolved in ethanol, stirred and dispersed for 30 minutes, the solvent was removed, and the mixture was dried under reduced pressure at 37° C., crushed, and passed through an 80-mesh sieve to obtain a solid dispersion.

[0044] Wherein, the mass ratio of the 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:3:3.

[0045] Example 3

[0046] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:3:5.

[0047] Example 4

[0048] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:3:7.

[0049] Example 5

[0050] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:3:9.

[0051] Example 6

[0052] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:6:3.

[0053] Example 7

[0054] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:6:5.

[0055] Example 8

[0056] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:6:7.

[0057] Example 9

[0058] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:6:9.

[0059] Example 10

[0060] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:9:3.

[0061] Embodiment 11

[0062] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:9:5.

[0063] Example 12

[0064] Same as Example 2, except that the mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:9:7.

[0065] Performance Test:

[0066] The solid dispersions of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate in different mass ratios were placed in a dissolution cup of 200 mL of aqueous solution. The speed of the dissolution apparatus was 100 r / min and the temperature was 37°C. 1 mL of samples were taken at 5 min, 10 min, 15 min, 30 min, 60 min, 90 min, 120 min, 180 min and 360 min, respectively. 1 mL of dissolution medium of the same temperature and quality was added to the dissolution cup, and the 1,3-bis[4-(trifluoromethyl)phenyl] content of the taken samples was determined.

[0067] Figure 1 As can be seen from a, b and c, the solubility of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersions with different ratios within 6 hours is different. Most of the solubility gradually decreases over time, while the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion with a mass ratio of 1:9:9 of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate has the highest solubility within 6 hours, proving that this ratio is most effective in improving the solubility of 1,3-bis[4-(trifluoromethyl)phenyl]urea.

[0068] The following model is established and corresponding drug intervention is carried out:

[0069] (1) Animal experiment: C57BL / 6 mice were induced with 3% DSS solution to establish a colitis model (freely drinking DSS aqueous solution for 10 days), and the mice were divided into groups, with 12 mice in each group, namely, 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion high-dose treatment group (DPU-H), 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion low-dose treatment group (DPU-H), Colitis-colitis group (colitis model group caused by using DSS chemical reagent, UC), and Ctrl-blank control group (healthy mice not treated with DSS chemical reagent, Control);

[0070] (2) The high-dose treatment group was gavaged with 5 mg / kg 11,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion daily; the low-dose treatment group was gavaged with 1 mg / kg 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion daily. The weight changes and DAI scores of the mice were recorded daily. The DAI score standard is shown in Table 1:

[0071] Table 1 DAI scoring criteria

[0072]

[0073] (3) Biological sample collection and analysis: On the 8th day, the mice were killed, the weights of the colon and spleen were recorded, and the therapeutic effect of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion on colitis mice was analyzed. The results are as follows: Figure 2 , Figure 3 , Figure 4 (a) and (b) and Figure 5 As shown, Figure 2 This is a line graph showing the average weight changes of the four groups of mice. Figure 3 The average DAI statistical results of the four groups of mice are shown in the figure. Figure 4 (a) and (b) show the macroscopic images of typical spleen and colon of four groups of mice and the average colon weight and length ratio. Figure 5 The average spleen weight and mouse body weight ratio of the four groups of mice.

[0074] Depend on Figure 2 and 3It can be seen that the high-dose and low-dose groups of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion can significantly reduce the weight loss and DAI index of colitis mice. It can be found that the weight of colitis mice showed a trend of first increasing and then decreasing, and the treatment with 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion significantly alleviated the trend of weight loss. At the same time, the DAI index of colitis mice continued to increase with the extension of modeling time, and the treatment with 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion significantly alleviated the increase in the DAI index, which shows that 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion has a significant effect on the weight loss and bloody stool characteristics of colitis mice.

[0075] Depend on Figure 4 (a) and (b) and Figure 5 It can be seen that 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion can inhibit the shortening of colon length and swelling of spleen in colitis mice. From the morphological diagram of colon and spleen, it can be intuitively found that the treatment of 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion can alleviate the shortening of colon and swelling of spleen caused by colitis. Similar conclusions can be obtained by analyzing the ratio of colon weight and length and spleen weight to body weight.

[0076] (4) Characterization of intestinal permeability function: On the 8th day, 3 mice were randomly selected from each group, and the intestinal permeability of mice was investigated using fluorescein isothiocyanate (FITC)-dextran. Specifically, the mice were fasted for 4 hours, and then 4kDa fluorescent dye fluorescein isothiocyanate (FITC)-dextran (60 mg / 100 g) was orally administered. After 5 hours, the concentration of FITC-dextran in the serum of each group of mice was calculated based on the standard curve prepared by serial dilution of FITC-dextran to evaluate the structural integrity of the intestinal barrier. The results are shown in Figure 6.

[0077] Depend on Figure 6 It can be seen that the treatment with 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion can significantly reduce the intestinal permeability of colitis mice. The intestinal permeability was investigated by fluorescein isothiocyanate (FITC) in mice. The concentration of FITC in the serum of colitis mice was significantly increased compared with that of healthy mice, and was significantly reduced after intervention with 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion.

[0078] Data statistics: Graphpad prism 8.4 (Graphpad, San Diego, CA) was used for statistical analysis. P < 0.05 ( * / # p<0.05, ** / ## p<0.01, *** / ###p<0.001) was considered statistically significant, and all data were expressed as mean ± SEM.

[0079] In the present invention, polyvinyl pyrrolidone and sodium dodecyl sulfate are used as a combined dispersion medium, 1,3-bis[4-(trifluoromethyl)phenyl]urea is used as an active drug, and a solid dispersion is prepared by a solvent evaporation method. The solid dispersion can effectively alleviate the symptoms of colitis-induced weight loss, increased disease activity index (DAI), colon and spleen enlargement in experimental animals, and has great prospects in the treatment of inflammatory bowel disease.

[0080] The above description is only for the best embodiment of the present invention, but it should not be understood as limiting the claims. The present invention is not limited to the above embodiments, and its specific structure is allowed to be changed. However, all changes made within the protection scope of the independent claims of the present invention are within the protection scope of the present invention.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used herein in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more related listed items.

Claims

1. A 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion, characterized in that: The invention comprises a drug and a carrier, wherein the drug is 1,3-bis[4-(trifluoromethyl)phenyl]urea and the carrier is a mixture of polyvinyl pyrrolidone and a solubilizer.

2. The 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion according to claim 1, characterized in that The solubilizing agent is dodecyl sulfonic acid.

3. The 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion according to claim 1, characterized in that The mass ratio of 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfate is 1:3-9:3-9.

4. A method for preparing a 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion, characterized in that: The following steps are involved: 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and a solubilizing agent are dissolved in a solvent, dispersed uniformly, dried, crushed and sieved to obtain a solid dispersion.

5. The method for preparing the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion according to claim 4, characterized in that: The solubilizing agent is dodecyl sulfonic acid.

6. The method for preparing the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion according to claim 4, characterized in that: When 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfonate are dissolved in a solvent, the mass ratio of the 1,3-bis[4-(trifluoromethyl)phenyl]urea, polyvinyl pyrrolidone and sodium dodecyl sulfonate is 1:3-9:3-9.

7. The method for preparing the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion according to claim 4, characterized in that: The solvent is ethanol; the drying method is reduced pressure drying, and the sieving is 80 mesh sieve.

8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises one of the solid dispersion according to any one of claims 1 to 3 and the solid dispersion prepared by any one of claims 4 to 7 and at least one intragranular excipient.

9. Use of the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion according to any one of claims 1 to 3 or the 1,3-bis[4-(trifluoromethyl)phenyl]urea solid dispersion prepared by any one of claims 4 to 7 in the preparation of a drug for treating inflammatory bowel disease.

10. The use according to claim 9, characterized in that: The inflammatory bowel disease is ulcerative colitis.

Images