Application of 3-ylurea propionic acid and pharmaceutical composition thereof in preparation of medicine for treating psoriasis

Abstract

The invention relates to the field of new application of compounds, in particular to application of 3-ylurea propionic acid and a pharmaceutical composition thereof in preparation of drugs for treating psoriasis. According to the invention, a BALB / c mouse psoriasis model is constructed through induction of imiquimod emulsifiable paste, and the therapeutic effect of a compound 3-ylurea propionic acid on the model is researched. Researches find that compared with a model group, apparent skin lesion and histopathologic lesion of back skin of a 3-ylurea propionic acid group are remarkably relieved; the spleen swelling and the spleen index are obviously reduced; and the levels of IL-6 and TNF-alpha in serum are reduced. Experimental exploration proves that the compound 3-ylurea propionic acid has an anti-inflammatory effect and has a treatment effect on a mouse psoriasis model. The invention not only provides a new application direction for 3-ylurea propionic acid, but also provides a new drug choice for psoriasis treatment.

Description

Technical Field

[0001] This invention relates to new applications of compounds, and in particular to the use of 3-acylurea propionic acid and its pharmaceutical compositions in the preparation of drugs for treating psoriasis. Background Technology

[0002] Psoriasis, also widely known as "cowhide rash," is a common polygenic inherited skin disease. Its clinical manifestations are diverse, mainly including: red plaques on the skin, often covered with silvery-white scales, accompanied by itching, burning, or pain; dry, cracked skin, and even bleeding. Some patients may also experience joint pain, swelling, and nail lesions.

[0003] Currently, the treatment goals for psoriasis focus on controlling disease progression and alleviating symptoms. Common methods include medication, phototherapy, and traditional Chinese medicine. Although the disease cannot be cured, active and standardized treatment can significantly reduce skin lesions, promote symptom resolution, and prevent serious complications, thereby effectively improving patients' quality of life. However, psoriasis has a high incidence, a prolonged course, and a high relapse rate. Furthermore, existing treatments are either expensive or have significant side effects, placing a heavy financial burden on patients and causing significant distress to their physical and mental health, impacting their daily lives and work.

[0004] Therefore, developing new drugs for psoriasis that are both highly effective and safe has significant clinical and social value. Summary of the Invention

[0005] The purpose of this invention is to provide the application of 3-acylurea propionic acid and its pharmaceutical composition in the preparation of drugs for treating psoriasis. Studies have found that topical application of 3-acylurea propionic acid to psoriatic skin can relieve skin symptoms and has a significant therapeutic effect.

[0006] The first aspect of the present invention provides the use of 3-acylurea propionic acid and pharmaceutical compositions thereof in the preparation of medicaments for treating psoriasis.

[0007] 3-Acylurea propionic acid, also known as N-carbamoyl β-alanine, has the molecular formula C4H8N2O3 and a molecular weight of 132.11800. Its molecular structure is as follows: .

[0008] Furthermore, the drug is used to alleviate superficial skin lesions and / or histopathological damage.

[0009] Furthermore, the drug is used to reduce symptoms of scaling, thickening, and / or bulging on the surface of skin lesions.

[0010] Furthermore, the drug is used to relieve splenomegaly and elevated spleen index.

[0011] Furthermore, the drug is used to inhibit the increase of intracellular inflammatory factors IL-6 and TNF-α.

[0012] A second aspect of the invention provides the use of a pharmaceutical composition in the preparation of a medicament for treating psoriasis, said pharmaceutical composition comprising an effective amount of 3-acylurea propionic acid and pharmaceutically acceptable excipients.

[0013] Furthermore, the excipients include at least one of diluents, excipients, fillers, binders, humectants, absorption promoters, surfactants, lubricants, stabilizers, flavorings, sweeteners, and colorings.

[0014] Furthermore, in the pharmaceutical composition, the concentration of 3-acylurea propionic acid is 0.1 mg / mL to 50 mg / mL. Preferably, in the pharmaceutical composition, the concentration of 3-acylurea propionic acid is 1 mg / mL to 30 mg / mL.

[0015] Furthermore, the dosage form of the pharmaceutical composition is an oral preparation, an injectable preparation, or a topical preparation; wherein, the topical preparation is a cream, ointment, gel, lotion, foam, spray, or oil.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides the application of 3-acylurea propionic acid and pharmaceutical compositions comprising an effective amount of 3-acylurea propionic acid in the preparation of drugs for treating psoriasis. This invention utilizes imiquimod cream to induce a BALB / c mouse psoriasis model and investigates the therapeutic effect of compound 3-acylurea propionic acid on this model. The study found that compared to the model group, the 3-acylurea propionic acid group showed reduced superficial skin lesions and histopathological damage on the back; splenomegaly was alleviated; and serum IL-6 and TNF-α levels were decreased. Experimental investigations demonstrate that compound 3-acylurea propionic acid has anti-inflammatory effects and exerts a therapeutic effect on the mouse psoriasis model. This not only provides a new application direction for 3-acylurea propionic acid but also offers a new drug option for the treatment of psoriasis. Attached Figure Description

[0017] Figure 1 This is a time flow chart of the experiments in the psoriasis model group and the drug treatment group in Example 1.

[0018] Figure 2 The image illustrates the effect of 3-acylurea propionic acid on the apparent skin lesions of IMQ mice.

[0019] Figure 3 The graph shows the effect of 3-acylurea propionate on spleen changes in IMQ mice. Figure 3 A in the figure represents the morphological observation of the spleen of a BALB / c mouse; Figure 3 B in the graph represents the spleen index calculation data of BALB / c mice (n=5).

[0020] Figure 4 Figure 1 shows the experimental results of the effect of 3-acylurea propionic acid on the histopathological changes of IMQ mice. Figure 4 In the image, A represents HE staining data of the dorsal tissue of BALB / c mice; Figure 4 B in the graph represents the Baker score (n=5) data for skin tissue lesions.

[0021] Figure 5 Figure 1 shows the experimental results of the effect of 3-acylurea propionate on the serum levels of inflammatory response-related factors in IMQ mice. Figure 5 In the figure, A represents the data on the effect of IL-6 levels on serum levels; Figure 5 In the figure, B represents the effect on serum TNF-α levels (n=5). Detailed Implementation

[0022] The present invention will now be described in further detail with reference to specific embodiments. However, this should not be construed as limiting the scope of the present invention to the following embodiments; all technologies implemented based on the content of the present invention fall within the scope of the present invention.

[0023] The first aspect of this embodiment provides the use of 3-acylurea propionic acid and pharmaceutical compositions thereof in the preparation of medicaments for treating psoriasis.

[0024] 3-Acylurea propionic acid, also known as N-carbamoyl β-alanine, has the molecular formula C4H8N2O3 and a molecular weight of 132.11800. Its molecular structure is as follows: .

[0025] In some embodiments, the drug is used to alleviate superficial skin lesions and / or histopathological damage.

[0026] In some embodiments, the drug is used to reduce symptoms of scaling, thickening, and / or elevation on the surface of skin lesions. And / or, the drug is used to relieve splenomegaly and elevated spleen index. And / or, the drug is used to inhibit the increase of intracellular inflammatory factors IL-6 and TNF-α.

[0027] A second aspect of this embodiment provides the use of a pharmaceutical composition in the preparation of a medicament for treating psoriasis, the pharmaceutical composition comprising an effective amount of 3-acylurea propionic acid and pharmaceutically acceptable excipients.

[0028] In some embodiments, the excipients include at least one of diluents, excipients, fillers, binders, humectants, absorption enhancers, surfactants, lubricants, stabilizers, flavorings, sweeteners, and colorings.

[0029] In some embodiments, in the pharmaceutical composition, the concentration of 3-acylurea propionic acid is 0.1 mg / mL to 50 mg / mL. Preferably, in the pharmaceutical composition, the concentration of 3-acylurea propionic acid is 1 mg / mL to 30 mg / mL.

[0030] In some embodiments, the dosage form of the pharmaceutical composition is an oral preparation, an injection preparation or a topical preparation; wherein, the topical preparation is a cream, an ointment, a gel, a lotion, a foam, a spray or an oil.

[0031] In order to further understand the technical solutions of the above embodiments, the present invention provides the following more specific implementation manners for further explanation.

[0032] Example 1 Experimental purpose To evaluate the efficacy of the potential anti-psoriasis compound 3-acylurea propionic acid in the treatment of psoriasis using an IMQ (imiquimod)-induced psoriasis model in BALB / c mice.

[0033] Materials and methods Mouse strain Six-week-old male BALB / c mice were purchased from Beijing Specific-pathogen-free Animal Technology Co., Ltd., SPF level, production license SCXK (Beijing) 2024-0001. The experimental animals were housed in an environment with a room temperature of (22 ± 2) °C, a humidity of 50% - 60%, and a light cycle of (12 hours light / 12 hours dark). The place where the animal experiments were carried out was the SPF animal breeding room of the College of Pharmacy, Chengdu University of Traditional Chinese Medicine, and they were housed individually in cages, with the use license SYXK (Sichuan) 2020-0124.

[0034] Experimental design After the adaptive feeding was completed and the mice were randomly grouped, the hair on the central area of the back of the mice was carefully shaved off with an electric hair clipper to form an exposed area of 2 cm × 3 cm, and then the surface fine hair was removed using a mild hair removal cream.

[0035] The BALB / c mice were randomly divided into a blank control group (Control), a psoriasis model group (IMQ), and a 3-acylurea propionic acid administration group (3-UA, 2.5 mg / mL), with 5 mice in each group. As Figure 1As shown, the model group received daily topical application of 5% imiquimod (IMQ) ointment (purchased from Sichuan Mingxin Pharmaceutical Co., Ltd.), approximately 62.5 mg per mouse, to the hairless skin on their backs for 7 consecutive days. In the treatment group, when significant inflammatory responses appeared on day 5 after application of 5% imiquimod (IMQ) ointment, 2.5 mg / mL 3-acylurea propionate (purchased from Sigma) PBS solution was applied to the hairless skin on the backs of the mice, continuing until day 7. The condition of the back skin was recorded daily by photograph. The study found that in some embodiments, 3-acylurea propionate could form a mixture with at least one of PBS buffer, water, ethanol, glycerol, and physiological saline.

[0036] After the administration was completed, on day 8, the mice were enucleated to collect blood, and then euthanized by cervical dislocation. Skin samples were taken from the lesion area on the back, fixed with paraformaldehyde, and then used for relevant tests.

[0037] Spleen Index Calculation Weigh the mouse, separate the spleen, remove the surrounding excess tissue, wash it in physiological saline to remove blood stains, blot dry with filter paper, weigh the spleen mass with an electronic balance, and calculate the spleen index.

[0038] Spleen index = spleen mass (mg) / mouse body weight (g).

[0039] HE staining for pathological changes in mouse dorsal skin Skin tissue was collected from the back of mice, fixed in 4% paraformaldehyde, routinely dehydrated, embedded in paraffin, and sectioned into 5 μm sections. After hematoxylin and eosin (HE) staining, the sections were mounted. The pathological features of the skin tissue were evaluated under an optical microscope, including hyperkeratosis, thinning or disappearance of the granular layer, acanthosis, wavy epidermis extending into the dermis, and inflammatory cell infiltration.

[0040] Skin tissue lesion score According to the Baker scoring criteria, the pathological damage of skin tissue stained with hematoxylin and eosin (HE) was scored. The scoring criteria are shown in the table below: Table 1 Baker Scoring Criteria for Skin Tissue Lesions

[0041] ELISA Blood was collected from the orbital region of mice, allowed to stand at room temperature for 30 min, and then centrifuged at 3500 r / min for 10 min to separate the serum, which was collected in 1.5 mL EP tubes. The levels of inflammatory response-related factors IL-6 and TNF-α were measured according to the ELISA kit instructions.

[0042] Statistical processing of data Data were processed using GraphPad Prism 9.3.0 software, and the data are expressed as mean ± SEM. Analysis of variance was used to compare means among multiple groups, and t-tests were used for pairwise comparisons between multiple groups. P < 0.05 was considered statistically significant.

[0043] Experimental results 3-Acylurea propionic acid improves epidermal lesions in a BALB / c mouse psoriasis model like Figure 2 As shown, compared with the blank group, the skin lesions of mice after IMQ modeling were covered with scales, which were in flakes; the lesions were thickened and significantly raised. Compared with the model group, the scaling, thickening, and raised features of the mouse skin lesions were significantly reduced after 3 days of 3-acylurea propionate intervention. This indicates that 3-acylurea propionate has a certain therapeutic effect on the skin lesions of the BALB / c mouse psoriasis model.

[0044] 3-Acylurea propionic acid reduces splenomegaly in a BALB / c mouse psoriasis model. like Figure 3 As shown, compared with the control group, the spleens of mice after IMQ modeling became darker and significantly enlarged, and the spleen index was significantly increased. P <0.001). Compared with the model group, 3-acylurea propionate intervention for 3 days reduced the degree of splenomegaly in mice and decreased the spleen index, which was statistically significant. P <0.05). This indicates that 3-acylurea propionic acid has a certain therapeutic effect on the BALB / c mouse psoriasis model.

[0045] 3-Acylurea propionic acid improves pathological damage in a BALB / c mouse psoriasis model. like Figure 4 As shown, HE staining results of mouse back skin tissue revealed that in the normal group, the epidermal structure was intact and clear, the epidermal layer was thinner, collagen fibers in the dermis were interwoven, and the cytoplasm was red-stained and uniform; the connective tissue and fat layer structures were clearly visible; the subcutaneous muscle layer muscle fibers were neatly arranged, uniform in size, with normal cell nuclei morphology, and nucleoli distributed around the periphery, with no obvious pathological changes. Compared with the normal group, the model group showed hyperkeratosis and parakeratosis of the stratum corneum, Munro microabscesses, thinning or disappearance of the granular layer, thickening of the epidermal acanthosis, elongation and undulation of the epidermal ridges, infiltration of mononuclear and multinucleated cells in the dermis, papillary elevation, and a significantly increased Baker pathological damage score. P <0.001). Compared with the model group, the 3-acylurea propionate group showed improvement in all the above-mentioned pathological damages, and the Baker pathological damage score was significantly reduced, which was statistically significant. P <0.01).

[0046] 3-Acylurea propionic acid reduces the levels of inflammatory response-related factors in a BALB / c mouse psoriasis model. like Figure 5 As shown, compared with the normal group, the serum IL-6 and TNF-α levels in the model group mice were increased ( P <0.001); Compared with the model group, the serum IL-6 and TNF-α levels in the 3-acylurea propionate group mice were significantly reduced (IL-6: P <0.05; TNF-α: P <0.001).

[0047] Experimental conclusions Psoriasis is a common, chronic, immune-mediated inflammatory skin disease that primarily affects the skin and has a complex genetic structure. Psoriasis is mainly caused by the release of immune-related cells such as macrophages, neutrophils, and T cells, and the increase of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), leading to long-term damage to various tissues (such as skin tissue) and organs (such as the spleen).

[0048] This study established a BALB / c mouse psoriasis model induced by imiquimod (IMQ) cream and investigated the therapeutic effect of the compound 3-acylurea propionate on this model. Compared with the normal group, the model group mice showed more severe superficial skin lesions and histopathological damage on the back; splenomegaly; and significantly elevated serum levels of inflammatory response-related factors IL-6 and TNF-α. Compared with the model group, the 3-acylurea propionate group showed reduced superficial skin lesions and histopathological damage on the back; splenomegaly was alleviated; and serum levels of IL-6 and TNF-α were decreased. In conclusion, this study preliminarily demonstrates that the compound 3-acylurea propionate has anti-inflammatory effects and exerts a therapeutic effect on the BALB / c mouse psoriasis model induced by IMQ.

[0049] 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, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. Application of 3-acylurea propionic acid in the preparation of drugs for treating psoriasis.

2. The application according to claim 1, characterized in that, The drug is used to reduce superficial skin lesions and / or histopathological damage.

3. The application according to claim 2, characterized in that, The medication is used to reduce symptoms of scaling, thickening, and / or bulging on the surface of skin lesions.

4. The application according to claim 1, characterized in that, The drug is used to relieve splenomegaly and elevated spleen index.

5. The application according to any one of claims 1-4, characterized in that, The drug is used to inhibit the increase of inflammatory factors IL-6 and TNF-α.

6. The use of a pharmaceutical composition in the preparation of a drug for treating psoriasis, characterized in that, The pharmaceutical composition comprises an effective amount of 3-acylurea propionic acid and pharmaceutically acceptable excipients.

7. The application according to claim 6, characterized in that, The excipients include at least one of the following: diluent, excipient, filler, binder, humectant, absorption promoter, surfactant, lubricant, stabilizer, flavoring agent, sweetener, and coloring agent.

8. The application according to claim 6, characterized in that, In the pharmaceutical composition, the concentration of 3-acylurea propionic acid is 0.1 mg / mL to 50 mg / mL.

9. The application according to claim 8, characterized in that, In the pharmaceutical composition, the concentration of 3-acylurea propionic acid is 1 mg / mL to 30 mg / mL.

10. The application according to any one of claims 6-9, characterized in that, The dosage form of the pharmaceutical composition is an oral preparation, an injectable preparation, or a topical preparation; wherein, the topical preparation is a cream, ointment, gel, lotion, foam, spray, or oil.

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