Application of 3-hydroxyoctadecenoic acid in the preparation of drugs for preventing and treating psoriasis

Abstract

The present invention discloses the application of 3-hydroxyoctadecenoic acid in the preparation of a medicament for preventing and treating psoriasis, relating to the technical field of medicine. By using 3-hydroxyoctadecenoic acid as an active ingredient in the medicament for preventing and treating psoriasis, it shows good prevention and treatment effects in a psoriasis treatment model, can reduce the epidermal thickening at the psoriasis-affected area, reduce the infiltration of lymphocytes in the dermis at the psoriasis-affected area, reduce the parakeratosis at the psoriasis-affected area, and alleviate the erythema at the psoriasis-affected area, and can be used as a new drug for resisting the development of psoriasis.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and more particularly, to the use of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis. Background Art

[0002] Psoriasis is a common chronic, recurrent, inflammatory skin disease with a global incidence rate of about 2% - 4%. Clinically, it mainly presents as well-defined scaly erythema and plaques, and some are accompanied by joint symptoms, etc. Histopathologically, it shows acanthosis, capillary dilation and congestion, and at the same time, there is infiltration of inflammatory cells such as T cells, neutrophils, dendritic cells (DC) and macrophages in the epidermis and dermis.

[0003] Although the clinical or histopathological manifestations of psoriasis are relatively clear, the detailed etiology and pathogenesis have not been fully elucidated. Currently, it is believed that external triggers, under the action of genetic background, induce the activation of DC, Th1 and Th17, and release various inflammatory factors such as IL-23, IL-12 and IL-17, etc., triggering the body's immune response. Among them, the signal pathway mediated by IL-17 is the main factor leading to excessive proliferation and abnormal differentiation of keratinocytes, forming psoriasis skin lesions. The course of this disease is long, and it recurs and lingers, bringing huge mental and psychological burdens and economic pressures to patients, greatly affecting the quality of life of patients. Although the related biological agents targeting the IL-17 signal pathway have better efficacy and higher safety compared with traditional treatment methods, these drugs can temporarily relieve symptoms, but they will cause serious side effects. Among them, secukinumab has good efficacy for the treatment of psoriasis, but it is expensive, and there are still some patients who cannot benefit from it.

[0004] In view of this, the present invention is specifically proposed. Summary of the Invention

[0005] The purpose of the present invention is to provide the use of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis.

[0006] The present invention is implemented as follows:

[0007] In a first aspect, the present invention provides the use of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis.

[0008] Optionally, the concentration of 3-hydroxyoctadecenoic acid is 10% - 25%.

[0009] Optionally, the concentration of 3-hydroxyoctadecenoic acid is 10% - 20%.

[0010] Optionally, preventing and treating psoriasis includes at least one of reducing the epidermal thickness of the psoriasis-affected area, reducing the thickness of the stratum spinosum, reducing the infiltration of lymphocytes in the dermis, and reducing epidermal cell parakeratosis.

[0011] Optionally, reducing the epidermal thickness of the psoriasis-affected area is reducing the thickness of the stratum spinosum.

[0012] Optionally, the drug consists of 3-hydroxyoctadecenoic acid and a pharmaceutically acceptable carrier.

[0013] Optionally, the drug is a topical drug.

[0014] Optionally, the dosage form of the drug includes any one of lotion, ointment, patch, film-forming agent, gel, microneedle, aerosol or spray.

[0015] Optionally, the drug includes petrolatum and 3-hydroxyoctadecenoic acid.

[0016] Optionally, psoriasis includes any one of pustular psoriasis, psoriatic arthritis, plaque psoriasis or erythrodermic psoriasis.

[0017] The present invention has the following beneficial effects:

[0018] The present invention provides an application of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis. By using 3-hydroxyoctadecenoic acid as the active ingredient in the drug for preventing and treating psoriasis, it shows good prevention and treatment effects in the psoriasis treatment model, can reduce the epidermal thickening of the psoriasis-affected area, reduce the infiltration of lymphocytes in the dermis of the psoriasis-affected area, reduce the cell parakeratosis of the psoriasis-affected area, and reduce the erythema of the psoriasis-affected area, and can be used as a new drug to resist the development of psoriasis. Description of the Drawings

[0019] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, without creative efforts, other related drawings can also be obtained based on these drawings.

[0020] Figure 1 It is the dorsal skin state diagram of mice in different groups during the modeling process provided by Embodiment 1 of the present invention;

[0021] Figure 2 It is the PASI erythema score diagram during the modeling process provided by Embodiment 1 of the present invention;

[0022] Figure 3 It is the PASI scale score diagram during the modeling process provided by Embodiment 1 of the present invention;

[0023] Figure 4 This is the PASI dermal cell infiltration score chart during the modeling process provided in Example 1 of the present invention;

[0024] Figure 5 This is the total PASI score chart during the modeling process provided in Example 1 of the present invention;

[0025] Figure 6 This is the mouse body weight change chart during the modeling process provided in Example 1 of the present invention;

[0026] Figure 7 This is the optical microscopic image of the mouse skin tissue after HE staining provided in Example 1 of the present invention;

[0027] Figure 8 This is the result chart of the protein immunoblotting experiment provided in Example 2 of the present invention. Detailed implementation manners

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. For those not specified in the embodiments, the conventional conditions or the conditions recommended by the manufacturer are followed. For the reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0029] The features and properties of the present invention will be further described in detail below in conjunction with the embodiments.

[0030] In a first aspect, the present invention provides an application of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis.

[0031] 3-Hydroxyoctadecenoic acid (C18-3OH) is a fatty acid. Fatty acids are widely present in organisms and are important components of many complex lipids (such as triglycerides, phospholipids, etc.). Under sufficient cell oxygen supply, they can be oxidized and decomposed into CO 2 and H 2 O, providing a large amount of energy support for the body. The present invention utilizes the characteristics of 3-hydroxyoctadecenoic acid, such as its lipid solubility, easy absorption by the skin, anti-inflammatory effect, and relatively low cost compared to antibody drugs, to prepare a drug for preventing and treating psoriasis, which can reduce the epidermal thickening at the psoriasis lesion site, reduce the lymphocyte infiltration in the dermis layer of the psoriasis lesion site, reduce the parakeratosis of the cells at the psoriasis lesion site, and reduce the erythema at the psoriasis lesion site, and can be used as a new drug to resist the development of psoriasis.

[0032] In an alternative embodiment, the concentration of 3-hydroxyoctadecenoic acid is 10% to 25%, for example, it can be any value among 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, or 25%, or a range value between any two values.

[0033] In an alternative embodiment, the concentration of 3-hydroxyoctadecenoic acid is 10% to 20%, for example, it can be any value among 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, or a range value between any two of these values.

[0034] As an active ingredient for preventing and treating psoriasis, the addition of 3-hydroxyoctadecenoic acid can effectively relieve the specific symptoms of psoriasis, such as epidermal thickening, incomplete keratinization of epidermal cells, and lymphocyte infiltration in the dermis layer. However, controlling the concentration of 3-hydroxyoctadecenoic acid within the above range is beneficial to improving the prevention and treatment effect of psoriasis.

[0035] In an alternative embodiment, preventing and treating psoriasis includes at least one of reducing the epidermal thickness of the psoriasis affected area, reducing the thickness of the stratum spinosum, reducing lymphocyte infiltration in the dermis layer, and reducing incomplete keratinization of epidermal cells.

[0036] In an alternative embodiment, reducing the epidermal thickness of the psoriasis affected area is to reduce the thickness of the stratum spinosum. Psoriasis stimulates the continuous proliferation of basal cells, resulting in an increase in spinous cells in the stratum spinosum and thickening of the stratum spinosum. More spinous cells will lead to an increased frequency of keratinocyte renewal and shedding, resulting in increased scaly or semi-shed keratin. Preventing and treating psoriasis with 3-hydroxyoctadecenoic acid can reduce the thickness of the stratum spinosum, thereby alleviating the symptoms of psoriasis.

[0037] In an alternative embodiment, the drug consists of 3-hydroxyoctadecenoic acid and a pharmaceutically acceptable carrier.

[0038] In an alternative embodiment, the drug is a topical drug.

[0039] In an alternative embodiment, the dosage form of the drug includes any one of lotion, ointment, patch, film-forming agent, gel, microneedle, aerosol or spray.

[0040] In an alternative embodiment, the drug includes petrolatum and 3-hydroxyoctadecenoic acid. As a carrier for 3-hydroxyoctadecenoic acid, petrolatum not only facilitates the storage and transportation of the drug but also is convenient for coating and use.

[0041] To ensure uniform dispersion of 3-hydroxyoctadecenoic acid, when preparing the 3-hydroxyoctadecenoic acid drug, it should be added to petrolatum in a small amount and multiple times. After each addition of 3-hydroxyoctadecenoic acid is evenly dispersed, a certain amount of 3-hydroxyoctadecenoic acid is added for dispersion.

[0042] In an alternative embodiment, psoriasis includes any one of pustular psoriasis, psoriatic arthritis, plaque psoriasis or erythrodermic psoriasis.

[0043] Example 1

[0044] This embodiment provides an application of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis, as follows:

[0045] S01. Preparation of drugs for preventing and treating psoriasis

[0046] 100 mg of 3-hydroxyoctadecenoic acid powder was weighed and dissolved in 1 g of vaseline. The 3-hydroxyoctadecenoic acid powder was added to the vaseline in small amounts and repeatedly, and sufficient stirring was maintained during the addition process until the ointment had no powdery particles on the outside and had a uniform color, to prepare an ointment with an active ingredient of 3-hydroxyoctadecenoic acid at a concentration of 10% (hereinafter referred to as 10% 3H ointment).

[0047] Weigh 200 mg of 3-hydroxyoctadecenoic acid powder and dissolve it in 1 g of vaseline. Add the 3-hydroxyoctadecenoic acid powder to the vaseline in small amounts and repeatedly, and keep stirring fully during the addition process until the ointment has no powdery particles on the outside and has a uniform color, to prepare an ointment with an active ingredient of 3-hydroxyoctadecenoic acid at a concentration of 20% (hereinafter referred to as 20% 3H ointment).

[0048] Among them, 3-hydroxyoctadecenoic acid powder was purchased from Shanghai Jizhi Biochemical Technology Co., Ltd., and vaseline was purchased from Haishi Hainuo Group Co., Ltd.

[0049] S02. Induction of psoriasis model and prevention and treatment of psoriasis

[0050] The experimental mice were female Balb / c mice (SPF grade, 8 weeks old, weighing about 20 g) purchased from Beijing Sibeifu Company, and the animal study was approved by the Ethics Committee of Xinxiang Medical College.

[0051] Balb / c mice with basically the same growth conditions were raised at a temperature of 24±2°C, a humidity of 40-50%, a light / dark cycle of 12h and pathogen-free conditions, and were given sufficient food and water. After one week of feeding, the Balb / c mice were randomly divided into three groups (vaseline group, 10% 3H group and 20% 3H group), with five mice in each group. The back of the mice was depilated one day before modeling, and the depilated area was 2×2.5cm.

[0052] Starting from the day of modeling, 62.5 mg of imiquimod (IMQ) cream was applied to the depilatory area on the back of the three groups of Balb / c mice at 9 am every day, and 62.5 mg of vaseline was applied to the depilatory area on the back of the vaseline group at 13:00 every day, 62.5 mg of 10% 3H ointment was applied to the depilatory area on the back of the 10% 3H group, and 62.5 mg of 20% 3H ointment was applied to the depilatory area on the back of the 20% 3H group. The control group did not receive any treatment for six consecutive days.

[0053] Among them, imiquimod (IMQ) was purchased from Sichuan Mingxin Pharmaceutical Co., Ltd.

[0054] S03. Experimental results

[0055] S031. Photographing the dorsal skin phenotype of Balb / c mice: From the day of modeling, at the same time point every day before applying imiquimod, the dorsal skin of each group of Balb / c mice was photographed, and the results were as Figure 1 shown.

[0056] As Figure 1 can be seen, on the 3rd day, there were no obvious scales on the skin of the 10% 3H group, and a small amount of scales appeared on the skin of the 20% 3H group, but still less than those of the control group. After several days of imiquimod induction, the scales in the petrolatum group increased continuously, and the erythema increased. The skin conditions of the 10% 3H group and the 20% 3H group were alleviated compared with the control group, with reduced psoriasis, reduced erythema, and reduced local infiltration.

[0057] The changes in the dorsal skin phenotype of Balb / c mice photographed during the six-day modeling process were statistically analyzed and PASI scores were calculated, and the results were as Figures 2 to 5 shown.

[0058] Among them, the PASI score includes erythema score, scale score, and skin thickness score for the skin lesions of Balb / c mice, and the sum of the above scores is calculated. The scoring criteria are as follows:

[0059] Erythema score: 0 = none; 1 = mild; 2 = obvious; 3 = severe; 4 = very severe.

[0060] Scale score: 0 = none; 1 = mild; 2 = obvious; 3 = severe; 4 = very severe.

[0061] Skin thickness: 0 = none; 1 = mild; 2 = obvious; 3 = severe; 4 = very severe.

[0062] As Figures 2 to 5 can be seen, both the 10% 3H group and the 20% 3H group showed good effects in reducing psoriasis symptoms, and there were varying degrees of improvement compared with the control group in terms of erythema score, scale score, and skin thickness score.

[0063] S032. Measurement of the body weight of Balb / c mice: From the day of modeling, the body weight of Balb / c mice was measured and recorded at the same time point every day before applying imiquimod. After the experiment, the body weight changes of all mice were statistically analyzed, and the results were as Figure 3 shown.

[0064] As Figure 6It can be seen that the degree of weight loss in the 10% 3H group and the 20% 3H group of mice is lower than that in the control group. It is understandable that when psoriasis symptoms appear, the mice may be affected physically and psychologically to varying degrees due to the degree of psoriasis symptoms, which may indirectly affect appetite or activity enthusiasm, etc. In the present invention, 3-hydroxyoctadecenoic acid is used to treat imiquimod-induced mice. The 10% 3H group and the 20% 3H group Figures 1 to 5 As can be seen from the shown effects, the psoriasis symptoms of the mice in these groups have a significant effect of reducing the symptoms, so the impact on the body weight of the mice is smaller than that of the control group.

[0065] S033. After the modeling was completed, the mice were sacrificed, and mouse skin tissues with a length of about 0.5×0.5 cm were cut and fixed in 4% paraformaldehyde solution; tissue sections (longitudinal section 5 μm) were prepared by paraffin embedding; after dewaxing, H&E staining was performed (dewaxing, gradient rehydration, hematoxylin staining of nuclei, decolorization with hydrochloric acid alcohol, eosin staining of cytoplasm); after sealing with neutral resin, the pathological histological changes were observed and photographed under an optical microscope to obtain Figure 7 the results as shown.

[0066] From Figure 7 it can be seen that psoriasis-like phenotypes such as epidermal thickening, epidermal cell parakeratosis, spinous layer thickening, and dermal lymphocyte infiltration appeared in the skin of the three groups of mice. However, the spinous layer thickness in the 10% 3H group and the 20% 3H group decreased compared with the comparative example, the parakeratotic epidermal cells decreased, and the dermal lymphocyte infiltration decreased, indicating that 3-hydroxyoctadecenoic acid has a good effect on preventing and treating psoriasis and can be used as an active ingredient in drugs for preventing and treating psoriasis.

[0067] Example 2

[0068] HaCat cells (human immortalized keratinocytes) were cultured in a six-well plate. 3-Hydroxyoctadecenoic acid powder was dissolved in DMSO to form a 3-hydroxyoctadecenoic acid solution with a concentration of 5 mM, and the 3-hydroxyoctadecenoic acid was diluted 1:1000 with a medium (89% DMEM medium + 10% FBS + 1% double antibody) to a 5 μM 3H-containing medium. The cells in wells 4, 5, and 6 were treated for 2 hours. After 2 hours, the cells in wells 1, 4 and 5, 6 were stimulated with IL-17-containing medium for 4 hours and 8 hours respectively. After the stimulation was completed, proteins were extracted and a Western blot experiment was performed. The phosphorylated proteins P-P65 and P-P38 and the non-phosphorylated proteins P65 and P38 of the NF-κB and MAPK signaling pathways were detected to obtain Figure 8 the results as shown.

[0069] From Figure 8 it can be seen that the expression level of phosphorylated proteins in the cells pretreated with 3-hydroxyoctadecenoic acid was significantly lower than that in the control group, indicating that 3-hydroxyoctadecenoic acid inhibited the activation of the NF-κB and MAPK signaling pathways.

[0070] Comparative Example 1

[0071] Based on the application in Example 1, 5% of 3H ointment was prepared. The preparation method was the same as that in Example 1, except that the mass of 3-hydroxyoctadecenoic acid was 50 mg. The 5% 3H ointment was tested according to the method in Example 1 to verify the application effect of 3-hydroxyoctadecenoic acid in the preparation of drugs for preventing and treating psoriasis, and the results are as Figures 1 - 7 shown below.

[0072] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Use of 3-hydroxyoctadecenoic acid in the preparation of a drug for preventing and treating psoriasis, characterized in that: The concentration of the 3-hydroxyoctadecenoic acid is 10% to 20%, and the medicine is an external medicine.

2. The use according to claim 1, characterized in that: The method for preventing and treating psoriasis comprises at least one of reducing the thickness of the epidermis in the psoriasis affected area, reducing the thickness of the stratum spinosum, reducing the lymphocyte infiltration in the dermis, and reducing the parakeratosis of epidermal cells.

3. The use according to claim 2, characterized in that: The reducing the thickness of the epidermis in the psoriasis affected area is reducing the thickness of the stratum spinosum.

4. The use according to claim 1, characterized in that: The medicine consists of the 3-hydroxyoctadecenoic acid and a pharmaceutically acceptable carrier.

5. The use according to claim 1, characterized in that: The dosage form of the drug includes any one of lotion, ointment, patch, film coating, gel, microneedle, aerosol or spray.

6. The use according to claim 1, characterized in that: The drug includes petrolatum and the 3-hydroxyoctadecenoic acid.

7. The use according to claim 1, characterized in that: The psoriasis includes any one of pustular psoriasis, articular psoriasis, psoriasis vulgaris or erythrodermic psoriasis.

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