Application of 10-hydroxy-2-decenoic acid in preparation of medicine for treating psoriasis

Abstract

The invention relates to an application of 10-hydroxy-2-decenoic acid in preparation of a medicine for treating psoriasis. The invention discloses an application of 10-hydroxy-2-decenoic acid or a salt thereof in preparation of a medicine for treating psoriasis and atopic dermatitis co-disease caused by psoriasis. The invention discloses a 10-hydroxy-2-decenoic acid ointment for treating psoriasis and atopic dermatitis co-diseases caused by the psoriasis, and a preparation method of the 10-hydroxy-2-decenoic acid ointment. The invention discloses a 10-hydroxy-2-decenoic acid zinc-containing ointment which is used for treating psoriasis and atopic dermatitis codiseases caused by the psoriasis. The invention discloses a 10-hydroxy-2-decenoic acid gel for treating psoriasis and AD (Alzheimer's disease) codiseases caused by the psoriasis. The 10-hydroxy-2-decenoic acid or zinc salt ointment and the 10-hydroxy-2-decenoic acid gel are beneficial to being coated on the surface of the skin, play a role in treating the psoriasis and the AD co-disease caused by the psoriasis, and can be used for remarkably improving the psoriasis and the AD co-disease caused by the psoriasis.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to the use of 10-hydroxy-2-decenoic acid or its salt in the preparation of a medicament for treating psoriasis and the comorbidity of atopic dermatitis (AD) induced by psoriasis. Background Art

[0002] Psoriasis, commonly known as "psoriasis", is a chronic relapsing inflammatory skin disease mediated by multiple factors such as genetics, immunity, and infection. Its clinical manifestations are skin reactions throughout the body: the damaged skin areas have well-defined red plaques or papules, covered with multiple layers of white or silver scales on the surface, and the skin lesions are located locally or throughout the body. At the same time, the skin lesions can cause varying degrees of itching, burning, and pain. In addition, psoriasis is also closely related to many complications, including psoriatic arthritis, metabolic syndrome, cardiovascular diseases, and mental diseases such as depression and anxiety. Although psoriasis is not contagious, due to its low cure rate and high recurrence rate, and the disease is mostly seen in the body skin, it has a great negative impact on the quality of life and mental health of patients. According to statistics, there are at least 125 million psoriasis patients worldwide, accounting for about 2% of the total population. With the increasing pressure of modern social life and the influence of environmental factors, the incidence of psoriasis is still on the rise year by year.

[0003] The specific pathogenesis of psoriasis is not yet clear, and it is generally believed that it is caused by the complex interaction between the immune mechanism, genetic susceptibility, and environmental stimuli. At present, there are many clinical treatment methods for psoriasis, including topical drugs, oral drugs, and physical therapies, etc. The main treatment goals are to control the condition, relieve symptoms, reduce skin lesions, and prevent its continuous development and recurrence to improve the quality of life of patients, but there are certain deficiencies and defects. So far, there is no therapy that can completely cure psoriasis.

[0004] Topical drugs are commonly used in the treatment of mild psoriasis and are also the first choice in clinical practice. Topical drugs mainly include: corticosteroids such as betamethasone, retinoids such as tazarotene, vitamin D3 derivatives such as calcipotriol, and calcineurin inhibitors such as tacrolimus. Applying topical drugs to the surface of the skin lesions and absorbing them through the skin can avoid the irritation reaction caused by drug absorption through the intestine. However, long-term local application may induce adverse reactions such as skin atrophy, pigmentation, telangiectasia, and irritant dermatitis. Suddenly stopping the drug may also induce severe psoriasis.

[0005] Oral medications include systemic immunosuppressants (methotrexate, cyclosporine, acitretin), small molecule compounds (JAK inhibitor tofacitinib, phosphodiesterase inhibitor apremilast), and biological agents (TNF-α antagonist adalimumab, IL-17 antagonist ixekizumab). Common adverse reactions of oral medications include intestinal irritation, mucosal ulcers, stomatitis, etc. Immunosuppressants may even cause serious side effects such as myelosuppression and aplastic anemia.

[0006] Physical therapy is often used in combination with topical or oral medications to improve efficacy, shorten the course of the disease, and reduce the adverse reactions of single drug use. Common physical therapies include ultraviolet irradiation and photodynamic therapy. By using a photosensitizer and combining it with specific ultraviolet irradiation, photochemical and photobiological reactions are generated, causing damage to the diseased tissue to achieve the therapeutic purpose.

[0007] It is worth mentioning that numerous studies have reported that with the widespread use of biological agents in patients with psoriasis in recent years, eczematous skin lesions and atopic dermatitis (AD) often occur in psoriasis patients treated with biological agents. Interestingly, psoriasis-like skin lesions often occur in AD patients treated with biological agents. This disease conversion between psoriasis and AD caused by biological agents has attracted wide attention. Highly specific biological agents may iatrogenically change the immune balance between the two diseases. Over time, patients will experience disease conversion or comorbidity. Disease conversion and AD comorbidity make the treatment of psoriasis more difficult, seriously affecting the quality of life and life health of patients.

[0008] In summary, the currently commonly used therapeutic drugs have varying degrees of side effects and are not suitable for long-term use. Physical therapy may damage normal skin; biological agents are prone to cause AD comorbidity or disease conversion; the treatment rate of common topical medications is low and the recurrence rate is high. The etiology of psoriasis is complex and the course of the disease is long, causing serious stress and burden to the physical and mental health of patients. Therefore, developing new drugs for psoriasis that are safe, effective, and inclusive has profound research significance and clinical value.

[0009] 10-Hydroxy-2-decenoic acid (10-HDA, chemical formula: C 10 H 18 O3), also known as royal jelly acid, has the following structural formula:

[0010]

[0011] 10-Hydroxy-2-decenoic acid is a white crystal at room temperature, with stable properties, being insoluble in water, soluble in methanol, ethanol and chloroform, slightly soluble in acetone, and having a melting point of 64°C. Whether 10-hydroxy-2-decenoic acid can improve inflammatory skin damage has not been studied alone, and there is no literature disclosing the pharmacological effects of 10-hydroxy-2-decenoic acid on psoriasis. Summary of the Invention

[0012] In view of the deficiencies of the prior art, the inventors have found through research that 10-HDA or its salts have a significant co-treatment effect on psoriasis and the atopic dermatitis (AD) induced by it, and are expected to become effective drugs for treating psoriasis. The object of the present invention is to provide the use of 10-hydroxy-2-decenoic acid or its salts in the preparation of drugs for treating the co-disease of psoriasis and AD, and a pharmaceutical composition containing 10-hydroxy-2-decenoic acid or its salts.

[0013] The technical solution of the present invention is as follows:

[0014] Use of 10-hydroxy-2-decenoic acid or its salts in the preparation of drugs for treating the co-disease of psoriasis and atopic dermatitis (AD) induced by psoriasis.

[0015] The dosage form of the drug is ointment, gel, film, patch, oral solid preparation, oral suspension.

[0016] The salt of 10-hydroxy-2-decenoic acid is zinc 10-hydroxy-2-decenoate. Zinc 10-hydroxy-2-decenoate is the reaction product of 10-hydroxy-2-decenoic acid and zinc oxide.

[0017] A 10-hydroxy-2-decenoic acid ointment for treating the co-disease of psoriasis and AD induced by psoriasis, which is prepared from the following components in parts by weight: 2-30 parts of 10-hydroxy-2-decenoic acid, 3-20 parts of glycerol, 3-20 parts of propylene glycol, 3-15 parts of ethanol, 0.2-5.0 parts of meglumine, 1-6 parts of beeswax, 2-15 parts of lanolin, 10-55 parts of petrolatum, 0.1-1.0 part of methylparaben, 0.1-1.0 part of propylparaben; or 2-30 parts of 10-hydroxy-2-decenoic acid, 3-20 parts of glycerol, 3-20 parts of propylene glycol, 3-15 parts of ethanol, 0.2-2.0 parts of sodium lauryl sulfate, 1-6 parts of beeswax, 2-15 parts of lanolin, 10-55 parts of petrolatum, 0.1-1.0 part of methylparaben, 0.1-1.0 part of propylparaben.

[0018] Preferably, the total amount of 10-hydroxy-2-decenoic acid, glycerol, propylene glycol, ethanol, meglumine, beeswax, lanolin and petrolatum is 100 parts; the total amount of 10-hydroxy-2-decenoic acid, glycerol, propylene glycol, ethanol, sodium lauryl sulfate, beeswax, lanolin and petrolatum is 100 parts.

[0019] Preferably, every 5 - 20 g of the 10 - hydroxy - 2 - decenoic acid ointment contains 0.2 - 4.0 g of 10 - hydroxy - 2 - decenoic acid.

[0020] Preferably, every 10 g of the 10 - hydroxy - 2 - decenoic acid ointment contains 0.6 - 1.8 g of 10 - hydroxy - 2 - decenoic acid, 0.5 - 1.5 g of glycerol, 0.5 - 1.5 g of propylene glycol, 0.5 - 1.0 g of ethanol, 0.2 - 0.6 g of meglumine, 0.2 - 1.0 g of beeswax, 0.5 - 2.0 g of lanolin, 2.0 - 5.5 g of petrolatum, 0.01 - 0.05 g of methyl paraben, 0.01 - 0.05 g of propyl paraben; or contains 0.6 - 1.8 g of 10 - hydroxy - 2 - decenoic acid, 0.5 - 1.5 g of glycerol, 0.5 - 1.5 g of propylene glycol, 0.5 - 1.0 g of ethanol, 0.05 - 0.2 g of sodium lauryl sulfate, 0.2 - 1.0 g of beeswax, 0.5 - 2.0 g of lanolin, 2.0 - 5.5 g of petrolatum, 0.01 - 0.05 g of methyl paraben, 0.01 - 0.05 g of propyl paraben.

[0021] More preferably, every 10 g of the 10 - hydroxy - 2 - decenoic acid ointment contains 0.6 - 0.9 g of 10 - hydroxy - 2 - decenoic acid, 1.0 - 1.2 g of glycerol, 1.0 - 1.2 g of propylene glycol, 0.5 - 1.0 g of ethanol, 0.2 - 0.4 g of meglumine, 0.5 - 0.6 g of beeswax, 0.9 - 1.0 g of lanolin, 4.0 - 5.0 g of petrolatum, 0.01 - 0.03 g of methyl paraben, 0.01 - 0.03 g of propyl paraben; or 0.6 - 1.8 g of 10 - hydroxy - 2 - decenoic acid, 1.0 - 1.2 g of glycerol, 1.0 - 1.2 g of propylene glycol, 0.5 - 1.0 g of ethanol, 0.05 - 0.15 g of sodium lauryl sulfate, 0.3 - 0.5 g of beeswax, 0.9 - 1.2 g of lanolin, 3.9 - 5.0 g of petrolatum, 0.01 - 0.03 g of methyl paraben, 0.01 - 0.03 g of propyl paraben.

[0022] Specifically, the 10 - hydroxy - 2 - decenoic acid ointment is prepared from the following components by weight:

[0023] 6 parts of 10 - hydroxy - 2 - decenoic acid, 10 parts of glycerol, 10 parts of propylene glycol, 5 parts of ethanol, 3 parts of meglumine, 6 parts of beeswax, 10 parts of lanolin, 50 parts of petrolatum, 0.2 part of methyl paraben, 0.2 part of propyl paraben;

[0024] or 6 parts of 10 - hydroxy - 2 - decenoic acid, 12 parts of glycerol, 12 parts of propylene glycol, 10 parts of ethanol, 3 parts of meglumine, 5 parts of beeswax, 9 parts of lanolin, 40 parts of petrolatum, 0.2 part of methyl paraben, 0.2 part of propyl paraben;

[0025] Or 6 parts of 10-hydroxy-2-decenoic acid, 10 parts of glycerol, 10 parts of propylene glycol, 6 parts of ethanol, 1 part of sodium lauryl sulfate, 5 parts of beeswax, 12 parts of lanolin, 50 parts of petrolatum, 0.2 part of methylparaben, 0.2 part of propylparaben;

[0026] Or 18 parts of 10-hydroxy-2-decenoic acid, 10 parts of glycerol, 10 parts of propylene glycol, 10 parts of ethanol, 1 part of sodium lauryl sulfate, 3 parts of beeswax, 9 parts of lanolin, 39 parts of petrolatum, 0.2 part of methylparaben, 0.2 part of propylparaben.

[0027] Another object of the present invention is to provide a preparation method of the above-mentioned 10-hydroxy-2-decenoic acid ointment, including:

[0028] Mix beeswax, lanolin and petrolatum, heat them in a water bath to 80-85°C to melt them, then add methylparaben and propylparaben, and mix well to obtain Component A; mix ethanol, glycerol and propylene glycol, add meglumine or sodium lauryl sulfate to the mixed solvent, stir and dissolve to prepare a meglumine or sodium lauryl sulfate solution as Component B; add 10-hydroxy-2-decenoic acid to Component B, heat it in a water bath to 55-60°C, stir and dissolve to obtain Component C; add Component C to Component A, mix well, and let it stand and cool to room temperature to obtain the ointment.

[0029] A zinc-containing 10-hydroxy-2-decenoic acid ointment for treating psoriasis and the AD comorbidity caused by psoriasis is prepared from the following components in parts by weight: 5-30 parts of 10-hydroxy-2-decenoic acid, 1.0-10.0 parts of zinc oxide, 5-35 parts of glycerol, 0.5-6.0 parts of sodium carboxymethylcellulose, 10-80 parts of distilled water; and the molar ratio of 10-hydroxy-2-decenoic acid to zinc oxide is 1.75:1 to 2:1.

[0030] Preferably, the molar ratio of 10-hydroxy-2-decenoic acid to zinc oxide is 1.75:1 to 1.99:1.

[0031] Preferably, every 5-20 g of the zinc-containing 10-hydroxy-2-decenoic acid ointment contains 0.5-8.0 g of zinc 10-hydroxy-2-decenoate.

[0032] Preferably, every 10 g of the zinc-containing 10-hydroxy-2-decenoic acid ointment is prepared from the following components: 1.0-3.0 g of 10-hydroxy-2-decenoic acid, 0.2-1.0 g of zinc oxide, 0.1-0.5 g of sodium carboxymethylcellulose, 2.0-4.0 g of glycerol, 2.0-6.0 g of distilled water.

[0033] More preferably, every 10 g of the zinc-containing 10-hydroxy-2-decenoic acid ointment is prepared from the following components: 1.0 - 2.0 g of 10-hydroxy-2-decenoic acid, 0.2 - 0.5 g of zinc oxide, 0.2 - 0.3 g of sodium carboxymethyl cellulose, 2.5 - 3.0 g of glycerol, and 4.0 - 6.0 g of distilled water.

[0034] Specifically, the zinc-containing 10-hydroxy-2-decenoic acid ointment is prepared from the following components in parts by weight:

[0035] 20 parts of 10-hydroxy-2-decenoic acid, 4.4 parts of zinc oxide, 2.6 parts of sodium carboxymethyl cellulose, 30 parts of glycerol, and 43 parts of distilled water;

[0036] 20 parts of 10-hydroxy-2-decenoic acid, 5 parts of zinc oxide, 3 parts of sodium carboxymethyl cellulose, 29 parts of glycerol, and 43 parts of distilled water;

[0037] 30 parts of 10-hydroxy-2-decenoic acid, 6.6 parts of zinc oxide, 2.4 parts of sodium carboxymethyl cellulose, 25 parts of glycerol, and 36 parts of distilled water;

[0038] 10 parts of 10-hydroxy-2-decenoic acid, 2.2 parts of zinc oxide, 1.8 parts of sodium carboxymethyl cellulose, 30 parts of glycerol, and 56 parts of distilled water.

[0039] Another object of the present invention is to provide a preparation method of the zinc-containing 10-hydroxy-2-decenoic acid ointment, including:

[0040] Take 1 / 2 - 3 / 4 of the prescribed amount of 10-hydroxy-2-decenoic acid and the total amount of glycerol, mix evenly, heat to 40 - 45 °C, and add the total amount of zinc oxide and 1 / 2 - 3 / 4 of the prescribed amount of distilled water preheated to 40 - 45 °C under stirring. Continue to heat to 107 - 110 °C, and 10-hydroxy-2-decenoic acid reacts with zinc oxide to form zinc 10-hydroxy-2-decenoate. After the reaction is completed, add sodium carboxymethyl cellulose to the system to dissolve it completely. When the temperature slightly drops to 103 - 105 °C, slowly add the remaining amount of 10-hydroxy-2-decenoic acid and distilled water preheated to 40 - 45 °C, and continuously stir to prevent the precipitation of solids. When the system cools to 50 - 55 °C, grind evenly, divide into portions; let it stand and cool to room temperature to obtain the zinc salt-containing 10-hydroxy-2-decenoic acid ointment.

[0041] A 10-hydroxy-2-decenoic acid gel for treating psoriasis and the AD comorbidity caused by psoriasis is prepared from the following components in parts by weight: 2 - 15 parts of 10-hydroxy-2-decenoic acid, 1 - 5 parts of sodium carboxymethyl cellulose, 2.0 - 15.0 parts of meglumine, 2 - 10 parts of absolute ethanol, 4 - 20 parts of glycerol, 4 - 20 parts of propylene glycol, and 10 - 60 parts of distilled water.

[0042] Preferably, every 5-20 g of the 10-hydroxy-2-decenoic acid gel contains 0.2-1.0 g of 10-hydroxydecenoic acid.

[0043] More preferably, every 10 g of the 10-hydroxy-2-decenoic acid gel contains 0.5-1.0 g of 10-hydroxy-2-decenoic acid, 0.1-0.3 g of sodium carboxymethylcellulose, 0.65-1.2 g of meglumine, 1.0-2.0 g of glycerol, 1.0-2.0 g of propylene glycol, 0.5-1.0 g of ethanol, and 4.0-6.0 g of distilled water.

[0044] Most preferably, every 10 g of the 10-hydroxy-2-decenoic acid gel contains 0.5-1.0 g of 10-hydroxy-2-decenoic acid, 0.15-0.25 g of sodium carboxymethylcellulose, 0.65-1.2 g of meglumine, 1.0-2.0 g of glycerol, 1.0 g of propylene glycol, 0.3-0.8 g of ethanol, and 4.75-5.2 g of distilled water.

[0045] Another object of the present invention is to provide a method for preparing the 10-hydroxy-2-decenoic acid gel, comprising:

[0046] Disperse sodium carboxymethylcellulose in ethanol as component A; dissolve meglumine in 1 / 2-2 / 3 of the prescribed amount of distilled water, then add 10-hydroxy-2-decenoic acid, and heat to 55-60 °C to dissolve it; then add glycerol and propylene glycol, and mix evenly as component B; add component A to component B, and add the remaining amount of distilled water, disperse evenly, and remove air bubbles by ultrasonic treatment to obtain the 10-hydroxy-2-decenoic acid gel.

[0047] Advantages of the present invention:

[0048] The inventors found through research that adding meglumine or sodium lauryl sulfate can increase the solubility of 10-hydroxy-2-decenoic acid in ointments / gels to produce better medicinal effects. Specifically, meglumine or sodium lauryl sulfate can significantly improve the phenomenon of particle precipitation in the 10-hydroxy-2-decenoic acid ointment, and the texture of the ointment is uniform; meglumine can improve the dispersion and solubility of 10-hydroxy-2-decenoic acid in the gel, making the texture of the gel preparation uniform.

[0049] The 10-hydroxy-2-decenoic acid ointment, gel, and 10-hydroxy-2-decenoic acid zinc-containing ointment of the present invention have stable preparations, simple preparation processes, and are suitable for large-scale production.

[0050] 10-Hydroxy-2-decenoic acid or zinc salt ointment and 10-hydroxy-2-decenoic acid gel are conducive to being coated on the skin surface, exerting the therapeutic effect on psoriasis and the AD comorbidity caused by psoriasis, and can significantly improve psoriasis and the AD comorbidity caused by psoriasis. Moreover, the anti-psoriasis pharmacodynamic effect of the zinc salt ointment preparation containing 10-hydroxy-2-decenoic acid is significantly better than that of the oral preparation. Description of the Drawings

[0051] Figure 1 It is the research result of the effect of 10-hydroxy-2-decenoic acid on the spleen index and skin damage of psoriasis model mice. Among them, A: The start and end times of modeling and drug administration; B: Spleen coefficient (the percentage of spleen weight in the total body weight); C: Psoriasis-like skin lesion area and disease severity score (PASI score); Analyzed by one-way ANOVA, **p < 0.01, ****p < 0.0001.

[0052] Figure 2 It is the picture of the effect of 10-hydroxy-2-decenoic acid on the skin appearance of psoriasis model mice.

[0053] Figure 3 It is the HE staining picture of the effect of 10-hydroxy-2-decenoic acid on the skin pathology of psoriasis model mice.

[0054] Figure 4 It is the effect of 10-hydroxy-2-decenoic acid on the spleen index of AD-like model mice; among them, A: The start and end times of modeling and drug administration; B: Spleen coefficient (the percentage of spleen weight in the total body weight), analyzed by one-way ANOVA, *p < 0.05, ***p < 0.001.

[0055] Figure 5 It is the picture of the effect of 10-hydroxy-2-decenoic acid on the skin appearance of AD-like model mice.

[0056] Figure 6 It is the HE staining picture of the effect of 10-hydroxy-2-decenoic acid on the skin pathology of AD-like model mice.

[0057] Figure 7 It is the effect of 10-hydroxy-2-decenoic acid on the level of skin junction protein Claudin-1 in AD-like model mice; analyzed by one-way ANOVA, *p < 0.05, **p < 0.01. Detailed Embodiments

[0058] The following embodiments can enable those skilled in the art to more comprehensively understand the technical solutions of the present invention, but do not limit the present invention within the scope of the described embodiments. "Appropriate amount" in the embodiments is the range conventionally selected by those skilled in the art.

[0059] Example 1

[0060] Formulation and Preparation of 10-Hydroxy-2-decenoic Acid Ointment

[0061] Prepare ointments according to each formulation in Table 1. Specification: Each 10 g of ointment contains approximately 0.6 - 1.8 g of 10-hydroxy-2-decenoic acid.

[0062] Table 1. Formulation of 10-Hydroxy-2-decenoic Acid Ointment

[0063]

[0064]

[0065] Preparation Process:

[0066] For Formulations 1 and 5: Take beeswax, wool fat, and petrolatum, heat and melt them in an 80°C water bath, then add methyl paraben and propyl paraben, mix well to obtain Component A; mix absolute ethanol, glycerol, and propylene glycol, add meglumine to this mixed solvent, stir to dissolve, and prepare meglumine solution as Component B; add 10-hydroxy-2-decenoic acid to Component B, heat in a water bath to 55°C, stir to dissolve to obtain Component C; add Component C to Component A at approximately 80°C, mix well, let it stand and cool to room temperature, then package to obtain the ointment. Each 10 g of Formulations 1 and 5 ointments contains approximately 0.6 g and 0.9 g of 10-hydroxy-2-decenoic acid respectively.

[0067] For Formulations 2 and 6: Take beeswax, wool fat, and petrolatum, heat and melt them in an 80°C water bath, then add methyl paraben and propyl paraben, mix well to obtain Component A; mix absolute ethanol, glycerol, and propylene glycol, add sodium lauryl sulfate to this mixed solvent, stir to dissolve, and prepare sodium lauryl sulfate solution as Component B; add 10-hydroxy-2-decenoic acid to Component B, heat in a water bath to 55°C, stir to dissolve to obtain Component C; add Component C to Component A at approximately 80°C, mix well, let it stand and cool to room temperature, then package to obtain the ointment. Each 10 g of Formulations 2 and 6 ointments contains approximately 0.6 g and 1.8 g of 10-hydroxy-2-decenoic acid respectively.

[0068] For Formulations 3 and 4: Take beeswax, wool fat, and petrolatum, heat and melt them in an 80°C water bath, then add methyl paraben and propyl paraben, mix well to obtain Component A; mix absolute ethanol, glycerol, and propylene glycol as Component B; add 10-hydroxy-2-decenoic acid to Component B, heat in a water bath to 55°C, stir to dissolve to obtain Component C; add Component C to Component A at approximately 80°C, mix well, let it stand and cool to room temperature, then package to obtain the ointment. Each 10 g of Formulations 3 and 4 ointments contains approximately 0.6 g and 0.9 g of 10-hydroxy-2-decenoic acid respectively.

[0069] As can be seen from Table 1, when meglumine or sodium lauryl sulfate was not added, a small amount of particles precipitated from the ointment after cooling and standing. However, the addition of meglumine or sodium lauryl sulfate could significantly improve the phenomenon of particle precipitation, and the prescription with meglumine had a better effect, and the texture of the ointment was more uniform.

[0070] Example 2

[0071] Prescription and Preparation of Zinc Salt 10-Hydroxy-2-decenoic Acid Ointment

[0072] Prepare zinc salt 10-hydroxy-2-decenoic acid ointment according to each prescription in Table 2, specification: about 1.1 - 3.5 g of zinc 10-hydroxydecenoate per 10 g of ointment.

[0073] Table 2. Prescription of Zinc Salt 10-Hydroxy-2-decenoic Acid Ointment

[0074] Prescription 1 2 3 4 10-Hydroxy-2-decenoic acid (g) 20 20 30 10 Zinc oxide (g) 4.4 5 6.6 2.2 Sodium carboxymethyl cellulose (g) 2.6 3 2.4 1.8 Glycerol (g) 30 29 25 30 Distilled water (g) 43 43 36 56 Ointment state Occasional granules Uniform texture Slightly caked Uniform texture

[0075] Preparation process:

[0076] Take three-quarters of the amount of 10-hydroxy-2-decenoic acid and the full amount of glycerin according to the above prescription, add them to the reaction pot, heat to about 40°C, and add the full amount of zinc oxide and half of the preheated distilled water at 40°C with stirring; continue to heat to 107 - 110°C, and 10-hydroxy-2-decenoic acid reacts with zinc oxide to form zinc 10-hydroxy-2-decenoate. After the reaction is completed, gradually add sodium carboxymethylcellulose to the system to dissolve it completely; when the temperature drops slightly to about 104°C, slowly add the remaining amount of 10-hydroxy-2-decenoic acid and the remaining amount of preheated distilled water at 50°C, and keep stirring, otherwise large chunks of zinc 10-hydroxy-2-decenoate are likely to precipitate. Continue to stir and cool to 50 - 60°C, grind evenly, and package; let it stand and cool to room temperature to obtain zinc salt 10-hydroxy-2-decenoic acid ointment. Each 10 g of zinc salt 10-hydroxy-2-decenoic acid ointment in Prescription 1, 2, 3, and 4 contains about 2.3, 2.3, 3.5, and 1.1 g of zinc 10-hydroxy-2-decenoate respectively.

[0077] The main component of zinc salt 10-hydroxy-2-decenoic acid ointment is the zinc 10-hydroxy-2-decenoate formed by the reaction. The reaction of 10-hydroxy-2-decenoic acid with zinc oxide is as follows:

[0078]

[0079] Control the reaction temperature at 107 - 110°C. Avoid too low temperature, as zinc 10-hydroxy-2-decenoate is likely to form lumps, affecting grinding; too high temperature, 10-hydroxy-2-decenoic acid is likely to volatilize and be lost, affecting the content of the effective drug.

[0080] Example 3

[0081] Formulation and Preparation of 10-Hydroxy-2-decenoic Acid Gel

[0082] Prepare 10-hydroxy-2-decenoic acid gels according to the formulations in Table 3, with the 10 g specification containing 0.5 - 1 g of 10-hydroxydecenoic acid respectively.

[0083] Table 3. Formulation of 10-Hydroxy-2-decenoic Acid Gel

[0084] Prescription 1 2 3 4 5 10-Hydroxy-2-decenoic acid (g) 5.0 5.0 5.0 5.0 10.0 Meglumine (g) 6.0 6.0 6.0 6.5 12.0 Sodium carboxymethyl cellulose (g) 1.5 3.0 2.0 1.5 2.5 Glycerol (g) 20.0 10.0 20.0 20.0 10.0 Propylene glycol (g) 10.0 20.0 10.0 10.0 10.0 Absolute ethanol (g) 5.0 10.0 5.0 5.0 8.0 Distilled water (g) 52.5 46.0 52.0 52.0 47.5 Gel state Occasional granules Occasional granules Occasional caking Uniform texture Uniform texture

[0085] Preparation Process:

[0086] Disperse sodium carboxymethylcellulose in absolute ethanol as Component A; dissolve meglumine in 30 mL of distilled water, then add 10-hydroxy-2-decenoic acid, and heat to 55 °C to dissolve 10-hydroxy-2-decenoic acid; then add glycerol and propylene glycol, mix evenly as Component B; add Component A to Component B, and add the remaining distilled water, disperse evenly, remove bubbles by ultrasonic treatment for 15 minutes, and fill into containers to obtain 10-hydroxy-2-decenoic acid gel. In Formulations 1, 2, 3, 4, and 5, each 10 g of 10-hydroxy-2-decenoic acid gel contains approximately 0.5, 0.5, 0.5, 0.5, and 1 g of 10-hydroxy-2-decenoic acid respectively.

[0087] As can be seen from Table 3, compared with Formulation 3, the gel prepared according to Formulation 4 has a more uniform texture, indicating that increasing the content of meglumine helps the dispersion of 10-hydroxy-2-decenoic acid in the gel system. In addition, the gel preparation made according to Formulation 5 also shows a uniform texture. The content of meglumine in Formulation 5 is approximately 12%, and the content of 10-hydroxy-2-decenoic acid is approximately 10%, both significantly higher than other formulations, indicating that increasing the content of meglumine in the system can improve the solubility of 10-hydroxy-2-decenoic acid in the gel.

[0088] Example 4

[0089] 10-Hydroxy-2-decenoic Acid Oral Suspension and Its Preparation

[0090] Prepare 10-hydroxy-2-decenoic acid oral suspension according to the formulation in Table 4, specification: each 10 g of oral suspension contains approximately 0.15 g of 10-hydroxydecenoic acid.

[0091] Table 4. Formulation of 10-Hydroxy-2-decenoic Acid Suspension

[0092] Prescription 1 10-Hydroxy-2-decenoic acid (g) 1.5 Sodium carboxymethyl cellulose (g) 0.5 Distilled water (g) 100.0

[0093] Preparation Process:

[0094] Weigh 0.5 g of sodium carboxymethylcellulose, disperse and dissolve it in 100 mL of distilled water to prepare a sodium carboxymethylcellulose solution with a concentration of 0.5%. Weigh 1.5 g of 10-hydroxy-2-decenoic acid, disperse and suspend it in the sodium carboxymethylcellulose solution with a concentration of 0.5%, and shake and suspend it evenly to obtain an oral suspension of 10-hydroxy-2-decenoic acid.

[0095] Example 5

[0096] Pharmacodynamic study of 10-hydroxy-2-decenoic acid ointment and oral suspension on imiquimod-induced psoriasis

[0097] Animal species selection: SPF-grade BALB / c mice (male, 6 - 8 weeks old, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., body weight 20 ± 2 g) were used. They were adaptively fed for one week in a standard breeding environment (free diet and water, 12-hour day and night cycle).

[0098] Modeling agent selection: The imiquimod (IMQ)-induced mouse model is the most widely used. It not only well simulates the psoriatic-like skin lesions but also has certain innate and acquired immune disorders similar to psoriasis to a certain extent. IMQ is a Toll-like receptor (TLR7 / 8) agonist. When it acts on TLR ligands, keratinocytes produce neutrophil chemotactic factors CXCL1, CXCL2, and IL-8. And within a certain range, IMQ induces the expression of CXCL1, CXCL2, and IL-8 mRNA in a concentration-dependent manner. After local application of IMQ to the mouse skin, it produces phenomena such as erythema, scales, and epidermal thickening in terms of skin phenotype; histologically, it causes abnormal differentiation and overproliferation of keratinocytes, neovascularization, and infiltration of immune inflammatory cells, etc., with phenotypic and pathological characteristics similar to human psoriasis. The psoriatic-like skin lesions induced by IMQ in mice are the most severe on the 6 - 8th day (times / day) of modeling and then gradually subside.

[0099] IMQ cream (content 5%) was purchased from Hubei Keyi Pharmaceutical Co., Ltd.

[0100] Establishment of animal model and administration method: As Figure 1After 7 days of adaptive cultivation of BALB / c mice, they were randomly divided into 4 groups: blank control group, psoriasis model group, 10-HDA zinc salt administration group, and 10-HDA intragastric administration group. The mice in each group were housed separately in cages. The back skin area (about 2 cm × 3 cm) of all mice was shaved using an animal hair clipper, and after shaving, hair removal cream was used for hair removal. Except for the blank control group, the remaining mice were smeared with IMQ cream (dose: 62.5 mg / mouse) on the back hair removal area, and the blank control group mice were smeared with an equal amount of vaseline on the back hair removal area. Once a day, starting from the first day of applying the medicine, for 8 consecutive days, a psoriasis model was established. Since the 3rd day of modeling, the mice in the 10-HDA intragastric administration group were given 10-HDA oral suspension (Example 4), and the dose was calculated based on the oral suspension: 0.2 mL / mouse, once a day; the mice in the 10-HDA zinc salt administration group were treated with 10-hydroxydecenoic acid ointment containing zinc salt (Prescription 2 of Example 2), and the dose was calculated based on the ointment: 0.1 g / mouse, applied to the affected area, once a day. The blank control group and the psoriasis model group mice were both smeared with vaseline.

[0101] PASI score statistics: Photos were taken daily for recording. Objective scoring was performed according to the Psoriasis Area and Severity Index Score (PASI score). The PASI scoring criteria are shown in Table 4. Scoring was performed based on three items: erythema (E), desquamation (D), and infiltration (I). The maximum score for each item was 4 points, and the total score was 12 points. Among them, erythema refers to red and dark red inflammatory plaques, and the color can fade when pressed; desquamation refers to the phenomenon of flaky exfoliation of epidermal cells; infiltration can also be regarded as skin thickness, referring to the relatively blurred boundary of the skin lesion, gradually spreading to the surrounding area, and having a certain sense of substance when pressed. The severity of erythema, desquamation, and infiltration of the skin lesions of the mice in each group was scored, and the sum of the scores of the three items was the cumulative score. After taking the average daily score of each group, a trend change graph of the skin lesion score was drawn.

[0102] Table 4. Psoriasis Area and Severity Index Score Table (PASI)

[0103] Severity Erythema (E) Scales (D) Infiltration (I) Score None No erythema None Flat 0 Mild Small part of the skin is light red Covered with fine scales The skin lesion is slightly higher than the normal skin 1 Moderate Most of the skin is red Covered with flaky scales The edge of the plaque is thick and sloping 2 Severe Almost all the skin is dark red All covered with thick scales The skin lesion bulges significantly higher than the normal skin 3 Extremely severe All skin areas are dark red Thick scales The skin lesion bulges significantly higher than the normal skin 4

[0104] The results showed that compared with the mice in the blank control group, after 5 days of modeling with IMQ, the back skin of the mice in the psoriasis model group showed obvious redness, swelling, and fine scales; after 8 days of modeling, the skin lesions of the mice in the psoriasis model group became more severe, and the skin elevation was significantly higher than that of the normal skin, indicating that IMQ could induce psoriasis-like symptoms in BALB / c mice ( Figure 2)。After administration of 10-HDA, whether it was the intragastric administration group or the zinc salt administration group of 10-HDA, the skin lesions of the mice were significantly improved: the redness and swelling improved significantly, no obvious scales were seen, and the degree of skin elevation decreased. The PASI score could also intuitively show that 10-HDA administration could improve the psoriasis-like symptoms induced by IMQ( Figure 1 C).

[0105] Analysis of spleen coefficient: The spleen is an important immune organ of the body, with various physiological functions, including participating in immune defense, removing aging red blood cells and pathogens in the blood, storing and releasing blood, etc. The spleen coefficient (spleen / bodyweight ratio) is a commonly used indicator to evaluate the proportion of the mouse spleen relative to the total body weight, which can reflect the intensity of the body's immune response and the state of immune function. The spleen of psoriasis mice is significantly enlarged, mainly due to three influencing factors. First, psoriasis is a chronic skin disease mediated by the immune system, and mice are prone to autoimmune reactions, attacking their own tissues and organs. This autoimmune reaction may lead to spleen enlargement. Second, psoriasis is an inflammatory skin disease, and mice may be affected by over-activated inflammatory reactions. Abnormally expressed cytokines and inflammatory substances may enter the spleen through the circulatory system, causing inflammatory reactions and volume enlargement of the spleen. Third, the enlargement of the spleen in psoriasis mice may be related to hepatosplenic dysfunction. The functions of the liver and spleen are coordinated with each other. The liver is mainly involved in metabolism and detoxification, while the spleen is mainly involved in immunity and hematopoiesis. Abnormal hepatosplenic function leads to unsmooth blood circulation and accumulation of toxic substances, thereby causing lesions and enlargement of the spleen.

[0106] The results of spleen coefficient analysis are shown in Figure 1 B, showing that compared with the mice in the blank control group, the spleen coefficient of the mice in the psoriasis model group was significantly increased (p < 0.0001), indicating that IMQ modeling could cause severe autoimmune reactions and inflammatory activation. Compared with the mice in the psoriasis model group, zinc salt ointment of 10-HDA could significantly reduce the spleen coefficient of psoriasis mice, and the difference was statistically significant (p < 0.01). After intragastric administration of 10-HDA oral suspension, the spleen coefficient of the mice also decreased, but no significant difference was seen. It shows that 10-HDA administration can reduce the inflammatory reaction and spleen damage of IMQ-induced psoriasis mice, improve the body's immune ability of IMQ-induced psoriasis mice, and compared with oral administration, the efficacy of the zinc salt ointment preparation is better and the difference is more significant.

[0107] The skin pathological effects of 10-hydroxy-2-decenoic acid on IMQ-induced psoriasis mice

[0108] HE staining: On the 9th day after modeling, the back skin of the mice was taken. After sampling, the skin tissue was rinsed thoroughly with pre-cooled PBS buffer, and after blotting dry with filter paper, it was fixed in 4% paraformaldehyde for over 24 hours. The tissue was taken out of the fixative and trimmed flat at the target site with a scalpel in the fume hood. The trimmed tissue and the corresponding label were placed in an embedding frame. The dehydration cassette was put into the dehydrator and dehydrated successively with gradient alcohol: 75% alcohol for 4 hours, 85% alcohol for 2 hours, 90% alcohol for 2 hours, 95% alcohol for 1 hour, absolute ethanol I for 30 minutes, absolute ethanol II for 30 minutes, alcohol-benzene for 5 - 10 minutes, xylene I for 5 - 10 minutes, xylene II for 5 - 10 minutes, melted paraffin I at 65°C for 1 hour, melted paraffin II at 65°C for 1 hour, melted paraffin III at 65°C for 1 hour; then gradient dehydration was carried out: 70% ethanol solution for 30 minutes - 80% ethanol solution for 30 minutes - 90% ethanol solution for 30 minutes - 95% ethanol solution for 30 minutes - absolute ethanol for 60 minutes - absolute ethanol for 60 minutes - xylene for 60 minutes - xylene for 60 minutes - paraffin for 60 minutes - paraffin for 60 minutes - paraffin for 60 minutes; after dehydration, the skin tissue was paraffin-embedded. The tissue block was soaked in an ice-water mixture, and then cut into 5-μm-thick tissue with a microtome, adhered to a glass slide, and then HE staining was carried out. The sections were successively put into environment-friendly dewaxing solution I for 20 minutes - environment-friendly dewaxing solution II for 20 minutes - absolute ethanol I for 5 minutes - absolute ethanol II for 5 minutes - 75% alcohol for 5 minutes, and washed with water. The sections were put into hematoxylin staining solution and stained for 3 - 5 minutes, washed with water, differentiated with a differentiating solution, washed with water, blued with a bluing solution, and rinsed with running water. The sections were successively put into 85% and 95% gradient alcohol for dehydration for 5 minutes each, and stained in eosin staining solution for 5 minutes. The sections were successively put into absolute ethanol I for 5 minutes - absolute ethanol II for 5 minutes - absolute ethanol III for 5 minutes - xylene I for 5 minutes - xylene II for 5 minutes for transparency, and sealed with neutral gum. After it was naturally air-dried, it was examined under an upright microscope, and images were collected and analyzed.

[0109] The results of HE staining are shown in Figure 3 , showing that: compared with the mice in the blank control group, the skin of the mice in the psoriasis model group was damaged, specifically manifested as hyperkeratosis in the epidermis, obvious thickening of the non-keratinized layer, elongation of the rete pegs, and accompanied by infiltration of a large number of inflammatory cells. Compared with the mice in the psoriasis model group, both transdermal administration and intragastric administration could relieve the skin pathological state of the mice, the keratinization phenomenon and inflammatory infiltration were alleviated, and the pathological changes in the non-keratinized layer were significantly reduced. There were also differences between the two drug administration groups. The skin of the mice in the zinc salt administration group was thinner than that of the oral preparation group and was closer to the blank control group.

[0110] The above experimental results show that: administering 10-hydroxy-2-decenoic acid can significantly improve the skin lesions and inflammatory responses of IMQ-induced psoriasis mice. Moreover, both the spleen coefficient and the HE staining results reflect that the zinc salt ointment preparation has better efficacy, indicating that compared with oral administration, the zinc salt preparation is more conducive to the anti-psoriasis efficacy of 10-hydroxy-2-decenoic acid.

[0111] Example 6

[0112] Pharmacodynamic study of 10-hydroxy-2-decenoic acid ordinary ointment and zinc salt ointment on DNCB-induced AD complications

[0113] As mentioned in the background art, psoriasis patients treated with biological agents often develop AD-like complications. Therefore, the present invention constructs an AD-like model and explores whether 10-HDA is effective.

[0114] Animal species selection: SPF-grade BALB / c mice (female, 6-8 weeks old, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., weighing 20±2 g) were adaptively fed for one week in a standard breeding environment (free diet and water, 12-hour day and night cycle).

[0115] Modeling agent selection: 1-Chloro-2,4-Dinitrobenzene (DNCB) is a chemical agent with hapten properties that can combine with the soluble part of proteins in epithelial tissues to form a complete antigen, and then activate T lymphocytes to become sensitized cells. When the hapten DNCB enters the body again and contacts the sensitized lymphocytes, an allergic reaction will be triggered. DNCB is commonly used to treat alopecia areata and detect the cellular immune function of the body. Reports indicate that repeated application of a certain dose of DNCB to stimulate the skin of mice can induce AD-like symptoms. Therefore, in the present invention, DNCB is used to establish an AD model to simulate the eczematous dermatitis complications that occur during the treatment of psoriasis with biological agents.

[0116] Establishment of animal model and administration method: As Figure 4After 7 days of adaptive feeding of BALB / c mice, they were randomly divided into 4 groups: blank control group, AD model group, 10-HDA zinc salt administration group, and 10-HAD ointment administration group. The mice in each group were housed separately. Use an animal hair clipper to shave the back skin area (about 2 cm × 2 cm) of all mice, and then use depilatory cream for hair removal. Except for the blank control group, apply 150 μL of 1% DNCB solution (dissolve DNCB in a mixture of acetone and olive oil with a volume ratio of 3:1) on the back skin of mice in each group once a day for 4 days. Starting from the 5th day, apply 150 μL of 0.2% DNCB on the back skin three times a week for four weeks. Mice in the blank control group were smeared with an equal amount of control solvent (a mixture of acetone and olive oil with a volume ratio of 3:1). Since the 5th day of modeling, mice in the 10-HDA ointment administration group were smeared with 10-HDA ordinary ointment (ointment of Prescription 1 in Example 1, with a 10-HDA content of about 6%) at a dose of 0.3 g / only (calculated by ointment) every day; mice in the 10-HDA zinc salt administration group were smeared with zinc salt-containing ointment (zinc salt-containing ointment of Prescription 4 in Example 2, with a 10-HDA content of about 10%) at a dose of 0.18 g / only (calculated by ointment) every day, once a day for four weeks. Mice in the blank control group and the AD model group were smeared with vaseline.

[0117] Analysis of spleen coefficient: Figure 4 As shown in B, compared with the blank control group, the spleen coefficient of mice in the AD model group was significantly increased (p < 0.001), indicating that after DNCB modeling, the innate immune ability of BALB / c mice was significantly decreased. Compared with the AD model group, both the zinc salt ointment or ordinary ointment containing 10-HDA could significantly reduce the spleen coefficient of psoriasis mice, and the difference was statistically significant. It shows that transdermal administration of 10-HDA can increase the body's immune ability of AD mice induced by DNCB and reduce the body's inflammatory response.

[0118] Analysis of skin lesion results: As Figure 5 shown, compared with the blank control group, the skin of AD-like model mice showed macroscopic pathological changes such as flushing, desquamation, and occasional crusting, indicating that DNCB modeling can cause severe skin damage in BALB / c mice. Compared with the AD model group, both the ordinary ointment containing 10-HDA and the zinc salt ointment could significantly improve the skin condition of AD mice, and no severe damaged phenomena such as desquamation and crusting were observed, indicating that 10-HDA can reduce AD-like skin lesions caused by DNCB.

[0119] Analysis of HE staining results: The HE staining procedure was the same as that in "HE staining" of Example 5. Compared with the blank control group, the skin of mice in the AD model group was damaged, specifically manifested as thickening of the epidermal layer, hyperkeratosis, elongation of rete pegs, and infiltration of lymphocytes in the dermis ( Figure 6)。However, in both the ointment group and the zinc salt group, the phenomena of keratinization and inflammatory infiltration were alleviated to some extent, and the skin condition of the mice was comparable to that of the blank control group. It indicates that 10-HDA significantly improved the AD-like skin damage state caused by DNCB modeling.

[0120] Example 7

[0121] Effect of 10-Hydroxy-2-decenoic Acid on Tight Junctions in Mouse Skin

[0122] Selection of detection indicators: Tight junctions are anastomotic belt-like structures of proteins and lipids mediated by a connection complex composed of tight junction proteins, surrounding the lateral membranes of epithelial or endothelial cells and sealing the outermost part of the intercellular space. In human and mouse epidermis, keratinocytes in the granular layer are sealed together by functional tight junctions, which can not only prevent harmful substances from passing through but also maintain cell polarity. The Claudin family of tight junction proteins is the most important component of the tight junction structure, mainly expressed on the lateral walls of keratinocytes in the epidermal granular layer, preventing external antigens, microorganisms, etc. from entering the body through the skin, and regulating substance transport, epidermal cell proliferation and differentiation, and the polar secretion of lamellar body lipids, etc. Claudins play an important role in the integrity of tight junctions and the epidermal permeability barrier function. Changes in their expression increase epidermal permeability, weaken intercellular adhesion, and are closely related to the occurrence of various skin diseases.

[0123] Altered expression of tight junction proteins is an early event in psoriasis. The expression of Claudin-1 is reduced in psoriasis, and its content level has a significant negative correlation with the severity of skin lesions. The expression of Claudin-1 is decreased in the epidermis of AD patients, increasing skin susceptibility. Specifically, the decrease in Claudin-1 leads to an increase in the expression of IL-1β in keratinocytes, promoting an increase in reactive oxygen species (ROS) and inflammation, and accompanied by skin water loss and the penetration of allergens (such as microorganisms like bacteria, molds, dust mites, and pollen). Therefore, restoring the expression of Claudin-1 is of great significance for alleviating psoriasis and its AD comorbidity.

[0124] Protein extraction and quantification: After the animal model establishment and drug administration in Example 6 were completed, the back skin of the mice was taken. After sampling, the skin tissue was rinsed thoroughly with pre-cooled PBS buffer, and the moisture was blotted dry with filter paper, then stored in a -80°C refrigerator. 20 mg of skin tissue was accurately weighed into a 1.5 mL Eppendorf tube, 0.5 mL of RIPA lysis buffer (containing 1% PMSF) was added, zirconia beads were added, and it was ground in a rocking grinder and placed on ice for 15 min; centrifuged at 4°C * 12000 rpm * 10 min, and 400 μL of the supernatant was taken. 10 μL was taken from the supernatant and diluted 30 times with 290 μL of ultrapure water, and the extracted protein sample was quantified using a BCA protein quantification kit. According to the measured protein concentration, the remaining supernatant was diluted to 10 μg / μL with RIPA, and then 4× Loading Buffer was added according to a volume ratio of 3:1, dissolved thoroughly, boiled and denatured at 100°C for 10 min, and stored at -20°C.

[0125] Western Blot experiment: The protein samples were added to the stacking gel lanes in sequence, and at the same time, a Marker pre-stained protein was added as a control. The molecular weight of the target protein Claudin-1 is 23 kDa, and the molecular weight of the internal reference protein GAPDH is 37 kDa. Electrophoresis conditions: The stacking gel was electrophoresed at a constant voltage of 75 V for 45 min for sample concentration; the separating gel was electrophoresed at a constant voltage of 115 V for about 1 h for separation, and the electrophoresis degree was judged according to the position of the Marker. Transfer conditions: The wet transfer method was used. First, a PVDF membrane of appropriate size was soaked in methanol for 2 min for activation, then soaked in deionized water for 3 min, and finally equilibrated in transfer buffer for 10 min. The bottom electrode was the anode, and filter paper soaked in transfer buffer, PVDF membrane, gel, and filter paper were placed on it in sequence, air bubbles were removed, clamped and placed in the sandwich, and transferred at a constant voltage of 100 V for 60 min. Blocking and antibody incubation: Blocked at room temperature on a shaker with a 5% skim milk solution for 2 h. The Claudin-1 primary antibody was diluted 1:1000 with the primary antibody diluent, and the GAPDH primary antibody was diluted 1:10000. The membrane was incubated with the corresponding antibody in a hybridization bag and hybridized overnight at 4°C. Washed the membrane 3 times with TBST (shaker, room temperature, 10 min each time) to remove the primary antibody. The rabbit secondary antibody was diluted 1:10000 with TBST solution and incubated at room temperature on a shaker for 2 h. Washed the membrane 3 times with TBST (shaker, room temperature, 10 min each time) to remove the secondary antibody. Chemiluminescent imaging: The enhanced chemiluminescence method (ECL method) was used to detect the target protein and internal reference protein in the ChemDocTM XRS+ gel imaging system, and densitometric analysis and semi-quantitative comparison were performed using the Image LabTM software.

[0126] WB result analysis: The content of Claudin-1 in each group of samples was compared according to the ratio of Claudin-1 to GAPDH. Compared with the blank control group, the expression of Claudin-1 in the skin of mice in the AD model group was significantly decreased ( Figure 7 ), indicating that the tight junction structure of the skin of mice in the AD model group was damaged, the inflammation was aggravated, and the skin homeostasis was impaired. Relatively, compared with the AD model group, both the zinc salt ointment containing 10-HDA and the ordinary ointment could increase the expression level of Claudin-1 in the skin of mice. It was shown that after topical administration of 10-HDA, the damaged state of the skin of mice was alleviated, the tight junction function was partially restored, the inflammatory response was reduced, and the skin homeostasis was restored and maintained.

[0127] In summary, the inventors found that the 10-hydroxy-2-decenoic acid (zinc salt) ointment could significantly improve IMQ-induced psoriasis and the AD comorbidity caused by psoriasis. 10-Hydroxy-2-decenoic acid can reduce inflammation, improve the body's immunity, increase the expression level of skin tight proteins, and relieve pathological skin damage.

Claims

1. Use of 10-hydroxy-2-decenoic acid or its salt in the preparation of a medicament for treating psoriasis and atopic dermatitis comorbidity caused by psoriasis.

2. The application according to claim 1, wherein: The dosage form of the medicament is an ointment, a gel, a film, a patch, an oral solid preparation, or an oral suspension.

3. A 10-hydroxy-2-decenoic acid ointment for treating psoriasis and the comorbidity of atopic dermatitis caused by psoriasis, characterized in that: It is prepared from the following components in parts by weight: 2-30 parts of 10-hydroxy-2-decenoic acid, 3-20 parts of glycerol, 3-20 parts of propylene glycol, 3-15 parts of ethanol, 0.2-5.0 parts of meglumine, 1-6 parts of beeswax, 2-15 parts of lanolin, 10-55 parts of petrolatum, 0.1-1.0 part of methyl paraben, 0.1-1.0 part of propyl paraben; or 2-30 parts of 10-hydroxy-2-decenoic acid, 3-20 parts of glycerol, 3-20 parts of propylene glycol, 3-15 parts of ethanol, 0.2-2.0 parts of sodium lauryl sulfate, 1-6 parts of beeswax, 2-15 parts of lanolin, 10-55 parts of petrolatum, 0.1-1.0 part of methyl paraben, 0.1-1.0 part of propyl paraben.

4. The 10-hydroxy-2-decenoic acid ointment according to claim 3, characterized in that: Each 10 g of the 10-hydroxy-2-decenoic acid ointment contains 0.6-1.8 g of 10-hydroxy-2-decenoic acid, 0.5-1.5 g of glycerol, 0.5-1.5 g of propylene glycol, 0.5-1.0 g of ethanol, 0.2-0.6 g of meglumine, 0.2-1.0 g of beeswax, 0.5-2.0 g of lanolin, 2.0-5.5 g of petrolatum, 0.01-0.05 g of methyl paraben, 0.01-0.05 g of propyl paraben; or contains 0.6-1.8 g of 10-hydroxy-2-decenoic acid, 0.5-1.5 g of glycerol, 0.5-1.5 g of propylene glycol, 0.5-1.0 g of ethanol, 0.05-0.2 g of sodium lauryl sulfate, 0.2-1.0 g of beeswax, 0.5-2.0 g of lanolin, 2.0-5.5 g of petrolatum, 0.01-0.05 g of methyl paraben, 0.01-0.05 g of propyl paraben; preferably, each 10 g of the 10-hydroxy-2-decenoic acid ointment contains 0.6-0.9 g of 10-hydroxy-2-decenoic acid, 1.0-1.2 g of glycerol, 1.0-1.2 g of propylene glycol, 0.5-1.0 g of ethanol, 0.2-0.4 g of meglumine, 0.5-0.6 g of beeswax, 0.9-1.0 g of lanolin, 4.0-5.0 g of petrolatum, 0.01-0.03 g of methyl paraben, 0.01-0.03 g of propyl paraben; or 0.6-1.8 g of 10-hydroxy-2-decenoic acid, 1.0-1.2 g of glycerol, 1.0-1.2 g of propylene glycol, 0.5-1.0 g of ethanol, 0.05-0.15 g of sodium lauryl sulfate, 0.3-0.5 g of beeswax, 0.9-1.2 g of lanolin, 3.9-5.0 g of petrolatum, 0.01-0.03 g of methyl paraben, 0.01-0.03 g of propyl paraben.

5. A method for preparing the 10-hydroxy-2-decenoic acid ointment according to claim 3, characterized in that: Including: Beeswax, lanolin, and vaseline are mixed, heated in a water bath to 80-85° C. to melt, and then methylparaben and propylparaben are added and mixed evenly to obtain component A. Ethanol, glycerin, and propylene glycol are mixed, and meglumine or sodium lauryl sulfate is added to the mixed solvent, stirred and dissolved to obtain a meglumine or sodium lauryl sulfate solution, which is used as component B. 10-hydroxy-2-decenoic acid is added to component B, heated in a water bath to 55-60° C., stirred and dissolved to obtain component C. Component C is added to component A, mixed evenly, and allowed to cool to room temperature to obtain an ointment.

6. A zinc-containing ointment of 10-hydroxy-2-decenoic acid for treating psoriasis and atopic dermatitis comorbidity caused by psoriasis, characterized in that: The invention is prepared from the following ingredients in parts by weight: 5 to 30 parts of 10-hydroxy-2-decenoic acid, 1.0 to 10.0 parts of zinc oxide, 5 to 35 parts of glycerin, 0.5 to 6.0 parts of sodium carboxymethyl cellulose, and 10 to 80 parts of distilled water; and the molar ratio of 10-hydroxy-2-decenoic acid to zinc oxide is 1.75:1 to 2:

1.

7. The 10-hydroxy-2-decenoic acid zinc-containing ointment according to claim 6, characterized in that: Each 10 g of the 10-hydroxy-2-decenoic acid zinc-containing ointment is prepared from the following ingredients: 1.0-3.0 g of 10-hydroxy-2-decenoic acid, 0.2-1.0 g of zinc oxide, 0.1-0.5 g of sodium carboxymethyl cellulose, 2.0-4.0 g of glycerin, and 2.0-6.0 g of distilled water; preferably, each 10 g of the 10-hydroxy-2-decenoic acid zinc-containing ointment is prepared from the following ingredients: 1.0-2.0 g of 10-hydroxy-2-decenoic acid, 0.2-0.5 g of zinc oxide, 0.2-0.3 g of sodium carboxymethyl cellulose, 2.5-3.0 g of glycerin, and 4.0-6.0 g of distilled water.

8. A method for preparing the 10-hydroxy-2-decenoic acid zinc-containing ointment according to claim 6, characterized in that: include: Take 1 / 2 to 3 / 4 of the prescribed amount of 10-hydroxy-2-decenoic acid and the whole amount of glycerol, mix them evenly, heat them to 40 to 45° C., add the whole amount of zinc oxide and 1 / 2 to 3 / 4 of the prescribed amount of distilled water preheated to 40 to 45° C. while stirring, continue heating to 107 to 110° C., and the 10-hydroxy-2-decenoic acid reacts with the zinc oxide to generate zinc 10-hydroxy-2-decenoate; after the reaction is completed, add sodium carboxymethyl cellulose to the system and dissolve it completely; after the temperature drops to 103 to 105° C., slowly add the remaining amount of 10-hydroxy-2-decenoic acid and distilled water preheated to 40 to 45° C., and stir continuously; after the system is cooled to 50 to 55° C., grind evenly, and package; let it stand and cool to room temperature to obtain a zinc salt-containing 10-hydroxy-2-decenoic acid ointment.

9. A 10-hydroxy-2-decenoic acid gel for treating psoriasis and the AD comorbidity caused by psoriasis, characterized in that: It is prepared from the following components in parts by weight: 2-15 parts of 10-hydroxy-2-decenoic acid, 1-5 parts of sodium carboxymethyl cellulose, 2.0-15.0 parts of meglumine, 2-10 parts of absolute ethanol, 4-20 parts of glycerol, 4-20 parts of propylene glycol, and 10-60 parts of distilled water; preferably, every 10 g of the 10-hydroxy-2-decenoic acid gel contains 0.5-1.0 g of 10-hydroxy-2-decenoic acid, 0.1-0.3 g of sodium carboxymethyl cellulose, 0.65-1.2 g of meglumine, 1.0-2.0 g of glycerol, 1.0-2.0 g of propylene glycol, 0.5-1.0 g of ethanol, and 4.0-6.0 g of distilled water; most preferably, every 10 g of the 10-hydroxy-2-decenoic acid gel contains 0.5-1.0 g of 10-hydroxy-2-decenoic acid, 0.15-0.25 g of sodium carboxymethyl cellulose, 0.65-1.2 g of meglumine, 1.0-2.0 g of glycerol, 1.0 g of propylene glycol, 0.3-0.8 g of ethanol, and 4.75-5.2 g of distilled water.

10. A method for preparing the 10-hydroxy-2-decenoic acid gel according to claim 9, characterized in that: Including: Disperse sodium carboxymethyl cellulose in ethanol as component A; dissolve meglumine in 1 / 2 to 2 / 3 of the prescribed amount of distilled water, then add 10-hydroxydecenoic acid, and heat to 55-60 °C to dissolve it; then add glycerol and propylene glycol, mix evenly as component B; add component A to component B, and add the remaining amount of distilled water, disperse evenly, and remove bubbles by ultrasonic treatment to obtain the 10-hydroxy-2-decenoic acid gel.

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