Application of pedunculoside in preparation of medicine for treating psoriasis

Abstract

The invention discloses application of pedunculoside in preparation of a medicine for treating psoriasis, and relates to the technical field of medicines. The invention provides a natural candidate drug which is clear in structure and has both effectiveness and safety for clinical treatment of psoriasis.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology. More specifically, this invention relates to the use of ilex glycoside as the sole active ingredient in the preparation of a medicament for treating psoriasis. Background Technology

[0002] Psoriasis is a chronic, relapsing inflammatory skin disease driven by both genetic susceptibility and environmental factors. Its main pathological features include abnormal proliferation and differentiation of keratinocytes, vasodilation in the papillary dermis, and immune-inflammatory infiltration centered on T cells / dendritic cells. Current treatments include topical corticosteroids and vitamin D analogs, phototherapy, systemic medications such as desonide, methotrexate, cyclosporine, retinoids, and biologics and small molecule drugs targeting TNF-α, IL-17, and IL-23. While these drugs have some efficacy, long-term use still faces challenges such as high relapse rates, risks of immunosuppression-related infections, hepatotoxicity and nephrotoxicity, metabolic abnormalities, high costs, and inadequate response or secondary tolerance in some patients. Furthermore, current therapies often focus on inhibiting a single inflammatory pathway, while the pathogenesis of psoriasis involves complex interactions of multiple immune-inflammatory pathways, making the development of new, multi-modal, and safer treatments challenging. Pedunculoside (PE) is an active monomeric component derived from salinomycin and has pharmacological basis such as immunomodulation. Currently, there are no reports on the use of pedunculoside for the treatment of psoriasis. Summary of the Invention

[0003] This invention provides the use of long-stemmed holly glycoside as the sole active ingredient in the preparation of a drug for treating psoriasis, which provides a well-defined, effective, and safe natural candidate drug for the clinical treatment of psoriasis.

[0004] In order to achieve these objectives and other advantages according to the invention, the use of ileoside as the sole active ingredient in the preparation of a medicament for treating psoriasis is provided.

[0005] Preferably, the drug comprises a therapeutically effective amount of lecithin and a pharmaceutically acceptable carrier.

[0006] Preferably, the pharmaceutically acceptable carrier includes one or more of diluents, solvents, emulsifiers, thickeners, humectants, pH adjusters, and preservatives.

[0007] Preferably, the drug is a topical preparation, which is selected from creams, ointments, gels, lotions, or patches.

[0008] Preferably, the drug is a cream, and the cream comprises: a) The oil phase includes stearic acid, glyceryl monostearate, and castor oil; b) The aqueous phase, including water, glycerol, and triethanolamine; and c) Cosolvents, including 1,2-propanediol.

[0009] Preferably, the mass ratio of stearic acid, glyceryl monostearate, and castor oil in the oil phase is 1:(0.2-0.5):(0.6-1.0).

[0010] Preferably, the ratio of glycerol, water and triethanolamine in the aqueous phase is 1g:(4.0-6.0)mL:(0.1-0.2)mL.

[0011] Preferably, the psoriasis is plaque psoriasis, guttate psoriasis, psoriatic arthritis, or erythrodermic psoriasis.

[0012] Preferably, the dosage of lecithin is not less than 0.8 mg per administration.

[0013] Preferably, the drug downregulates the levels of IL-17A and IFN-γ proteins in skin tissue, inhibits the expression levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22, and inhibits the levels of Th17 cell-mediated inflammatory factors.

[0014] The present invention has at least the following beneficial effects: First, this invention uses holly glycoside as the sole active ingredient to prepare a drug for treating psoriasis. By regulating the release of inflammatory factors, inhibiting abnormal immune activation, and improving the inflammatory microenvironment of keratinocytes, it intervenes in the pathological closed loop of psoriasis: immune imbalance-inflammatory amplification-excessive epidermal proliferation, thus balancing efficacy and safety.

[0015] Secondly, the long-stemmed holly glycoside of this invention downregulates the expression of multiple key inflammatory factors such as IL-17A and IFN-γ, while inhibiting the level of Th17 cell-mediated inflammatory factors. Its mechanism of action is comprehensive and precise, covering the core links in the pathogenesis of psoriasis. Compared with some single-target drugs, it can more comprehensively inhibit the inflammatory response, improve abnormal epidermal proliferation, enhance the treatment effect, and reduce the risk of disease recurrence.

[0016] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0017] Figure 1 The effect of PE of the present invention on the skin of a mouse model of psoriasis; Figure 2 The effect of PE of the present invention on blood routine in psoriasis model mice; Figure 3 The effect of PE on the spleen of a psoriasis model mouse according to the present invention; Figure 4 The effect of PE of the present invention on the levels of IL-17A and IFN-γ in the skin tissue of psoriasis model mice; Figure 5 The effects of PE of the present invention on the levels of IL-6, IL-1β, TNF-α, IL-17A and IL-22 mRNA in the skin tissue of psoriasis model mice. Detailed Implementation

[0018] The present invention will now be described in further detail with reference to the accompanying drawings, so that those skilled in the art can implement it based on the description.

[0019] It should be understood that terms such as "having," "comprising," and "including" as used herein do not exclude the presence or addition of one or more other elements or combinations thereof. It should be noted that the experimental methods described in the following embodiments, unless otherwise specified, are conventional methods, and the reagents and materials, unless otherwise specified, are commercially available and therefore should not be construed as limiting the invention.

[0020] The use of holmite glycoside as the sole active ingredient in the preparation of drugs for the treatment of psoriasis. The psoriasis referred to here includes plaque psoriasis, guttate psoriasis, psoriatic arthritis, or erythrodermic psoriasis. Imiquimod-induced psoriasis-like dermatitis is a skin inflammation model with psoriasis-like pathological features established by topical application of imiquimod. Plaque psoriasis is the most common type of psoriasis, characterized by well-defined dark red plaques covered with silvery-white scales. Guttate psoriasis presents as scattered red papules or maculopapules several millimeters in diameter. Psoriatic arthritis, in addition to skin lesions, is accompanied by joint inflammation. Erythrodermic psoriasis presents as diffuse redness, swelling, and desquamation of the entire body.

[0021] The drug comprises a therapeutically effective amount of ilex glycoside and a pharmaceutically acceptable carrier. The therapeutically effective amount range of ilex glycoside is determined based on factors such as its pharmacological activity, the severity of psoriasis, and the drug formulation. Pharmaceutically acceptable carriers are screened, requiring that they do not chemically react with ilex glycoside and can promote its stable dispersion or dissolution. The therapeutically effective amount of ilex glycoside and the selected carrier are mixed according to conventional drug preparation procedures.

[0022] Pharmaceutically acceptable carriers include one or more of the following: diluents, solvents, emulsifiers, thickeners, humectants, pH adjusters, and preservatives. Diluents are primarily used to increase the volume of the formulation, such as a portion of the water or oil in an ointment; solvents are used to dissolve the active ingredients, such as 1,2-propylene glycol used in this embodiment; emulsifiers are used to uniformly mix the oil and water phases to form an emulsion, such as glyceryl monostearate and triethanolamine, which function as nonionic and anionic emulsifiers respectively in this embodiment; thickeners are used to adjust the viscosity of the formulation, such as stearic acid, which increases the consistency of the ointment at room temperature; humectants are used to prevent excessive moisture loss from the skin, such as glycerin; pH adjusters are used to adjust the pH of the formulation to be close to the physiological pH of the skin, reducing irritation; triethanolamine also has this function; and preservatives are used to prevent microbial growth and extend the shelf life of the formulation. By selecting appropriate excipients and optimizing the formulation performance, drugs containing holly glycosides are ensured to have good stability, applicability, and efficacy.

[0023] The drug is a topical preparation, selected from creams, ointments, gels, lotions, or patches. Psoriasis lesions are primarily located on the skin; therefore, topical administration is one of the preferred routes of administration, allowing the drug to act directly on the lesions, increasing local drug concentration, and reducing potential side effects from systemic absorption. Creams and lotions are semi-solid oil-in-water or water-in-oil emulsions, easy to apply and wash off, suitable for most plaque-like lesions. Ointments typically have a higher oil content and stronger occlusive properties, suitable for dry, thickened lesions. Gels are refreshing and non-greasy, suitable for the scalp or intertriginous areas. Lotions are mostly liquid preparations, suitable for widely distributed lesions or scalp psoriasis. Patches provide continuous drug release. By clarifying the topical form of holly glycoside, a clear direction is provided for developing the most suitable dosage form for psoriasis lesions of different locations and severity.

[0024] The drug is a cream, and the cream comprises: a) The oil phase includes stearic acid, glyceryl monostearate, and castor oil. Stearic acid is both a thickener and participates in the formation of soap base emulsions. Glyceryl monostearate is a nonionic emulsifier that can stabilize the oil-water interface. Castor oil is an oily component that can lubricate the skin and promote the penetration of certain fat-soluble components. The mass ratio of stearic acid, glyceryl monostearate, and castor oil is 1:(0.2-0.5):(0.6-1.0). b) The aqueous phase includes water, glycerol, and triethanolamine. Water is the continuous phase. Glycerol is a humectant. Triethanolamine reacts with stearic acid to form soap, which is an anionic emulsifier and also adjusts the pH. The ratio of glycerol, water, and triethanolamine is 1 g : (4.0-6.0) mL : (0.1-0.2) mL; and c) Cosolvents, including 1,2-propanediol, for pre-dissolving holly glycosides; The various components together constitute the pharmaceutical carrier system of holly glycoside, ensuring that holly glycoside exists in the cream in a stable and uniform form.

[0025] During preparation, the oil phase component is first heated and melted. Ilex chinensis glycosides are dissolved in heated 1,2-propylene glycol and added to the oil phase. The aqueous phase component is heated separately. Then, the oil phase is added to the aqueous phase under stirring to emulsify. Stirring is continued until it cools and solidifies. The final cream has a uniform, delicate texture and good stability. It can effectively carry Ilex chinensis glycosides and exert its therapeutic effect through topical application.

[0026] The dosage of haloxyfopsis glycoside should not be less than 0.8 mg per dose. Based on the pharmacological activity of haloxyfopsis glycoside and the treatment needs of psoriasis, the minimum dosage of haloxyfopsis glycoside is determined to ensure that each dose can achieve an effective therapeutic concentration. While ensuring the therapeutic effect, it also provides a scientific reference for adjusting the clinical dosage.

[0027] The drug downregulates the expression levels of IL-17A, IFN-γ, IL-6, IL-17A, IL-1β, TNF-α, and IL-22 mRNA in skin tissue, which can directly reduce the number of inflammatory mediators, inhibit the amplification of inflammatory responses, and relieve inflammatory symptoms such as skin erythema, swelling, and pain. It also inhibits the level of Th17 cell-mediated inflammatory factors, thereby blocking the initiation and persistence of the inflammatory response in psoriasis from the source, restoring the body's immune balance, and improving pathological changes such as excessive epidermal proliferation and abnormal keratinization caused by immune imbalance.

[0028] <Study on the Treatment Efficacy of Psoriasis> 1. Animal grouping: Mice were divided into five groups of equal numbers: control group, model group, PE group (PE 40 mg / kg), blank matrix group (no PE, only excipients), and positive drug desonide group.

[0029] 2. PE Cream Formulation and Preparation Method: First, weigh 2.4g of stearic acid, 0.8g of glyceryl monostearate, and 2.0g of castor oil as the oil phase, and dissolve them in an 80°C water bath. Weigh 0.25g of PE and dissolve it in 2.0mL of 1,2-propylene glycol in an 80°C water bath. Add the dissolved PE to the oil phase. Mix 10.0mL of water and 2.0g of glycerin as the aqueous phase, and heat it in an 80°C water bath. When the temperature reaches 80°C, add 0.3mL of triethanolamine to the aqueous phase while stirring. Slowly add the completely dissolved oil phase to the aqueous phase while stirring rapidly. Stir until the temperature returns to room temperature to obtain the PE cream.

[0030] 3. Modeling and drug administration The day before the experiment, mice in each group were lightly anesthetized and had hair removed from a 2.5cm × 2.5cm area on their backs. Fine hairs were then removed with depilatory cream, and the mice were rinsed with water to remove any residue. The mice were allowed to acclimatize to these conditions for one day. Except for the control group, all other groups were given 62.5mg / mouse of 5% imiquimod at 9:00 AM to induce modeling. Four hours later, the PE group, control matrix group, and positive control desonide group were given 62.5mg / mouse of PE cream (PE content 0.8mg), 62.5mg / mouse of control matrix (cream without PE, only excipients), and 62.5mg / mouse of positive control desonide, respectively. The corresponding drugs were administered four hours later for 14 consecutive days. Mice were sacrificed on the 15th day for sample collection.

[0031] 4. Detection Indicators 4.1 Skin condition: On day 15, the skin condition of the mice was photographed and recorded, the PASI score was calculated, and the skin tissue was stained with HE after sampling.

[0032] 4.2 Skin condition: Record spleen size.

[0033] 4.3 Blood routine values: The levels of white blood cells, neutrophils, lymphocytes, and the ratio of neutrophils to lymphocytes in the mouse blood were measured.

[0034] 4.4 ELISA assay: Skin tissue was taken to detect the levels of IL-17A and IFN-γ.

[0035] 4.5 RT-qPCR experiment: Mouse skin tissue was used to detect the mRNA levels of IL-6, IL-17A, IL-1β, TNF-α and IL-22.

[0036] 5. Experimental Results 5.1 Effects of PE on the skin of psoriasis model mice A psoriasis model was established using 5% imiquimod cream (IMQ). After continuous administration of PE cream for 14 days, from Figure 1 The results of the mouse back skin observation shown in Figure A indicate that PE cream significantly alleviated imiquimod-induced skin lesions, improved skin thickening, and reduced erythema and scaling. Figure 1 The HE staining results of mouse skin tissue shown in Figure B (scale bar = 100 μm) indicate that significant acanthosis, increased keratinization, and inflammatory cell infiltration were observed in the IMQ-induced psoriasis model group, while the PE group showed improvement in acanthosis, increased keratinization, and inflammatory cell infiltration. Furthermore, from... Figure 1The PASI scores of mouse skin tissue shown in Figure C indicate that, ***P < 0.001 vs. Model group, PE cream significantly reduced IMQ-induced skin thickening, scarring, and scaling. This suggests that PE cream has an ameliorative effect on psoriasis.

[0037] 5.2 Effects of PE on blood routine tests in psoriasis model mice Blood was collected from the eyes of mice, and a complete blood count (CBC) was used to measure the levels of white blood cells (WBC), neutrophils, and lymphocytes (LYMPH) in the mouse plasma. Figure 2 The effects of PE on mouse blood routine tests are shown in the figure. *P<0.05, **P<0.01, ***P<0.001 vs Model. Compared with the blank group, the model group had increased levels of white blood cells, neutrophils, and lymphocytes, while the PE group and the positive drug desonide group had significantly decreased levels.

[0038] 5.3 Effects of PE on the spleen of psoriasis model mice like Figure 3 The effect of PE on the spleen of mice shows that, compared with the blank group, the spleen of the model group was enlarged, and the PE group and the positive drug desonide group showed improvement, indicating that PE cream can regulate the immune system of mice and thus improve the symptoms of psoriasis.

[0039] 5.4 Effects of PE on IL-17A and IFN-γ levels in skin tissue of psoriasis model mice ELISA kits were used to detect the levels of IL-17A and IFN-γ in mouse skin tissue, such as... Figure 4 As shown in A and 4B, the effects of PE on the levels of IL-17A and IFN-γ in mouse skin tissue can be seen that, ***P<0.001 vs Model, compared with the blank group, the levels of IL-17A and IFN-γ in the model group were significantly increased, while the PE group and the positive drug desonide group could reduce the levels of IL-17A and IFN-γ, indicating that PE can improve psoriasis symptoms by regulating the levels of IL-17A and IFN-γ.

[0040] 5.5 Effects of PE on the levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22 mRNA in skin tissue of psoriasis model mice RT-qPCR was used to detect the mRNA levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22 in mouse skin tissue. Figure 5The effects of PE on the levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22 mRNA in mouse skin tissue shown in A, 5B, 5C, 5D, and 5E are as follows: ****P < 0.0001 vs Model. Compared with the control group, the model group showed significantly increased levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22 mRNA. The PE group and the positive control drug desonide group were able to reduce the levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22 mRNA, indicating that PE can improve psoriasis symptoms by regulating immune factors and reducing inflammatory factor levels.

[0041] 6. Conclusion In an imiquimod (IMQ)-induced psoriasis-like mouse model, administration of idemosiderin (PE) significantly improved the skin phenotype and histological damage: grossly, it manifested as thickened skin, reduced erythema and scaling, and a decreased PASI score; hematoxylin and eosin (HE) analysis showed relief of acanthosis, increased keratinization, and inflammatory cell infiltration. Simultaneously, PE reduced systemic inflammation and immune activation, decreased elevated levels of peripheral blood leukocytes, neutrophils, and lymphocytes in the model animals, and improved splenomegaly. Mechanistically, PE downregulated key inflammatory pathway-related factors in psoriasis: reducing IL-17A and IFN-γ protein levels in skin tissue, and inhibiting the mRNA expression of inflammatory and Th17-related factors such as IL-6, IL-1β, TNF-α, IL-17A, and IL-22.

[0042] In summary, PE cream has clear in vivo pharmacodynamic support for psoriasis, demonstrating its potential to exert therapeutic effects by inhibiting the Th17 / inflammatory cytokine network and improving the skin's inflammatory microenvironment.

[0043] The number of devices and processing scale described herein are for the purpose of simplifying the description of the invention. Applications, modifications, and variations of the invention will be readily apparent to those skilled in the art.

[0044] Although embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and illustrations shown and described herein.

Claims

1. The use of long-stemmed holly glycoside as the sole active ingredient in the preparation of drugs for the treatment of psoriasis.

2. The use as described in claim 1, characterized in that, The drug contains a therapeutically effective amount of idelaeoside and a pharmaceutically acceptable carrier.

3. The use as described in claim 2, characterized in that, The pharmaceutically acceptable carriers include one or more of the following: diluents, solvents, emulsifiers, thickeners, humectants, pH adjusters, and preservatives.

4. The use as described in any one of claims 1-3, characterized in that, The drug is a topical preparation, which is selected from creams, ointments, gels, lotions, or patches.

5. The use as described in claim 4, characterized in that, The drug is a cream, and the cream comprises: a) Oil phase, including stearic acid, glyceryl monostearate and castor oil; b) The aqueous phase, including water, glycerol, and triethanolamine; and c) Cosolvents, including 1,2-propanediol.

6. The use as described in claim 5, characterized in that, The mass ratio of stearic acid, glyceryl monostearate, and castor oil in the oil phase is 1:(0.2-0.5):(0.6-1.0).

7. The use as described in claim 5, characterized in that, The ratio of glycerol, water and triethanolamine in the aqueous phase is 1g:(4.0-6.0)mL:(0.1-0.2)mL.

8. The use as described in claim 1, characterized in that, The psoriasis referred to is plaque psoriasis, guttate psoriasis, psoriatic arthritis, or erythrodermic psoriasis.

9. The use as described in claim 1, characterized in that, The dosage of ide glycoside should not be less than 0.8 mg per administration.

10. The use as described in claim 1, characterized in that, The drug downregulates the levels of IL-17A and IFN-γ proteins in skin tissue, inhibits the expression levels of IL-6, IL-1β, TNF-α, IL-17A, and IL-22, and suppresses the levels of Th17 cell-mediated inflammatory factors.

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