CN115429807B

CN115429807B - Dehydroepoxymethylquinone mycin and its use for treating psoriasis

Info

Publication number: CN115429807B
Application number: CN202211312713.2A
Authority: CN
Inventors: 马俊; 陈勇; 侯代松
Original assignee: SHENZHEN WANHE PHARMACEUTICAL CO Ltd
Current assignee: SHENZHEN WANHE PHARMACEUTICAL CO Ltd
Priority date: 2022-10-25
Filing date: 2022-10-25
Publication date: 2023-06-23
Anticipated expiration: 2042-10-25
Also published as: CN115429807A

Abstract

The invention relates to dehydroepoxymethylquinone mycin and its use in treating psoriasis. According to the invention, the imiquimod is used for inducing the BALB/c mice to establish a psoriasis model, and animal experiments prove that the dehydroepoxymethylquinone mycin can inhibit the symptoms of psoriasis, red spots, thickness and the like; can inhibit proliferation of inflammatory keratinocytes and infiltration of inflammatory cells; at the same time, dehydroepoxymethylquinone mycin is capable of significantly reducing the levels of IL-17 and TNF-alpha inflammatory cytokines. The dehydroepoxymethylquinone mycin has wide application prospect in the treatment of psoriasis, and provides more drug choices for the treatment of psoriasis.

Description

Dehydroepoxymethylquinone mycin and its use for treating psoriasis

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to dehydroepoxymethylquinone mycin, pharmaceutical application thereof and a composition thereof, in particular to dehydroepoxymethylquinone mycin and application thereof in preparation of drugs for treating psoriasis.

Background

Dehydroepoxymethylquinone mycin (also commonly known in the art as DHMEQ) has the following chemical structural formula:

dehydrogenated epoxymethylquinone-mycin is a novel potent NF- κb inhibitor derived from epoxyquinolone-mycin C structure discovered in recent years, and this salicylamide derivative can be obtained by reacting 1:1 to specifically inhibit NF- κb activation and nuclear translocation, has shown better therapeutic potential at the animal level for certain cancers and inflammatory diseases, without significant toxic reactions [ Lin Y, ukaji T, koide N, et al, inhibition of late and early phases of cancer metastasis by the NF- κ B inhibitor DHMEQ derived from microbial bioactive metabolite epoxyquinomicin: a review [ J ]. Int J Mol Sci,2018, 19 (3): 729; jiang X, lan Y, wei B, et al External application of NF-kappa B inhibitor DHMEQ suppresses development of atopic dermatitis-like lesions induced with DNCB/OX in BALB/c mie [ J ]. Immunopharmacol Immunotoxicol,2017, 39 (6): 157-164]. It has been reported to have therapeutic effects on inflammation such as cancer, atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease.

Psoriasis is an immune-mediated, chronic, recurrent inflammatory autoimmune disease. Psoriasis affects about 1.25 million people worldwide. The typical clinical manifestations are: psoriasis, erythema or plaque of the skin, thickening of the epidermis. Psoriasis has wide distribution, and can occur on scalp, elbow, waist, thigh, knee, calf, etc. Psoriasis can also induce arthritis, which in severe cases leads to joint deformity and movement disorders. In addition, the research also shows that the probability of the psoriasis patient suffering from diabetes, hyperlipidemia, cardiovascular diseases and the like is higher than that of the common people. This applies heavy mental stress to the psoriasis patient, and thus the patient is liable to develop spells, autism, depression and the like, even suffering from psychological diseases. Finding new medicine for treating psoriasis is not easy. Psoriasis has a complex etiology, and at present, the exact pathogenesis of psoriasis has not been elucidated.

NF- κB is a transcription factor capable of regulating the expression of several inflammatory factors. Under physiological conditions, NF- κB regulates immunity and maintains tissue stability; under pathological conditions, NF- κB is overactivated to exacerbate the severity of inflammatory response. Thus, inhibition of excessive NF- κB activation during local tissue inflammation is of great importance in controlling inflammation. During the development of psoriasis, skin lymphocytes infiltrate and activate, abnormal crosstalk occurs between epidermal keratinocytes and immune cells, and nuclear factor κB (Nuclear factor kappa-B, NF- κB) proteins play a key role in these phenomena. Some compounds may significantly reduce the psoriatic inflammatory response by inhibiting NF- κb signaling pathways.

Psoriasis is a chronic inflammatory skin disease, and currently available external therapeutic agents include corticosteroids, vitamin D analogues, vitamin a, calcineurin inhibitors, keratolytic agents, targeted phototherapy agents, etc. [ Armstrong AW, read c.pathhysiology, clinical presentation, and treatment of psoriasis: a review [ J ]. JAMA,2020, 323 (19): 1945-1960]. During development of psoriasis, infiltration and activation of cutaneous lymphocytes occurs, abnormal crosstalk occurs between epidermal keratinocytes and immune cells, and nuclear factor κb (Nuclear factor kappa-B, NF- κb) proteins play a key role in these phenomena [ goldmiz AM, au SC, kim N, gottlieb AB, et al NF-kappaB: an essential transcription factor in psoriasis [ J ]. J Dermatol Sci,2013, 69 (2): 89-94]. Some compounds can significantly reduce the psoriatic inflammatory response by inhibiting NF- κb signaling pathway [ Xu F, xu J, xiong X, et al salidroside inhibitors MAPK, NF- κb, and STAT3 pathways in psoriasis-associated oxidative stress via SIRT1 activation [ J ]. Redox Rep,2019, 24 (1): 70-74; irrera N, vaccaro M, bitto A, et al BAY 11-7082 inhibitors of the NF-. Kappa.B and NLRP3 inflammasome pathways and protects against IMQ-induced psoriasis [ J ]. Clin Sci (Lond), 2017, 131 (6): 487-489]. The existing drug treatment can not thoroughly remove psoriasis, but can only inhibit the attack of diseases to a certain extent. In most cases, this inhibition is not entirely satisfactory for psoriasis patients. In addition, existing drug therapies tend to cause a number of side effects. Although the biological treatment has better effect than other treatment modes, the biological treatment is expensive and is not easy to popularize. In summary, there are many methods of treating psoriasis, but there are many drawbacks and limitations.

Thus, there remains a need in the art for new methods of treating psoriasis.

Disclosure of Invention

The object of the present invention is to provide a method for the treatment of psoriasis which is expected to exhibit some or some of the advantageous effects. The present inventors have unexpectedly found that formulation of dehydroepoxymethylquinone mycin as an ointment for transdermal application exhibits an effective psoriasis treatment effect, and have completed based on such findings.

To this end, in a first aspect the present invention provides the use of a dehydroepoxymethylquinone mycin of the formula:

according to the use of the first aspect of the invention, the psoriasis keratinocyte NF- κb signaling pathway is overactivated.

According to the use of the first aspect of the invention, the medicament is suitable for inhibiting abnormal proliferation of inflammatory keratinocytes, reducing inflammatory cytokine infiltration, and/or inhibiting inflammatory factor secretion by inflammatory keratinocytes.

The use according to the first aspect of the invention, wherein the medicament is a pharmaceutical composition for external use.

The use according to the first aspect of the invention, wherein the medicament is a pharmaceutical composition for topical application.

The use according to the first aspect of the invention, wherein the medicament is in a dosage form selected from the group consisting of: ointments, creams, solutions, suspensions.

The use according to the first aspect of the invention, wherein the concentration of dehydroepoxymethylquinone mycin in the medicament is from 0.01% to 1%, such as from 0.05% to 0.5%, such as 0.1%.

The use according to the first aspect of the invention, wherein the medicament has a formulation selected from the group consisting of:

DHMEQ 0.1g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline in an amount of 100g;

DHMEQ 0.1g, petrolatum in an amount of about 100g total weight;

DHMEQ 0.1g, propylene glycol in an amount to total 100g;

DHMEQ 0.1g, alanine 2.5g, sodium oleate 1.2g, liquid paraffin 10g, paraffin 8g, lanolin 10g, and vaseline in an amount of 100g;

DHMEQ 0.1g, alanine 2.5g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline in an amount of 100g; or (b)

DHMEQ 0.1g, sodium oleate 1.2g, liquid paraffin 10g, paraffin 8g, lanolin 10g, and vaseline in an amount of 100g.

DHMEQ 0.1g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline right amount to total weight 100g, the preparation method is: grinding DHMEQ and liquid paraffin into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling;

DHMEQ 0.1g, vaseline in right amount to total weight 100g, and the preparation method is as follows: grinding 0.1g of DHMEQ and about 10g of Vaseline in a mortar for 15 minutes, adding a proper amount of Vaseline to 100g of total weight of the composition, and continuously grinding to obtain a uniform composition;

DHMEQ 0.1g, propylene glycol in right amount to total weight 100g, the preparation method is as follows: grinding 0.1g of DHMEQ and about 10g of propylene glycol in a mortar for 15 minutes, adding a proper amount of propylene glycol to 100g of total weight of the composition, and continuously grinding to obtain a uniform composition;

DHMEQ 0.1g, alanine 2.5g, sodium oleate 1.2g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline proper amount to total weight 100g, the preparation method is: grinding DHMEQ, liquid paraffin, alanine and sodium oleate into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling to obtain the final product;

DHMEQ 0.1g, alanine 2.5g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline proper amount to total weight 100g, the preparation method is: grinding DHMEQ, liquid paraffin and alanine into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling; or (b)

DHMEQ 0.1g, sodium oleate 1.2g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline in proper amount to total weight 100g, and the preparation method comprises the following steps: grinding DHMEQ, liquid paraffin and sodium oleate into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.

Further, a second aspect of the present invention provides a composition comprising a dehydroepoxymethylquinone mycin of the formula:

the composition is a pharmaceutical composition for external use.

The composition according to the second aspect of the present invention is a pharmaceutical composition for topical application.

The composition according to the second aspect of the invention is in a dosage form selected from the group consisting of: ointments, creams, solutions, suspensions.

The composition according to the second aspect of the invention wherein the concentration of dehydroepoxymethylquinone mould is 0.01% to 1%, for example 0.05% to 0.5%, for example 0.1%.

The composition according to the second aspect of the invention has a formulation selected from the group consisting of:

DHMEQ 0.1g, petrolatum in an amount of about 100g total weight;

DHMEQ 0.1g, propylene glycol in an amount to total 100g;

Any technical feature provided in any aspect of the present invention or any embodiment of any aspect is equally applicable to any other embodiment or any other embodiment of any aspect, provided that they do not contradict each other, and of course the corresponding features can be modified appropriately as appropriate when applicable to each other. Various aspects and features of the invention are described further below.

All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this invention. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present invention.

Drawings

Fig. 1 is a typical photograph of skin at the back skin lesion of a mouse, showing that DHMEQ can alleviate psoriasis, erythema, thickness symptoms in imiquimod-induced psoriasis.

Fig. 2 is a graph of the HE staining of skin at the back skin lesion of mice (x 100), a. Blank, b.imq, c.dhmeq, d.cp, staining results showing that DHMEQ is capable of inhibiting imiquimod-induced thickening of the mouse epidermis, inflammatory cytokine infiltration;

Detailed Description

The present application may be further described by the following examples, however, the scope of the present application is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the present application without departing from the spirit and scope thereof. The materials used in the test and the test methods are generally and/or specifically described herein. Although many materials and methods of operation are known in the art for the purpose of this application, this application is nevertheless described in as much detail as possible. The following examples further illustrate the application, but do not limit the application.

The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional Biochemical reagent companies. DHMEQ used in the present invention is a powder that has been previously ground to pass a 200 mesh screen.

Example 1: therapeutic effect of dehydroepoxymethylquinone mycin ointment on psoriatic mice

This example attempts to investigate the protective effect of DHMEQ ointment on imiquimod-induced psoriasis-like lesions in mice to demonstrate its efficacy in treating psoriasis.

1. Material

1.1 instruments

JJ-12J dehydrator was purchased from Mehanjunjie electronics Inc.; RM2016 paraffin microtomes were purchased from Leka instruments Inc., shanghai; JB-P5 paraffin embedding machine is purchased from Wuhan Junje electronics Co., ltd; KD-P tissue tablet machine is purchased from Jin Huashi Kedi instruments and equipment limited company of Zhejiang province; BX51 biological microscope was purchased from Olympus corporation, japan; GFL-230 forced air drying oven was purchased from the lye glass run instruments, inc; 352 microplate reader was purchased from the company Labsystems Multiskan MS, finland.

1.2, pharmaceutical products and reagents

Imiquimod cream (Imiquimod, IMQ, H20040285), 5% in size, purchased from the Hubei department beneficial pharmaceutical company, inc.; clobetasol propionate cream (Clobetasol Propionate, CP, H34023860), 0.02% gauge, available from fotember pharmaceutical company, inc; DHMEQ ointment (Lot.18061401), specification 0.1%, shenzhen Wan and pharmaceutical Co., ltd; IL-17 and TNF-alpha enzyme-linked immunosorbent assay (ELISA) kits were purchased from Shanghai Uygur corkton, inc.; miquitting depilatory cream was purchased from lijie time household limited. Prescription of lot.18061401 ointment: DHMEQ 0.1g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline in proper amount to the total weight of ointment 100g, and the preparation method comprises: grinding DHMEQ and liquid paraffin into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.

1.3 animals

SPF-grade BALB/c mice, male, 6-8 weeks old, 18-22 g body mass, purchased from Beijing vitamin Toril Limited. Experimental animal production license number: SCXK (thunberg) 2020-0002; experimental animal pass number: 20210114Abzz0600000441. The mice eat drinking water freely during the feeding period, the ambient temperature is controlled to be 18-24 ℃, the relative humidity is controlled to be 40-70%, and the brightness and darkness are alternated for 12 hours.

2. Method and results

2.1, experimental grouping

Mice were acclimatized for 1 week and then divided into 4 groups, i.e., blank, IMQ (i.e., model, imiquimod), CP (i.e., positive drug, IMQ and clobetasol propionate) and DHMEQ (i.e., therapeutic, IMQ and DHMEQ), 6 each. Depilatory paste with depilation area of 2×2cm ² 。

Administration:

the blank groups are smeared with 120mg of Vaseline on the dehairing parts of the mice every day;

the IMQ group is coated with 120mg of imiquimod cream (weight of the preparation, the same applies below) every day;

the CP group is firstly coated with 120mg of imiquimod cream every day, and 160mg of clobetasol propionate cream is coated on the same day after 5 hours;

the DHMEQ group is firstly coated with imiquimod cream 120mg every day, and the DHMEQ ointment 180mg every day after 5 hours;

5d[Xie XJ,Di TT,Wang Y,et al.Indirubin ameliorates imiquimod-induced psoriasis-like skin lesions in mice by inhibiting inflammatory responses mediated by IL-17A-producing γδTcells [ J ]. Mol Immunol,2018, 101:386-395] are thus administered continuously.

2.2 skin loss scoring

Reference is made to Psoriasis Area and Severity Index (PASI) scoring criteria [ BOZEK a, REICH a. The reliability of three psoriasis as-segment tools: psoriasis area and severity index, body sur-face area and physician global assessment [ J ]. Adv Clin Exp Med,2017, 26 (5): 851-856]. From the molding 1d, the psoriasis, erythema and thickness of the skin lesions on the back were scored daily according to 0-4, the scoring criteria being shown in table 1. And adding the 3 scores to obtain a total score, namely the PASI total score. Experiment 5d, representative skin of each group of mice is shown in figure 1.

Table 1: psoriasis Area and Severity Index (PASI) scoring criteria

PASI scoring results are shown in table 2 below.

Table 2: severity Index (PASI) scoring results

* P <0.05, compared to IMQ group.

The results show that: the skin of mice in the blank group is unchanged, the skin of the skin lesion of the mice in the IMQ group is obviously thickened, psoriasis is densely and widely distributed, skin erythema under the psoriasis is obvious, and compared with the blank group, the PASI scores are obviously increased (P < 0.05), so that the successful modeling of the psoriasis is shown; the CP group showed an intervention of clobetasol propionate on psoriasis with anti-inflammatory corticosteroid positive drug, the group of mice had less psoriasis, less skin thickening and substantially normal skin color, the group of PASI had significantly reduced scores and total scores (P < 0.05) compared to the IMQ group; the DHMEQ group showed an intervention with potent NF- κb inhibitors against psoriasis, mice in this group had insignificant psoriasis and slightly thickened skin with milder erythema, and the PASI scores and total scores were significantly lower in 2-5 d compared to the IMQ group, indicating that DHMEQ showed a therapeutic effect against psoriasis. In general, both the CP group and DHMEQ group mice showed a significant improvement in skin lesions compared to IMQ group, with CP group being superior to DHMEQ group in both erythema and thickness scores, but CP group being slightly inferior to DHMEQ group in psoriasis score. The PASI on day 5 of treatment was slightly better in the CP group as a whole than in the DHMEQ group.

2.3 histopathological observations of skin lesions

Experiment 5d mice were sacrificed from the neck and skin from the back skin lesions were fixed in 4% paraformaldehyde solution. After skin was dehydrated with gradient alcohol, paraffin-embedded, sectioned, hematoxylin-eosin (HE) stained, paraffin-embedded and sectioned, and histopathological morphology was observed under a 100 x optical microscope and recorded by photographing.

The HE staining of skin tissue of each group of mice is shown in FIG. 2. The results show that the skin of the mice in the blank group is not abnormal; the mice in the IMQ group have hyperkeratosis accompanied by cuticle shedding, epidermis thickening accompanied by micro-abscess, and there is massive inflammatory cell infiltration in dermis [ Linguan, chen Xixue, wang, etc. ] parapsoriasis 81 cases clinical and pathological analysis [ J ]. J. Chinese dermatology, 2019, (11): 832-836]. The epidermis was slightly thickened in the DHMEQ group compared to the blank group, but less thickened than in the IMQ group; compared with the blank group, the epidermis of the Clobetasol Propionate (CP) group has no obvious change. Both DHMEQ and CP mice had a significant improvement in psoriasis symptoms, but the CP mice had slightly better improvement.

2.4 determination of cytokine content in skin

After experiment 5d, the mice were sacrificed by cervical removal and the skin at the small skin lesions was taken about 1cm ² Weighing, adding a certain amount of Phosphate Buffer Solution (PBS), homogenizing, and making into 20%(w/v) the homogenate was centrifuged at 3000r/min for 20min, and the supernatant was assayed for IL-17 and TNF- α content by enzyme-linked immunosorbent assay (ELISA). The specific operation steps are carried out according to the specification of ELISA kit. The results in Table 3 show that the content of IL-17 and TNF-alpha in the skin at the back skin lesion of the mice in the IMQ group is obviously increased compared with that in the blank group, which indicates that the molding is successful; the levels of these two cytokines were significantly reduced in the DHMEQ and CP groups, respectively, compared to the IMQ group (P<0.05 But there was no statistical difference between the two groups.

Table 3: IL-17 and TNF- α content in skin lesions of mice (μg/mL, n=6)

P <0.05 compared to IMQ group.

2.3 statistical methods

Data analysis using EXCEL2010, each set of data

Expressed, when P<The difference was considered statistically significant at 0.05.

3. Discussion of the invention

Psoriasis is a type of immune-mediated, chronic, recurrent inflammatory skin disease whose pathogenesis is complex. NF- κB is a transcription factor capable of regulating the expression of several inflammatory factors. Under physiological conditions, NF- κB regulates immunity and maintains tissue stability; under pathological conditions NF-. Kappa.B is overactivated and exacerbates the severity of the inflammatory response [ Liu A, zhao W, zhang B, et al Cimifugin ameliorates imiquimod-induced psoriasis by inhibiting oxidative stress and inflammation via NF-. Kappa.B/MAPK pathway [ J ]. Biosci Rep,2020, 40 (6): BSR20200471]. Thus, inhibition of excessive NF- κB activation during local tissue inflammation is of great importance in controlling inflammation.

DHMEQ is a novel NF- κb inhibitor derived from the C structure of epoxyquinolone mycin and has been reported to date to have therapeutic effects on cancer, atopic dermatitis, rheumatoid arthritis and inflammatory bowel disease and other inflammatory diseases [ Umezawa K, breborowicz a, gantsev s. Anticancer activity of novel NF-kappa B inhibitor DHMEQ by intraperitoneal adminisation. Oncol Res,2020, 28 (5): 541-550; ma J, zhang Y, sugai T, et al inhibition of cellular and animal inflammatory disease models by NF-kappa B inhibitor DHMEQ [ J ]. Cells,2021, 10 (9): 2271; jiang X, he H, xie Z, et al Dehydroymethylpoxyquinone suppresses atopic dermatitis-like lesions in a stratum corneum-removed murine model through NF- κB inhibition. Immunopotenthol Immunotoxicol,2019, 41 (1): 32-39].

The experiment results show that the symptoms of psoriasis, thickness and the like of the skin damage part of the mice treated by the DHMEQ are obviously relieved, and the PASI score of the DHMEQ is obviously lower than that of an IMQ group, so that the DHMEQ can relieve the symptoms of psoriasis, erythema, thickness and the like. In addition, compared with the IMQ group, the research result shows that the content of IL-17 and TNF-alpha in the skin damage part of the DHMEQ group is obviously reduced, which suggests that the DHMEQ possibly can inhibit the signal path by irreversibly combining with NF- κB, thereby inhibiting the expression of inflammatory factors and pro-inflammatory mediators and finally achieving the effect of reducing the psoriasis inflammatory reaction.

Comprehensively considering all evaluation indexes of the intervention capability of the mice psoriasis model, the DHMEQ is slightly inferior to the positive drug clobetasol propionate. Considering that DHMEQ can be metabolized mainly to salicylamide which is safer for humans after exhibiting inhibition of NF- κb, whereas clobetasol propionate exhibits a number of side effects in the treatment of psoriasis [ Kumar S, prasad M, rao r.topical delivery of clobetasol propionate loaded nanosponge hydrogel for effective treatment of psoriasis: formulation, physicochemical characterization, antipsoriatic potential and biochemical estination.mate Sci Eng C Mater Biol application.2021, 119:111605], DHMEQ would have the clinical advantage of lower side effects in the treatment of skin psoriasis.

Example 2: preparation of the composition

Composition 2a: grinding 0.1g of DHMEQ and about 10g of Vaseline in a mortar for 15 minutes, adding a proper amount of Vaseline to 100g of total weight of the composition, and continuously grinding to obtain a uniform composition.

Composition 2b: grinding 0.1g of DHMEQ and about 10g of propylene glycol in a mortar for 15 minutes, adding a proper amount of propylene glycol to 100g of total weight of the composition, and continuously grinding to obtain a uniform composition.

Composition 2c: prescription: DHMEQ 0.1g, alanine 2.5g, sodium oleate 1.2g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline added to the total weight of the composition 100g, and the preparation method comprises: grinding DHMEQ, liquid paraffin, alanine and sodium oleate into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.

Composition 2d: prescription: DHMEQ 0.1g, alanine 2.5g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline added to the total weight of the composition 100g, and the preparation method comprises: grinding DHMEQ, liquid paraffin and alanine into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.

Composition 2e: prescription: DHMEQ 0.1g, sodium oleate 1.2g, liquid paraffin 10g, paraffin 8g, lanolin 10g, vaseline in proper amount to the total weight of the composition 100g, and the preparation method comprises: grinding DHMEQ, liquid paraffin and sodium oleate into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.

The above are pastes except for composition 2b, which is a viscous suspension, which is a composition having a DHMEQ concentration of 0.1% as in the lot.18061401 ointment of example 1.

Example 3: therapeutic effect of dehydroepoxymethylquinone mycin ointment on psoriatic mice

The test was performed in parallel with example 1, wherein the DHMEQ group reagents were changed to the 5 compositions obtained in example 2, respectively, and the doses were given by weight of the formulation; the blank group, the model group, i.e., IMQ group, and the positive group, i.e., CP group, were each the groups in example 1.

The results on day 5 of the test in terms of severity index (PASI) score are shown in table 4 below.

Table 4:

in the table: p <0.05, < P <0.01 compared to IMQ group; compared to CP group, #p <0.05; in comparison to DHMEQ group,% P <0.01. As can be seen from the above results, it was unexpectedly found that composition 2c with both alanine and sodium oleate added was significantly better than the rest of the prescription made from DHMEQ.

The results are shown in Table 5 in terms of cytokine content in the skin.

Table 5: IL-17 and TNF- α content in skin lesions of mice (μg/mL, n=6)

P <0.05, < P <0.01 compared to IMQ group; in comparison to DHMEQ group,% P <0.1. The results show that composition 2c is superior to the rest of the prescription made from DHMEQ.

Example 4: therapeutic effect of dehydroepoxymethylquinone mycin ointment on psoriatic mice

In the results of Table 5 above, in particular TNF- α, the treatment groups differed less, and this example attempted to reduce the dose administered to compare differences in effect between the different compositions.

The test was performed in the same manner as in example 1, and 6 animal groups were increased, and the lot.18061401 ointment and the 5 compositions obtained in example 2 were administered in amounts of 100mg of the composition (instead of 180mg of the lot.18061401 ointment as in example 1), respectively, and the IL-17 and TNF-. Alpha.contents in the skin of the skin lesion were measured by the same test, and the results are shown in Table 6.

Table 6: IL-17 and TNF- α content in skin lesions of mice (μg/mL, n=6)

P <0.05, < P <0.01 compared to IMQ group; in comparison to DHMEQ group,% P <0.1. The results show that composition 2c is significantly better than the rest of the prescription made from DHMEQ, i.e. the composition with simultaneous addition of alanine and sodium oleate is significantly better in terms of biological activity than the case without addition of both.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description and the following exemplary examples, make and utilize the compounds of the present invention and practice the methods of the present invention. Although the invention has been described and illustrated with reference to various specific materials, methods, and embodiments, it is to be understood that the invention is not limited to the specific combination of materials and methods selected for this purpose. Those skilled in the art will recognize many variations of such detail cues. All patents, patent applications, and other references cited throughout this application are incorporated by reference in their entirety.

Claims

1. Use of a dehydroepoxymethylquinone mycin of the formula:

；

the medicament is a dosage form for external application of ointment and has the following formula: 0.1g of dehydroepoxymethylquinone mycin, 2.5g of alanine, 1.2g of sodium oleate, 10g of liquid paraffin, 8g of paraffin, 10g of lanolin and a proper amount of Vaseline to 100g of total weight.

2. Use according to claim 1, wherein the psoriatic keratinocyte NF- κb signaling pathway is overactivated.

3. The use according to claim 1, said medicament being suitable for inhibiting abnormal proliferation of inflammatory keratinocytes, reducing inflammatory cytokine infiltration, and/or inhibiting inflammatory factor secretion by inflammatory keratinocytes.

4. The use according to claim 1, the preparation of said medicament being: grinding dehydroepoxymethylquinone mycin, liquid paraffin, alanine and sodium oleate into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.

5. A composition comprising a dehydroepoxymethylquinone mycin of the formula:

，

the composition is in the form of an ointment for external application and has the following formula: 0.1g of dehydroepoxymethylquinone mycin, 2.5g of alanine, 1.2g of sodium oleate, 10g of liquid paraffin, 8g of paraffin, 10g of lanolin and a proper amount of Vaseline to 100g of total weight.

6. The composition according to claim 5, which is prepared by: grinding dehydroepoxymethylquinone mycin, liquid paraffin, alanine and sodium oleate into paste, heating and melting the rest materials, cooling to 65deg.C, adding the paste, stirring, and naturally cooling.