WO2023109906A1

WO2023109906A1 - Pharmaceutical composition comprising tapinarof and corticosteroid

Info

Publication number: WO2023109906A1
Application number: PCT/CN2022/139319
Authority: WO
Inventors: 马志龙; 陈明; 贾剑敏
Original assignee: 上海泽德曼医药科技有限公司
Priority date: 2021-12-16
Filing date: 2022-12-15
Publication date: 2023-06-22
Also published as: CN116265017A

Abstract

A pharmaceutical composition for inflammatory skin diseases, a preparation method therefor, and a use thereof in preparation of drugs for treating and/or preventing immunological, inflammatory and autoimmune diseases. The pharmaceutical composition is a cream, and comprises, by weight, 0.5%-1.5% of tapinarof or a pharmaceutically acceptable salt thereof, 0.01%-1.5% of at least one corticosteroid, 15%-50% of an oil phase matrix, 0.1%-8% of a surfactant, 5%-20% of a solvent, and/or a penetration enhancer and water.

Description

A pharmaceutical composition comprising Benvimod and corticosteroids

technical field

The present disclosure belongs to the field of medicinal chemistry and relates to a pharmaceutical composition comprising Benvimod and a corticosteroid, or its use in the treatment of immune, inflammatory and autoimmune diseases.

Background technique

Autoimmune diseases are a type of disease characterized by the immune system's reduced tolerance to the body's own antigens, the production of a large number of autoantibodies and immune complexes, and ultimately the impairment of the functions of various tissues and organs (Guan SY et al., Inflammation, 2017, 40 (1):303-310). As early as 1999, the World Health Organization listed autoimmune diseases as the third major killer threatening human health after cardiovascular disease and cancer. One of the diseases (Pan Haifeng et al., Chinese Journal of Disease Control, 2018, 22(11): 1093-1095, 1105). The spectrum of autoimmune diseases is widely distributed, with different clinical manifestations, mainly including more than 70 diseases, such as systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, etc. (Fang Xinyu et al., Chinese Journal of Disease Control, 2021, 25(8 ):869-873).

Psoriasis is a common chronic, inflammatory, immune-mediated skin disease characterized by rapid epithelial cell proliferation and renewal, thickening of the epidermis, and production of inflamed, swollen skin lesions and elevations covered with silvery-white scales, Inflamed, thickened and scaly lesions are prone to itching, burning, stinging and bleeding. As one of the most serious non-communicable diseases, about 125 million people worldwide have psoriasis, which greatly reduces the quality of life of patients. Atopic dermatitis, a common chronic, relapsing, inflammatory skin disease, is usually characterized by the overgrowth of Staphylococcus aureus, which then triggers proteolytic disruption of the epidermal barrier and immune dysregulation. Although atopic dermatitis is not life-threatening, it can have a profound impact on the quality of life of patients and their relatives. It is reported that the disease is the skin disease with the highest non-fatal disease burden (Psoriasis Professional Committee of Dermatology and Venereology Branch of Chinese Medical Association, Chinese Journal of Dermatology, 2019, 52(10), 667-710).

Although there are many treatment options for patients with immune, inflammatory and autoimmune diseases, such as psoriasis, atopic dermatitis and other chronic inflammatory skin diseases, conventional external drug treatment is still the main clinical basic treatment, and corticosteroids are used as the first-line drug , long-term use has high side effects, and intermittent use has a short remission period and is prone to relapse. Non-hormonal topical drugs such as vitamin _D3 derivatives, retinoic acid, and calcineurin inhibitors have defects such as slow onset of action, limited curative effect, common local side effects, and poor patient compliance. The existing external preparations can only provide temporary relief, are prone to relapse, and have unsatisfactory curative effects. More effective therapeutic preparations are still needed for clinical use.

Benvimod Cream is the world's first national Class 1 new drug with complete independent intellectual property rights. It is a major scientific and technological achievement of my country's "Major New Drug Creation". Topical treatment of psoriasis vulgaris.

The chemical structural formula of Benvimod is as follows:

This compound is also known as 5-[(E)-2-styryl]-2-isopropyl-1,3-benzenediol. Previously used names include "Benzene Moder", "Tapinarof", "GSK2894512", "WBI-1001" and so on.

Benvimod was first disclosed as an antibiotic by Paul et al. (Journal of Chemical Ecology, 1981, 7(3):589-597). WO1995003695A1 (Agro-Biotech Corporation) discloses the fungicidal activity of this compound. This compound is further described in WO2001042231A2 (Welichem Biotech Inc.) for use in the treatment of various important skin disorders including psoriasis and inflammation. Example 3 of US Pat. No. 7,868,047 B2 describes a cream formulation in which the active ingredient is prepared in a Galax base. WO2016185428A1 (GlaxoSmithKline Inc.) provides a method for preparing a topical medicinal emulsion composition involving the compound.

The immunosuppressive effects of corticosteroids are known to be critical for suppressing the pro-inflammatory environment and T cell activation; Benvimod suppresses underlying inflammation and normalizes skin homeostasis, regulates keratinocyte proliferation and differentiation, and provides immune modulation, And can play an immune regulatory role on Th2, Th17 and T-reg cells. The pharmaceutical combination or pharmaceutical composition provided by the present disclosure has complementary effects on the underlying pathophysiology of inflammatory diseases such as psoriasis and atopic dermatitis, and can increase the curative effect of single active ingredient therapy.

Aiming at the problems of low curative effect, easy relapse, and low compliance of existing external preparations, the present disclosure provides a novel pharmaceutical composition, which can be applied locally to treat immune, inflammatory, and autoimmune diseases, effectively improve clinical efficacy, and reduce disease recurrence rate and improve patient compliance.

Contents of the invention

In order to solve the problems of low curative effect, easy relapse, and low compliance of external preparations in the prior art, the present disclosure provides a pharmaceutical composition comprising Benvimod or a pharmaceutically acceptable salt thereof and a A corticosteroid; the pharmaceutical composition is a cream.

The present disclosure provides a pharmaceutical composition, characterized in that, the pharmaceutical composition is a cream, and in terms of the total weight percentage of the pharmaceutical composition, the pharmaceutical composition comprises:

Benvimod or a pharmaceutically acceptable salt thereof in an amount of 0.5% to 1.5% by weight;

One or more corticosteroids in amounts ranging from 0.01% to 1.5% by weight, respectively;

Oil phase base, its amount is 15% to 50% by weight; Said oil phase base comprises petrolatum and light liquid paraffin;

Surfactants in amounts ranging from 0.1% to 8% by weight;

solvents and/or penetration enhancers in amounts of 5% to 20% by weight; and

The rest is the aqueous phase.

In another aspect, the present disclosure provides a preparation method of a pharmaceutical composition, comprising the following steps:

1) Oil phase: add the oil phase matrix into a suitable size container, heat to 65-85°C to dissolve evenly, then optionally add preservatives, stir and dissolve to obtain solution A, keep warm for later use; wherein the oil phase matrix includes white Vaseline and light liquid paraffin;

2) Water phase: add surfactant to purified water, heat to 65-85°C to dissolve evenly to obtain solution B, keep it warm for later use;

3) Active ingredient solvent: add Benvimod and corticosteroid into the solvent, heat to 65-85°C to dissolve evenly, and obtain solution C and keep it warm for later use; wherein the solvent is preferably propylene glycol;

4) Mixing and emulsification: adding solution A to solution C and mixing, stirring evenly; then adding solution B, stirring homogeneously to form stable emulsion droplets, and cooling to normal temperature to obtain the pharmaceutical composition.

On the other hand, the present disclosure also provides the use of the pharmaceutical composition of the present disclosure in the preparation of medicines for the treatment and/or prevention of immune, inflammatory and autoimmune diseases, preferably in the preparation of medicines for the treatment and/or prevention of skin diseases or a disorder selected from the group consisting of psoriasis, atopic dermatitis, acne and pruritus.

The technical solution of the present disclosure is described in detail as follows:

Benvimod compound or pharmaceutically acceptable salt thereof described in the present disclosure

Benvimod compound belongs to the prior art, and its chemical name is 5-[(E)-2 styryl]-2-isopropyl-1,3-benzenediol, which has the following structural formula:

For the preparation method and chemical properties of Benvimod compound or its pharmaceutically acceptable salt, please refer to CN103467281B, CN104003848B, CN103992212B, WO2019063002A1, CN108066279A, CN112811985A, CN111148729A and CN113024357A.

The present disclosure relates to a pharmaceutical composition, characterized in that, the pharmaceutical composition is a cream, and in terms of the total weight percentage of the pharmaceutical composition, the pharmaceutical composition comprises:

Surfactants in amounts ranging from 0.1% to 8% by weight;

solvents and/or penetration enhancers in amounts of 5% to 20% by weight; and

The rest is the aqueous phase.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, based on the total weight percentage of the pharmaceutical composition, the content of Benvimod or a pharmaceutically acceptable salt thereof is 0.5 by weight. % to 1.25%, preferably 0.5% to 1.25%, more preferably 0.75% to 1.25%, most preferably 0.75% to 1%; the content of Benvimod or its pharmaceutically acceptable salt can be 0.5% , 0.75%, 1% and 1.25%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, based on the total weight percentage of the pharmaceutical composition, the content of the corticosteroid is 0.01% to 1% by weight, preferably 0.01% to 0.75%, more preferably 0.01% to 0.5%, further preferably 0.01% to 0.25%, further preferably 0.01% to 0.2%, most preferably 0.01% to 0.1%; specifically, the content of the corticosteroid can be 0.01%, 0.05%, 0.075%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.25%, 0.3%, 0.5% and 1%.

In some embodiments of the present disclosure, in the cream described in the present disclosure, the corticosteroid is selected from the group consisting of aclomethasone or its derivatives, amcinonide or its derivatives, betamethasone or its derivatives, clobeta Chlorcotolone or its derivatives, Desonide or its derivatives, Dexamethasone or its derivatives, Diflorasone or its derivatives, Fluocinolone or its derivatives, Fluticasone or its derivatives Derivatives, halcinonide or its derivatives, ubetazol or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicate or its derivatives, triamcinolone acetonide or its derivatives One or more of its derivatives, fludrosolidine or its derivatives, dexamethasone or its derivatives, and methylprednisolone or its derivatives;

Preferably, the corticosteroid is selected from betamethasone or its derivatives, clocotorone or its derivatives, doxamethasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, hydrocortisone One or more of pine or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives, triamcinolone acetonide or its derivatives, fludrocetal or its derivatives;

More preferably, the corticosteroid is selected from betamethasone or its derivatives, clocotorone or its derivatives, doxamethasone or its derivatives, fluocinolone or its derivatives, fluticasone or its derivatives, hydrocortisone One or more of pine or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives and triamcinolone acetonide or its derivatives;

Further preferably, the corticosteroid is selected from one or more of betamethasone or its derivatives;

Further preferably, the corticosteroid is selected from one or more of betamethasone dipropionate, betamethasone acetate and betamethasone valerate;

Further preferably, the corticosteroid is selected from betamethasone or its derivatives;

Further preferably, the corticosteroid is selected from betamethasone, betamethasone dipropionate, betamethasone acetate and betamethasone valerate;

Most preferably, the corticosteroid is betamethasone or betamethasone dipropionate.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, based on the total weight percentage of the pharmaceutical composition, the total content of the oil phase base is 15% to 50%, preferably 15% to 40%, more preferably 15% to 30%, most preferably 15% to 25%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the oil phase base is selected from petrolatum (preferably white petrolatum), stearic acid, paraffin (preferably light liquid paraffin), myristic acid One or more of isopropyl esters, beeswax, medium-chain triglycerides, higher alcohols and lanolin, preferably selected from white petrolatum, light liquid paraffin, stearic acid, isopropyl myristate, medium-chain triglycerides , one or more of cetyl alcohol, stearyl alcohol and cetostearyl alcohol, more preferably one or more of white petrolatum, light liquid paraffin, cetyl alcohol, stearyl alcohol and cetostearyl alcohol kind.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the oil phase base is selected from one or more of white petrolatum, light liquid paraffin, cetyl alcohol, stearyl alcohol and cetostearyl alcohol The content of each oil phase base is 5% to 25%, preferably 5% to 20%, more preferably 5% to 15%, most preferably 5% to 10%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the surfactant is selected from emulsifying waxes, stearyl ethers, polysorbates, glyceryl monostearate, monostearic acid One or more of fatty acid glycerides, West Marco 1000, sorbitan fatty acid esters and macrogol cetostearyl ether, preferably glyceryl monostearate, glyceryl monostearate , stearyl ethers, polysorbates, cetumago 1000, sorbitan fatty acid esters and macrogol cetostearyl ether, more preferably glyceryl monostearate or monostearate Glyceryl Distearate.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the surfactant is glyceryl monostearate or glyceryl monostearate, and its amount is 0.1% to 6% by weight , preferably 0.5% to 6%, most preferably 0.75% to 6%; specifically, the total content of the surfactant can be 0.1%, 0.25%, 0.5%, 0.75%, 1%, 1.5%, 2% %, 3%, 4%, 5% and 6%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the solvent and/or penetration enhancer is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerin and PEG400, preferably It is one or more of propylene glycol, diethylene glycol monoethyl ether and PEG400, more preferably propylene glycol and/or diethylene glycol monoethyl ether, most preferably propylene glycol.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, based on the total weight percentage of the pharmaceutical composition, the total content of the solvent and/or penetration enhancer is 5% to 20% by weight. %, preferably 10% to 20%, more preferably 10% to 15%; specifically, the content of the surfactant can be 5%, 10%, 15% and 20%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the solvent and/or penetration enhancer is propylene glycol, and its content is 5% to 20% by weight; preferably, the content of the propylene glycol 10% to 20%.

In some embodiments of the present disclosure, the pharmaceutical composition described in the present disclosure further includes a pH regulator, the pH regulator is a buffer, and the buffer is preferably selected from citrate/citric acid, acetate/ One or more of acetic acid, phosphate/phosphoric acid, citrate/citric acid, propionate/propionic acid, lactate/lactic acid, and ammonium salt/ammonia, preferably citrate/citric acid .

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the content of the pH regulator is an appropriate amount, and the pH value of the pharmaceutical composition is adjusted to 3-7; preferably, the pharmaceutical composition The pH value of the pharmaceutical composition is to 3-6; more preferably, the pH value of the pharmaceutical composition is to 4-6; most preferably, the pH value of the pharmaceutical composition is to 4.5-5.5; specifically, the pharmaceutical composition The pH can be 4, 4.5, 5, 5.5 and 6.

In some embodiments of the present disclosure, the content of the pH regulator is 0.01% to 5% by weight, preferably 0.1% to 3%, more preferably 0.1% to 2%, further preferably 0.1% to 1% %, most preferably from 0.1% to 0.5%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the pH regulator is citrate/citric acid, the content of which is 0.01% to 5%; preferably, the pH regulator is lemon salt/citric acid, the content of which is 0.1% to 1%; most preferably, the pH regulator is citrate/citric acid, and the content is 0.1% to 0.5%.

In some embodiments of the present disclosure, the pharmaceutical composition described in the present disclosure, the pharmaceutical composition further includes a stabilizer, the amount of which is 0.005% to 2% by weight, preferably 0.01% to 2%, more preferably 0.05% to 2%, more preferably 0.075% to 1.5%, most preferably 0.1% to 1%.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the stabilizer is selected from citric acid and its salts, glucuronic acid and its salts, sodium hexametaphosphate, zinc hexametaphosphate, ethylenediamine One or more of tetraacetic acid (EDTA) and its salts and phosphonates; preferably, the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts; more preferably, the stabilizer is EDTA -2Na.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, the stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salts, and the amount thereof is 0.01% to 2% by weight; preferably, Described stabilizing agent is ethylenediaminetetraacetic acid (EDTA) and its salt, and its amount is 0.05% to 2% by weight; More preferably, described stabilizing agent is ethylenediaminetetraacetic acid (EDTA) and its salt, The amount thereof is 0.1% to 1% by weight.

In some embodiments of the present disclosure, the pharmaceutical composition described in the present disclosure further includes a preservative.

Preservatives such as benzalkonium chloride, polyhexamethylene hydrochloride (PHMB), sorbic acid, ethylparaben, methylparaben, propylparaben, salicylic acid, etc. One or more of methyl esters, benzyl alcohol, and phenoxyethanol.

In some embodiments of the present disclosure, in the cream described in the present disclosure, based on the total weight percentage of the cream, the total content of the preservative is 0.005% to 1%, preferably 0.01% to 0.5%, More preferably, it is 0.01% to 0.25%; specifically, the content of the preservative can be 0.01%, 0.05%, 0.1%, 0.15%, 0.2% and 0.25%.

In some embodiments of the present disclosure, the pharmaceutical composition described in the present disclosure further includes an antioxidant.

Antioxidants such as butylated hydroxytoluene (BHT), disodium ethylenediaminetetraacetic acid (EDTA-2Na), butylhydroxyanisole (BHA), vitamin E, One or more of vitamin E acetate, vitamin E nicotinate, etc.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, based on the total weight percentage of the pharmaceutical composition, the total content of the antioxidant is 0.001% to 1%, preferably 0.01% to 0.5%, more preferably 0.01% to 0.1%; specifically, the content of the antioxidant can be 0.01%, 0.05%, 0.1%, 0.15, 0.2, 0.3%, 0.5% and 1%.

In some embodiments of the present disclosure, the particle size of the pharmaceutical composition described in the present disclosure is less than 10 μm, preferably 1-5 μm, more preferably 1-3 μm.

In some embodiments of the present disclosure, in the pharmaceutical composition described in the present disclosure, based on the total weight percentage of the pharmaceutical composition, the content of Benvimod or a pharmaceutically acceptable salt thereof is 0.5% to 1.25%; the content of the corticosteroid (preferably betamethasone or its derivatives) is 0.01% to 1%; the oil phase base is selected from white petrolatum, light liquid paraffin, cetyl alcohol, stearyl alcohol and cetyl alcohol One or more of stearyl alcohols, the content of each oil phase base is 5% to 25%; the surfactant is glyceryl monostearate or glyceryl monostearate, and its amount is according to 0.1% to 6% by weight; the solvent and/or penetration enhancer is propylene glycol, and its total amount is 5% to 20% by weight; the pH regulator is citrate/citric acid or citric acid Salt/citric acid, its content is 0.01% to 5%; The said stabilizer is ethylenediaminetetraacetic acid (EDTA) and its salt, its amount is 0.01% to 2% by weight; The preservative (preferably and the total content of the antioxidant (preferably BHT) is 0.01% to 0.5%.

In some aspects of the present disclosure, the pharmaceutical composition further includes emulsifiers, antibacterial preservatives and stabilizers.

In some aspects of the present disclosure, the mass of Benvimod or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is 50 mg-200 mg, preferably 100 mg-200 mg, more preferably 150 mg-200 mg. The quality of the corticosteroid in the pharmaceutical composition is 0.01mg-10mg. It is preferably 1 mg to 50 mg, more preferably 5 mg to 20 mg, most preferably 15 mg to 20 mg.

In some aspects of the present disclosure, the amount of Benvimod or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 0.1 to 10% wt, preferably 0.1 to 5%, more preferably 0.5 to 2%, and most preferably Preferably 0.5-1%, and the amount of corticosteroid is selected from 0.005-5%wt, preferably 0.01-1%, most preferably 0.05-0.5%.

In some aspects of the present disclosure, the emulsifier is selected from glyceryl monostearate, glyceryl distearate, polysorbate 80, ceteareth-20, polysorbate 80, cetyl alcohol.

In some aspects of the present disclosure, the antibacterial preservative is selected from sorbic acid, ethylparaben or a mixture thereof.

In some aspects of the present disclosure, the stabilizer is selected from polyethylene glycol monostearate, sorbitol solution or a mixture thereof.

In some aspects of the present disclosure, the pH of the pharmaceutical composition is selected from 5-8, preferably 5-6.

In some solutions of the present disclosure, the emulsifier, antibacterial preservative, humectant and stabilizer may also be added independently in batches or all at once for mixing. When auxiliary materials such as emulsifiers, antibacterial preservatives, humectants and stabilizers are added in batches, those skilled in the art can determine the ratio of adding in batches according to needs.

The pharmaceutical composition obtained through the preparation method of the present disclosure can have excellent uniformity and stability.

In some aspects of the present disclosure, the active ingredients of the pharmaceutical composition of the present disclosure include:

A) In the partial scheme, the active ingredients of the pharmaceutical composition include:

0.5-2.0%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.01-2.5%wt of corticosteroids or pharmaceutically acceptable salts thereof;

B) In the partial scheme, the active ingredients of the pharmaceutical composition include:

0.8%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.025% wt of a triamcinolone acetonide compound or a pharmaceutically acceptable salt thereof;

C) In the partial scheme, the active ingredients of the pharmaceutical composition include:

1.0%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.1%wt triamcinolone acetonide compound or pharmaceutically acceptable salt thereof;

D) In the partial scheme, the active ingredients of the pharmaceutical composition include:

1.2%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.1% wt of betamethasone compound or pharmaceutically acceptable salt thereof;

E) In the partial scheme, the active ingredients of the pharmaceutical composition include:

1.5%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.1%wt of chlorcotorone compound or its pharmaceutically acceptable salt;

F) In the partial scheme, the active ingredients of the pharmaceutical composition include:

2.0%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.1% wt of mometasone compound or pharmaceutically acceptable salt thereof;

G) In the partial scheme, the active ingredients of the pharmaceutical composition include:

0.8%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.05%wt of a deoxymethasone compound or a pharmaceutically acceptable salt thereof;

H) In the partial scheme, the active ingredients of the pharmaceutical composition include:

1.0%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.05% wt of fluticasone compound or pharmaceutically acceptable salt thereof;

I) in some schemes, the active ingredients of the pharmaceutical composition include:

1.5%wt Benvimod compound or a pharmaceutically acceptable salt thereof;

0.05%wt of fludrocetone compound or pharmaceutically acceptable salt thereof.

In some embodiments of the present disclosure, the single dose of the pharmaceutical composition is 50 mg to 200 mg, preferably 100 mg to 200 mg, preferably 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170mg, 180mg, 190mg, 200mg.

The present disclosure further relates to the use of a pharmaceutical composition as described above in the preparation of medicines for the treatment and/or prevention of immune, inflammatory and autoimmune diseases, preferably in the preparation of medicines for the treatment and/or prevention of skin diseases or Use in medicine for disorders; wherein, the skin disease or disorder is selected from psoriasis, atopic dermatitis, acne and pruritus; preferably, the skin disease or disorder is psoriasis.

The present disclosure further relates to the use of a pharmaceutical composition as described above in the preparation of a medicament for treating and/or preventing psoriasis.

The present disclosure also relates to a method of treating and/or preventing immune, inflammatory and autoimmune diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition as described above.

The present disclosure also relates to a method of treating and/or preventing a skin disease, comprising administering a therapeutically effective amount of the pharmaceutical composition as described above to a patient in need, the skin disease or disorder being selected from psoriasis, atopic dermatitis, Acne and itchy skin.

The present disclosure also relates to a method of treating and/or preventing psoriasis comprising administering a therapeutically effective amount of the pharmaceutical composition as described above to a patient in need thereof.

The present disclosure also relates to a pharmaceutical composition as described above for use as a medicine.

The present disclosure also relates to a pharmaceutical composition as described above as a medicine for treating and/or preventing immune, inflammatory and autoimmune diseases.

The present disclosure also relates to a pharmaceutical composition as described above for use as a medicament for the treatment and/or prevention of skin diseases or disorders selected from psoriasis, atopic dermatitis, acne and pruritus.

The present disclosure also relates to a pharmaceutical composition as above used as a medicine for treating and/or preventing psoriasis.

Preferably, the skin disease or disorder described in the present disclosure is psoriasis.

drug combination

The present disclosure provides a pharmaceutical combination comprising Benvimod or a pharmaceutically acceptable salt thereof and a corticosteroid or a pharmaceutically acceptable salt or ester thereof.

In some aspects of the present disclosure, the corticosteroid is selected from the group consisting of alclomethasone or derivatives thereof, amcinonide or derivatives thereof, betamethasone or derivatives thereof, clobetasol or derivatives thereof, clocotor Desonide or its derivatives, Dexamethasone or its derivatives, Diflurasone or its derivatives, Fluocinolone or its derivatives, Fluticasone or its derivatives, Halcinonide or its derivatives Ubetasol or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednikarlate or its derivatives, triamcinolone acetonide or its derivatives, fludrocetone or its Derivatives, one or more of dexamethasone or its derivatives, methylprednisolone or its derivatives; preferably betamethasone or its derivatives, clocotorone or its derivatives, deoxymethasone Fluocinonide or its derivatives, fluticasone or its derivatives, fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicate or its derivatives, triamcinolone or its derivatives One or more of , fludrosolone or its derivatives; more preferably betamethasone or its derivatives, clocotorone or its derivatives, doxamethasone or its derivatives, fluocinolone or its derivatives One or more of , fluticasone or its derivatives, hydrocortisone or its derivatives, mometasone or its derivatives, prednicarbate or its derivatives and triamcinolone acetonide or its derivatives; most preferably triamcinolone Anetide or its derivatives.

Triamcinolone acetonide belongs to the prior art, and its chemical name is 9-fluoro-11b,21-dihydroxy-16a,17-[(1-methylethylene)bis(oxy)]-pregna-1,4- Diene-3,20-dione, which has the following structural formula:

For the preparation method and chemical properties of triamcinolone acetonide or a pharmaceutically acceptable salt thereof, reference can be made to CN107573398B, CN103421075B, CN101618019B, CN104971039B and CN109206471A.

The components in the pharmaceutical combination of the present disclosure may be administered independently, or some or all of them together, in a suitable variety of routes, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes) ). In some embodiments, the components of the pharmaceutical combination of the present disclosure may be administered independently, or some or all of them together, topically or by injection, such as skin administration or intravenous or glass bulb injection.

The components in the pharmaceutical combination of the present disclosure can be each independently, or some or all of them are in the same dosage form, including but not limited to, cream, ointment, gel, spray, lotion, cream, foam, solution, Dosage forms of dispersions, injections and sustained-release preparations for oral or parenteral administration.

In some aspects of the present disclosure, the pharmaceutical combination is used to treat immune, inflammatory and autoimmune diseases in a patient. In some aspects of the present disclosure, the drug combinations are used simultaneously, separately or sequentially for the treatment of immune, inflammatory and autoimmune diseases in patients. In some regimens of the present disclosure, one treatment cycle of the drug combination is 2-8 weeks. In some aspects of the present disclosure, the drug combination may be administered for 1, 2, 3, 4 or more treatment cycles.

The components in the pharmaceutical combination of the present disclosure may each independently, or part or all of them jointly contain pharmaceutically acceptable carriers and/or excipients.

Benvimod or its pharmaceutically acceptable salts or corticosteroids may be the same or different in terms of dosage regimen, dose, and administration method.

In some schemes of the present disclosure, in the drug combination, the dosing regimen of Benvimod or a pharmaceutically acceptable salt thereof can be given daily, for example, given once, twice, three times or once a day. More often; once every two, three, four, or five days; once every week, two, three, or four weeks; once every month, two or more months .

In some schemes of the present disclosure, in the drug combination, the dosage regimen of corticosteroids is once a day to three times a day, once every two days, three days, four days, or five days; every week , two weeks, three weeks or four weeks to give once; every month, two months or more to give once.

In some schemes of the present disclosure, the drug combination comprises that in a single treatment cycle, the weight ratio of Benvimod or a pharmaceutically acceptable salt thereof to a corticosteroid or a pharmaceutically acceptable salt or ester thereof is (0.1 -100): 1, preferably (1-80): 1, more preferably (1-20): 1, further preferably (5-20): 1; most preferably (5-10): 1.

In some aspects of the present disclosure, the Benvimod or a pharmaceutically acceptable salt thereof and the corticosteroid of the pharmaceutical combination are each in the form of a pharmaceutical composition or present in the same pharmaceutical composition.

In some aspects of the present disclosure, in the pharmaceutical combination, Benvimod or a pharmaceutically acceptable salt thereof and a corticosteroid are each in the form of a pharmaceutical composition, and can be administered simultaneously, sequentially or at intervals.

In some aspects of the present disclosure, in the pharmaceutical combination, Benvimod or a pharmaceutically acceptable salt thereof and a corticosteroid are present in the same pharmaceutical composition and can be administered simultaneously.

Embodiments of pharmaceutical combinations/compositions

In some embodiments of the present disclosure, the individual to whom the pharmaceutical combination/composition is administered is a psoriasis vulgaris patient.

In some embodiments of the present disclosure, the individual to whom the pharmaceutical combination/composition is administered receives a certain course of topical administration of the pharmaceutical combination or composition, and is evaluated and detected for drug-related therapeutic effects.

psoriasis, atopic dermatitis

The pathogenesis of psoriasis and atopic dermatitis is closely related to the release of individual dendritic cytokines, the activation of adaptive immune response, the release of Th17 cytokines, the activation of keratinocytes, the release of pro-inflammatory mediators, and the regulation of Treg cells; in addition, The release of Th1 cytokines in individuals with psoriasis and the release of Th2 cytokines in individuals with atopic dermatitis are also important factors in pathogenesis.

The immunosuppressive effect of corticosteroids is essential to suppress the pro-inflammatory environment and T cell activation; Benvimod suppresses underlying inflammation and normalizes skin homeostasis, regulates keratinocyte proliferation and differentiation, and provides immune regulation, and can Immunomodulatory effect on Th2, Th17 and T-reg cells. The pharmaceutical combination or pharmaceutical composition provided by the present disclosure has complementary effects on the underlying pathophysiology of inflammatory diseases such as psoriasis and atopic dermatitis, and can increase the curative effect of single active ingredient therapy.

Beneficial effect

The pharmaceutical combination or pharmaceutical composition provided by the application has a synergistic effect on the curative effect of the disease during administration to individuals with psoriasis, atopic dermatitis or other immune, inflammatory and autoimmune diseases. It can improve the curative effect of component drugs, reduce the side effects of corticosteroids, and improve the compliance of individuals. details as follows:

1. Synergistic effect

The body's immune dysfunction is the basis of inflammatory diseases such as psoriasis and atopic dermatitis, and bacterial colonization, especially Staphylococcus aureus, is one of the important reasons for inducing or aggravating immune dysfunction. Corticosteroids are immunosuppressive, dampen the pro-inflammatory environment, are critical for T cell activation, and produce potent anti-inflammatory effects. Benvimod has high antibacterial activity against Staphylococcus aureus, which is highly involved in the inflammatory response of atopic dermatitis. While Th17/Treg imbalance plays an important role in psoriasis, Benvimod can induce immunoregulatory Th17/T-reg cell responses, corticosteroids inhibit this effect, drug combination/composition treatment can reduce the immune response The conditioning process produces a mild induction.

Aryl hydrocarbon receptor AHR has been proved to be closely related to immune and inflammatory diseases. Benvimod regulates and treats the lesion by specifically binding and activating AHR, inhibiting pro-inflammatory factors, promoting normal differentiation of skin cells, proliferation and differentiation of keratinocytes.

In addition, pro-inflammatory cytokines that initiate pro-inflammatory feedback loops contribute to the development of disease inflammatory responses. Benvimod combined with corticosteroids can enhance the inhibition of pro-inflammatory cytokines such as IL-6, IL-8, IL-17C, IL-20, IFN-c and AMPs.

In summary, the drug combination/composition exerts a synergistic therapeutic effect on the pathogenesis of inflammatory diseases such as psoriasis and atopic dermatitis, and the drug combination/composition increases the curative effect of single active ingredient therapy.

2. Security

Corticosteroid treatment may lead to decreased skin thickness and increased transepidermal water loss, resulting in loss of skin barrier function and skin atrophy. The atrophy of the dermis caused by it often occurs at the site of application, mainly due to the reduction of collagen synthesis after binding to special receptors. For skin atrophy, there is currently no good treatment except minimally invasive surgery for injection of relevant skin tissue. Vimod works locally and can induce the expression of skin barrier protein genes, activate Nrf2 to inhibit oxidative stress, promote the recovery and integrity of skin barrier function, and prevent transepidermal water loss. The pharmaceutical combination/composition minimizes skin atrophy and reduces the risks associated with corticosteroid therapy. The drug combination/composition reduces the side effects associated with monotherapy and provides better safety.

The clinical drug concentration selected for each unilateral drug in the drug combination/composition is not higher than the respective clinical commonly used concentration, and the expected clinical exposure will not exceed the clinical use dose of each unilateral drug.

In addition, in terms of pharmacodynamics, the two have different pharmacological mechanisms of action and different targets of action. Benvimod works locally, and the concentration entering the circulatory system in the body is extremely low. There is no interaction with corticosteroids, and there is no same or similar target organ toxicity or adverse reaction, and the drug combination/composition will not cause toxicity superposition and cause obvious toxicological concerns.

3. Compliance

The rapid response of corticosteroid treatment lesions in the drug combination/composition, as well as the long remission period of Benvimod, greatly improve the acceptance of treatment by patients. And the treatment of the drug combination/composition can provide good convenience for patients, and help to promote patients to adapt to the treatment of the drug combination/composition during long-term management, improve the quality of life and treatment confidence of patients, thereby improving the treatment of patients compliance. The drug combination/composition promotes rapid disease response and good long-term control, and improves patient compliance.

Definition and Description

Unless otherwise stated, the following terms used in this application have the following meanings. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art.

As used in the application, the Benvimod compound and corticosteroid include its non-salt form (for example, free acid or free base), and also includes its pharmaceutically acceptable salt, and the non-salt or salt is all included in the application. within the scope of protection.

The term "administering" or "using" or "administering" means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.

The term "individual" may be a mammal. In some embodiments, the subject is a mouse, a rat, or a rabbit. In some embodiments, the subject is a human.

The term "pharmaceutical combination" refers to the simultaneous, parallel or sequential use of two or more active ingredients.

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or a pharmaceutical combination or salt thereof and pharmaceutically acceptable auxiliary materials. The purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into semi-solid preparations, such as creams, ointments, gels and the like.

Semi-solid compositions can be prepared by conventional methods of mixing, stirring, emulsifying, and the like. It can be obtained, for example, by dissolving the active compound in a solvent, mixing it with other suitable excipients, and then processing the mixture to form a semi-solid. Suitable excipients include, but are not limited to: emulsifiers, antibacterial preservatives, stabilizers, viscosity regulators, humectants, and the like.

The term "pharmaceutically acceptable or pharmaceutically usable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt or ester" or "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt or ester" means within the definition of "pharmaceutically acceptable" A salt or ester of a compound of the present application.

Unless specifically stated otherwise, a singular term encompasses a plural term, and a plural term encompasses a singular term. The words "a" or "an" mean "at least one" or "at least one" unless specifically stated otherwise. The use of "or" means "and/or" unless stated otherwise.

In this document, unless otherwise stated, the terms "comprising, including and comprising" or equivalents are open-ended expressions meaning that in addition to the listed elements, components and steps, other unspecified elements, Components and steps.

All patents, patent applications, and other identified publications are hereby expressly incorporated herein by reference for the purposes of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present application. All statements as to the date of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation herein of these publications does not constitute an admission that the publications form part of the common general knowledge in the field in any country.

Description of drawings

Figure 1 shows the PASI75 response rate (%) diachronic analysis of patients using the pharmaceutical composition;

Fig. 2 shows the change situation of PASI score of the patient who uses pharmaceutical composition;

Fig. 3 shows the change situation of PGA score of the patient who uses pharmaceutical composition;

Figure 4 shows the erythema scores of patients using the pharmaceutical composition.

Detailed ways

For the sake of clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present application. All reagents used in this application are commercially available and used without further purification.

Example 1

Benvimod Cream, Triamcinolone Acetate Cream Drug Combination for Topical Application

Benvimod cream (1%) and triamcinolone acetonide acetate cream (0.1%) were applied locally to the skin lesions in turn, twice a day, and the effect of the drug combination on the disease site was observed.

Example 2

Benvimod Triamcinolone Cream

组成composition	配比(％)(w/w)Proportion (%) (w/w)
本维莫德Ben Vimod	0.8％0.8%
曲安奈德triamcinolone acetonide	0.05％0.05%
鲸蜡硬脂醇cetearyl alcohol	20％20%
白凡士林White Vaseline	25％25%
轻质液体石蜡light liquid paraffin	12％12%

丙二醇Propylene Glycol	20％20%
单硬脂酸甘油酯Glyceryl monostearate	0.2％0.2%
山梨酸Sorbic acid	0.05％0.05%
纯化水purified water	至100％to 100%

Preparation

Add Benvimod and triamcinolone acetonide dissolved in propylene glycol, add light liquid paraffin, white petrolatum and cetearyl alcohol and stir evenly, then add glyceryl monostearate to heat and melt, add purified water, stir and homogeneously form After stable milk drops, cool down to room temperature, and then add sorbic acid to get it.

Example 3

Benvimod Mometasone Furoate Cream

组成composition	配比(％)(w/w)Proportion (%) (w/w)
本维莫德Ben Vimod	1.5％1.5%
糠酸莫米松mometasone furoate	0.5％0.5%
单硬脂酸甘油酯Glyceryl monostearate	2.5％2.5%

白凡士林White Vaseline	10％10%
轻质液体石蜡light liquid paraffin	10％10%
丙二醇Propylene Glycol	30％30%

聚山梨酯80Polysorbate 80	5.0％5.0%
十六醇cetyl alcohol	25％25%
羟苯乙酯Ethylparaben	0.02％0.02%
纯化水purified water	至100％to 100%

Preparation

Dissolve Benvimod and mometasone furoate in propylene glycol, add white petrolatum, light liquid paraffin, cetyl alcohol and stir evenly, add glyceryl monostearate to heat and melt, add purified water, stir homogeneously to form stable milk droplets , cooling down, followed by adding ethylparaben and cooling to room temperature, that is.

Example 4

Preparation of Benvimod Betamethasone Cream

The method steps that above-mentioned raw materials are made emulsifiable paste are as follows:

Step 1, oil phase preparation: weigh cetostearyl alcohol, white petrolatum, light liquid paraffin, glyceryl monostearate according to the prescription, heat to 75-85°C to dissolve and mix; add ethylparaben, Stir to dissolve and keep warm at 80°C for later use.

Step 2, water phase preparation: Weigh purified water and polysorbate 80 according to the prescription, heat to 75-85°C, stir evenly, and keep warm at 80°C for later use.

Step 3, preparation of raw material drug solution: add Benvimod and betamethasone into propylene glycol, stir at 75-85°C to dissolve the raw material drug, and keep warm at 80°C for later use.

Step 4, mixing emulsification:

a. Add the crude drug solution into the oil phase and mix, and stir evenly;

b Add the water phase again, homogenize at 75-85°C, homogenize at a speed of 1800rpm, and homogenize for 10min;

c Stir and cool down to below 45°C to form a paste.

Example 5

Preparation of Benvimod Hydrocortisone Cream

Step 3, preparation of raw material drug solution: add Benvimod and hydrocortisone to propylene glycol, stir at 75-85°C to dissolve the raw material drug, and keep warm at 80°C for later use.

Step 4, mixing emulsification:

a. Add the crude drug solution into the oil phase and mix, and stir evenly;

c Stir and cool down to below 45°C to form a paste.

Example 6

Preparation of Benvimod Mometasone Furoate Cream

Step 3, preparation of raw material drug solution: add Benvimod and mometasone furoate to propylene glycol, stir at 75-85°C to dissolve the raw material drug, and keep warm at 80°C for later use.

Step 4, mixing emulsification:

a. Add the crude drug solution into the oil phase and mix, and stir evenly;

c Stir and cool down to below 45°C to form a paste.

Example 7

Preparation of Benvimod Betamethasone Cream

Step 4, mixing emulsification:

a. Add the crude drug solution into the oil phase and mix, and stir evenly;

c Stir and cool down to below 45°C to form a paste.

Example 8

Implement the psoriasis patient drug effect study of the application pharmaceutical composition:

Embodiment 4 pharmaceutical composition: Benvimod cream, betamethasone cream

Specific steps of medication: For patients with mild and moderate psoriasis, apply Benvimod and betamethasone compound cream on the diseased part of the patient, that is, a combination of the two drugs is used. Take it once a day in the morning and evening, and observe the improvement of the patient's disease regularly. The implementation results are as follows:

1. Time-lapse analysis of the PASI75 response rate (%) of patients using the pharmaceutical composition

In order to measure the curative effect of the clinical practice of the pharmaceutical composition, psoriasis patients were administered drug combination curative effect research, the results are shown in Figure 1, from the 6th week, the PASI 75 response rate of patients with the pharmaceutical composition was significantly higher than that of each activity Monotherapy of ingredients.

2. Changes in the PASI score of patients using the pharmaceutical composition

The results of psoriasis area and severity of patients with psoriasis before and after medication are shown in Figure 2. The PASI score of patients using this pharmaceutical composition has the largest change from the baseline, and it is significantly different from each single drug and the control group from the 6th week. It shows that the area and severity of psoriasis of patients using the pharmaceutical composition can be more effectively improved than that of single medicine, which proves that patients using the pharmaceutical composition have better clinical prospects.

3. Changes in the PGA score of patients using the pharmaceutical composition

Psoriasis patients are scored (PGA) on the overall injury situation before and after using the pharmaceutical composition, and the course of treatment is 8 weeks. Compared with the single drug, the overall damage of psoriasis in patients with this drug composition can be more effectively improved. When the course of treatment reaches 8 weeks, the PGA score is reduced by nearly 80%. %, demonstrating the good effect of the pharmaceutical composition on the overall impairment of the patient.

4. Erythema scores of patients using the pharmaceutical composition

The erythema of the disease site was explored before and after the use of the pharmaceutical composition in psoriasis patients. The results are shown in Figure 4. Compared with the single drug, the erythema symptoms improved faster and more obviously in patients using the pharmaceutical composition. From the second From the first week to the end of the 8th week of the course of treatment, the curative effect is better than that of each single drug treatment, which proves the curative effect and benefit of the drug composition on the improvement of erythema.

Claims

A pharmaceutical composition, characterized in that, the pharmaceutical composition is a cream, and in terms of the total weight percentage of the pharmaceutical composition, the pharmaceutical composition comprises:

Benvimod or a pharmaceutically acceptable salt thereof in an amount of 0.5% to 1.5% by weight;

One or more corticosteroids in amounts ranging from 0.01% to 1.5% by weight, respectively;

Oil phase base, its amount is 15% to 50% by weight; Said oil phase base comprises petrolatum and light liquid paraffin;

Surfactants in amounts ranging from 0.1% to 8% by weight;

solvents and/or penetration enhancers in amounts of 5% to 20% by weight; and

The rest is the aqueous phase.
The pharmaceutical composition according to claim 1, characterized in that, the content of Benvimod or its pharmaceutically acceptable salt is 0.5% to 1.25% by weight, preferably 0.75% to 1%.
The pharmaceutical composition according to any one of claims 1 or 2, characterized in that the content of the corticosteroid is 0.01% to 1% by weight.
The pharmaceutical composition according to any one of claims 1 to 3, wherein the corticosteroid is betamethasone or a derivative thereof; preferably, the corticosteroid is betamethasone or betapropionate Mison.
The pharmaceutical composition according to any one of claims 1 to 4, wherein the surfactant is selected from emulsifying waxes, steareths, polysorbates, glyceryl monostearate, One or more of glyceryl monostearate, West Marco 1000, sorbitan fatty acid esters and macrogol cetostearyl ether, preferably glyceryl monostearate, monostearin and double stearate One of glyceryl acid esters, stearyl ethers, polysorbates, Situma Ge 1000, sorbitan fatty acid esters and polyethylene glycol cetostearyl ether.
The pharmaceutical composition according to claim 5, wherein the surfactant is glyceryl monostearate or glyceryl monostearate, and its amount is 0.1% to 6% by weight.
The pharmaceutical composition according to any one of claims 1 to 6, wherein the solvent and/or penetration enhancer are selected from one or more of propylene glycol, diethylene glycol monoethyl ether, glycerin and PEG400 species, preferably propylene glycol and/or diethylene glycol monoethyl ether, more preferably propylene glycol.
The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a preservative in an amount of 0.05% to 10% by weight; and/or

Antioxidant, its amount is 0.05% to 10% by weight.
A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, comprising the following steps:

1) Oil phase: add the oil phase matrix into a suitable size container, heat to 65-85°C to dissolve evenly, then optionally add preservatives, stir and dissolve to obtain solution A, keep warm for later use; wherein the oil phase matrix includes white Vaseline and light liquid paraffin;

2) Water phase: add surfactant to purified water, heat to 65-85°C to dissolve evenly to obtain solution B, keep it warm for later use;

3) Active ingredient solvent: Add Benvimod and corticosteroid to the solvent, heat to 65-85°C to dissolve evenly, and keep solution C for later use; the solvent is preferably propylene glycol;

4) Mixing and emulsification: adding solution A to solution C and mixing, stirring evenly; then adding solution B, stirring homogeneously to form stable emulsion droplets, and cooling to normal temperature to obtain the pharmaceutical composition.
A use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of medicines for treating and/or preventing immune, inflammatory and autoimmune diseases, preferably in the preparation of medicines for treating and/or preventing Or the purposes in the medicine of prevention skin disease or disorder; Wherein, described skin disease or disorder are selected from psoriasis, atopic dermatitis, acne and pruritus; Preferably, described skin disease or disorder are psoriasis .