External preparation for treating psoriasis and preparation method thereof

Abstract

The invention discloses an external preparation for treating psoriasis and a preparation method. The external preparation includes a gel matrix and an active substance; the gel matrix is ​​composed of the following components in percentage by mass: 2%-4% thickener, 0.8-10% gel matrix, 1-5% glycerol, pH regulator, and the remainder is water; the active substance is composed of Deucravacitinib and borneol, and the amount of Deucravacitinib is 0.5%-0.1% of the gel matrix, and the amount of borneol is 1%-2% of the gel matrix. External use of Deucravacitinib can quickly control psoriasis lesions, and the effect is significant. And it is a highly selective small molecule inhibitor, does not have the side effects of glucocorticoids, i.e., skin atrophy and hirsutism, and does not have the irritation of vitamin A and D derivatives. Adding borneol to the gel can further enhance the anti-inflammatory effect of Deucravacitinib.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and relates to an external preparation of a tyrosine kinase 2 (Tyrosine kinase 2, TyK2) inhibitor and a preparation method thereof, in particular to an external preparation and a preparation method thereof for treating psoriasis. Background Art

[0002] Psoriasis is a common chronic inflammatory skin disease with a global prevalence of about 0.5-4%, and it is increasing year by year. The disease recurs repeatedly and is difficult to cure, causing huge mental and economic burdens on individuals, families and society. The global psoriasis treatment market value was US$18.3 billion in 2018 and will reach US$37.6 billion in 2026. Among them, more than 80% of psoriasis patients are mild (and the affected area is <10%), and the main treatment method is topical medication. Although patients with severe psoriasis can use a new generation of biological agents such as anti-IL-17A antibodies, they are expensive, prone to relapse after discontinuation of medication, and some stubborn skin lesions are ineffective. Therefore, topical medications are still the cornerstone and foundation of the treatment of psoriasis. Currently, commonly used topical medications in clinical practice include glucocorticoids, vitamin D and vitamin A derivatives. Although these topical medications have certain therapeutic effects, long-term use is irritating to the skin and may cause side effects such as skin atrophy and hirsutism. Therefore, it is very necessary to develop more targeted topical preparations for psoriasis with fewer side effects.

[0003] Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase family (JAK), which also includes three kinase targets, including JAK1, JAK2 and JAK3. As a member of the JAK family of non-receptor tyrosine kinases, it has been found to play a key role in mediating the signal transduction of multiple cytokines that cause inflammation. In recent years, the oral Tyk2 inhibitor Deucravacitinib (BMS-986165) has shown great potential in the treatment of psoriasis. It has a good therapeutic effect on severe psoriasis in phase 2 and 3 clinical trials (PMID: 30205746). However, in diseases, the effectiveness of a drug taken orally does not directly mean that the drug has the same effect when applied topically. For example, although another JAK1 inhibitor, Tofacitinib, has a good effect in the oral treatment of psoriasis (PMID: 26051365), the effect of its topical ointment is not ideal (PMID: 27716172). In addition, when changing oral drugs to topical drugs, many factors need to be considered, such as the physical and chemical properties of the oral drugs themselves and excipients, the stability of the newly prepared topical drugs, how to increase drug absorption and reduce toxic side effects, etc. Currently, there is no research on deucravacitinib-related topical preparations and their efficacy. Summary of the invention

[0004] In view of the shortcomings and deficiencies of the prior art, the present invention provides a deucravacitinib external preparation and a preparation method thereof, so as to treat psoriasis with high efficiency and without side effects.

[0005] The deucravacitinib compound external preparation provided by the present invention comprises a gel matrix and an active substance; the gel matrix is ​​composed of the following components in percentage by weight: 2%-4% of a thickener, 0.8%-10% of a gel matrix, 1%-5% of glycerol, a pH regulator, and the balance is water; the active substance is composed of deucravacitinib and borneol, wherein the amount of deucravacitinib is 0.05%-0.1% of the mass of the gel matrix, and the amount of borneol is 1%-2% of the mass of the gel matrix.

[0006] Furthermore, the thickener is selected from at least one of the following: sodium alginate, sodium carboxymethyl cellulose, gelatin, and hydroxypropyl cellulose.

[0007] Furthermore, the gel matrix is ​​selected from at least one of the following: carbomer 940, carbomer 980, polyvinyl alcohol PVA-124, and methylcellulose.

[0008] Furthermore, the pH regulator can be selected from at least one of the following: boric acid, glacial acetic acid, triethanolamine, sodium hydroxide, sodium citrate, and the pH of the gel matrix is ​​adjusted to 7-9 with the pH regulator.

[0009] Furthermore, the deucravacitinib compound external preparation is an external gel preparation of deucravacitinib combined with borneol.

[0010] According to one embodiment of the present invention, the gel matrix is ​​composed of the following components in percentage by weight: 4% sodium alginate, 1% carbomer 940, 5% glycerol, 1% triethanolamine, and the balance is water;

[0011] According to one embodiment of the present invention, the gel matrix is ​​composed of the following components in percentage by mass: 2% sodium alginate, 0.8% carbomer 980, 3% glycerol, 1% triethanolamine, and the balance is water;

[0012] According to one embodiment of the present invention, the gel matrix is ​​composed of the following components in percentage by mass: 3% gelatin, 10% polyvinyl alcohol PVA-124, 2% glycerol, 0.5% sodium hydroxide, and the balance is water;

[0013] According to one embodiment of the present invention, the gel matrix is ​​composed of the following components in percentage by mass: 2% sodium carboxymethyl cellulose, 1% carbomer 940, 5% glycerol, 1% triethanolamine, and the balance is water.

[0014] According to one embodiment of the present invention, the active substance is composed of Deucravacitinib and borneol, wherein the amount of Deucravacitinib is 0.1% of the mass of the gel matrix, and the amount of borneol is 2% of the mass of the gel matrix;

[0015] According to one embodiment of the present invention, the active substance is composed of Deucravacitinib and borneol, wherein the amount of Deucravacitinib is 0.05% of the mass of the gel matrix, and the amount of borneol is 2% of the mass of the gel matrix;

[0016] According to one embodiment of the present invention, the active substance consists of Deucravacitinib and borneol, wherein the amount of Deucravacitinib is 0.1% of the mass of the gel matrix, and the amount of borneol is 1% of the mass of the gel matrix.

[0017] The present invention also provides a method for preparing the above-mentioned Deucravacitinib compound external preparation, comprising the following steps:

[0018] 1) stirring the thickener, gel matrix and glycerin to uniformly wet them, and adding water to soak them until they are fully swollen to obtain a swelling liquid;

[0019] 2) adding a pH adjuster to the swelling solution and stirring the solution to a pH of 7-9;

[0020] 3) Deucravacitinib and borneol were added in sequence, stirred, and oscillated using an ultrasonic oscillator until the gel was uniform.

[0021] The above-mentioned Deucravacitinib external preparation can be used for the treatment of psoriasis.

[0022] The present invention also protects a pharmaceutical composition for external use in treating psoriasis.

[0023] The topical pharmaceutical composition for treating psoriasis consists of Deucravacitinib and borneol, and the mass ratio of the two is (0.025-0.1):1.

[0024] Specifically, the mass ratio of Deucravacitinib to borneol can be 0.025:1, 0.05:1, or 0.1:1.

[0025] Compared with the prior art, the present invention has the following advantages and effects:

[0026] (1) Topical deucravacitinib can rapidly control psoriasis lesions with significant efficacy. It is a highly selective small molecule inhibitor that does not have the side effects of glucocorticoids, such as skin atrophy and hirsutism, nor does it have the irritation of vitamin A and D derivatives, and can be used safely.

[0027] (2) Adding borneol to the topical gel can further enhance the anti-inflammatory effect of deucravacitinib.

[0028] (3) In the present invention, glycerin and other thickeners are added during the preparation of the gel matrix to increase the moisturizing effect of the gel, which is beneficial for repairing the skin barrier damaged by psoriasis.

[0029] (4) Topical gels are more skin-friendly than ointments and creams, and provide a better user experience and comfort for areas prone to psoriasis and difficult to treat, such as the scalp. In addition, previous literature has reported that the drug permeation rate and cumulative permeation through the skin in gels are greater than those in other dosage forms, which can meet the need to increase drug concentration in lesions. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Schematic diagram of the imiquimod (IMQ)-induced psoriatic dermatitis mouse model and drug administration.

[0031] Figure 2 Deucravacitinib monotherapy topical gel significantly improves imiquimod (IMQ)-induced psoriatic dermatitis in patients with ear skin photographs and ear swelling measurements.

[0032] Figure 3 Photos of the mouse ear skin treated with borneol monotherapy topical gel, deucravacitinib monotherapy topical gel, and Deu / borneol compound topical gel, as well as the results of psoriasis scoring, the measurement of ear swelling, the number of cells in the cervical draining lymph nodes, and the thickness of the epidermis.

[0033] Figure 4 The figures are photos of the mouse ear skin treated with Deu / borneol compound external gel of different examples and the measurement results of ear swelling degree. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with specific examples, but the present invention is not limited to the following examples. The methods described are conventional methods unless otherwise specified. The raw materials described can be obtained from public commercial channels unless otherwise specified.

[0035] Example 1. Preparation of Deucravacitinib Compound Gel

[0036] (1) Preparation of gel matrix: The gel is composed of the following components in percentage by weight: sodium alginate 4%, carbomer 940 1%, glycerol 5%, triethanolamine 1%, and the balance is water.

[0037] For example, 400 mg of sodium alginate, 100 mg of carbomer, and 500 mg of glycerol are stirred and evenly moistened, and then added to 8.9 ml of distilled water and soaked until fully swollen. The swelling solution is obtained the next day. 100 mg of triethanolamine is added to the swelling solution, and the pH is 7-9 as measured by a test paper.

[0038] (2) Add 0.1% by weight of deucravacitinib and 2% by weight of borneol to the gel matrix in sequence, i.e., add 10 mg of deucravacitinib and 200 mg of borneol to the swelling solution in (1), stir evenly, oscillate on an ultrasonic oscillator for 10 minutes, dispense into 5 ml tubes, and store in a cool place.

[0039] Example 2, Preparation of Deucravacitinib Compound Gel

[0040] The gel matrix is ​​composed of the following components in percentage by weight: 4% sodium alginate, 1% carbomer 940, 5% glycerol, 1% triethanolamine, and the balance is water.

[0041] The mass percentage of the active substance Deucravacitinib is 0.05%, and the mass percentage of borneol is 2%. The preparation method is the same as that of Example 1.

[0042] Example 3. Preparation of Deucravacitinib Compound Gel

[0043] The gel matrix is ​​composed of the following components in percentage by weight: 2% sodium alginate, 0.8% carbomer 980, 3% glycerol, 1% triethanolamine, and the balance is water.

[0044] The mass percentage of the active substance Deucravacitinib is 0.05%, and the mass percentage of borneol is 2%. The preparation method is the same as that of Example 1.

[0045] Example 4. Preparation of Deucravacitinib Compound Gel

[0046] The gel matrix is ​​composed of the following components in percentage by weight: 3% gelatin, 10% polyvinyl alcohol PVA-124, 0.5% sodium hydroxide, 2% glycerol, and the balance is water.

[0047] The mass percentage of the active substance Deucravacitinib is 0.05%, and the mass percentage of borneol is 2%. The preparation method is the same as that of Example 1.

[0048] Example 5. Preparation of Deucravacitinib Compound Gel

[0049] The gel matrix is ​​composed of the following components in percentage by weight: 2% sodium carboxymethylcellulose, 1% carbomer 940, 5% glycerol, 1% triethanolamine, and the balance is water.

[0050] The mass percentage of the active substance Deucravacitinib is 0.1%, and the mass percentage of borneol is 1%. The preparation method is the same as that of Example 1.

[0051] Example 6: Effect Verification of Deucravacitinib Compound Gel

[0052] Topical imiquimod cream (IMQ) is a classic model for inducing psoriasis-like dermatitis in mice (or other animals), and is used here to explore the therapeutic effects of topical drugs.

[0053] The specific experimental method is: 5-8 8-week-old C57BL / 6 mice were selected from each group to establish a psoriasis dermatitis model and give different gel treatments. The specific method is as follows: 25 mg of imiquimod cream (Aidal Company) was applied to the ears of mice at 16:00 every afternoon to establish a psoriasis model, and the unmodeled group was coated with an equal amount of moisturizing cream (Vanicream Company). The treatment groups were given 25 mg of gel containing different ingredients at 8:00 am every day for 5 consecutive days. On the sixth day, the degree of ear swelling, psoriasis score, and neck drainage lymph node analysis were measured (see the process). Figure 1 ).

[0054] 1. Deucravacitinib single-agent gel can significantly improve imiquimod (IMQ)-induced psoriatic dermatitis.

[0055] Photos of the mouse ear skin in different treatment groups and the measurement results of ear swelling are shown in Figure 2 shown. Figure 2 From left to right in the figure are the unmodeled group, the modeled + gel matrix group (gel matrix preparation is the same as in Example 1), the modeled + 0.1% Deucravacitinib single-drug gel group (0.1% Deucravacitinib single-drug gel, matrix preparation is the same as in Example 1, and the active ingredient is 0.1% Deucravacitinib by mass), and the modeled + 0.05% Tazarotene gel group (0.05% Tazarotene gel, matrix preparation is the same as in Example 1, and the active ingredient is 0.05% Tazaotene by mass). Tazaotene (Tazarotene, Taza) is a vitamin A derivative that has been used externally in the clinic to treat psoriasis.

[0056] from Figure 2It can be seen that 0.1% Deucravacitinib gel can effectively improve IMQ-induced psoriasis skin inflammation, which is manifested by reduced erythema, scaling, and reduced ear swelling. However, short-term use of 0.05% Tazarotene gel caused significant irritant dermatitis, which was manifested by increased scaling and ear swelling.

[0057] 2. Camphor further enhances the therapeutic effect of Deucravacitinib.

[0058] Photographs of the ear skin of mice in different treatment groups, psoriasis score results, ear swelling degree, number of cells in the neck draining lymph nodes, and epidermal thickness Figure 3 The modeling and processing process is the same as Figure 1 The mouse psoriasis score refers to the clinical symptom score PASI (Psoriasis Area and Severity Index), including the measurement of skin infiltration, scaling, and erythema, which are scored using a 5-point system (0-4). Skin infiltration: 0-smooth skin without wrinkles, 1-slight wrinkles appear at the edge of the coating area, 2-slight wrinkles appear in half of the skin in the coating area, 3-slight wrinkles appear in all the skin in the coating area, and 4-the wrinkles deepen on the basis of 3; scaling: 0-smooth skin without scaling, 1-slight scaling appears in the coating area, 2-half of the skin in the coating area is covered with scaling, 3-the skin in the coating area is covered with scaling, and 4-the scaling in the coating area deepens; erythema: 0-smooth skin, 1-slight redness appears in the coating area, 2-half of the skin in the coating area turns red, 3-the skin in the coating area turns red, and 4-the redness in the coating area deepens. Total score: the sum of the three scores of skin thickness, crusting and erythema.

[0059] Figure 3 From left to right in the figure are modeling + gel matrix group (IMQ + vehicle), modeling + borneol gel group (IMQ + Borneol, wherein borneol gel, matrix preparation is the same as in Example 1, and the active ingredient is 2% by weight of borneol), modeling + Deu gel group (IMQ + Deu, wherein Deu gel, matrix preparation is the same as in Example 1, and the active ingredient is 0.1% by weight of Deucravacitinib), modeling + borneol / Deu compound gel group (IMQ + Borneol + Deu, borneol / Deu compound gel is the Deucravacitinib compound gel prepared in Example 1). Figure 3 As shown, in terms of gross appearance, psoriasis score, degree of ear swelling, and epidermal thickness, the compound gel preparation is superior to the other two single-drug gels in the treatment of psoriasis.

[0060] Figure 4 From left to right in the figure, they are modeling + gel matrix group, modeling + borneol / Deu compound gel group 1 (prepared in Example 2, the active ingredients are 0.05% Deucravacitinib and 2% borneol by mass), and modeling + borneol / Deu compound gel group 2 (prepared in Example 1, the active ingredients are 0.1% Deucravacitinib and 2% borneol by mass). Figure 4 As shown, both compound gel preparations 1 and 2 have significant therapeutic effects on ear swelling caused by psoriatic dermatitis, and the effect of compound preparation 2 is further superior to that of compound preparation 1.

[0061] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A deucravacitinib compound external gel preparation for treating psoriasis, comprising a gel matrix and an active substance; the active substance is composed of deucravacitinib and borneol, wherein: The amount of deucravacitinib used is 0.05%-0.1% of the mass of the gel matrix, and the amount of borneol used is 1%-2% of the mass of the gel matrix.

2. The deucravacitinib compound external gel preparation according to claim 1, characterized in that: The gel matrix is ​​composed of the following components in percentage by weight: 2%-4% thickener, 0.8%-10% gel matrix, 1-5% glycerol, pH regulator, and the balance is water.

3. The deucravacitinib compound external gel preparation according to claim 2, characterized in that: The thickener is selected from at least one of the following: sodium alginate, sodium carboxymethyl cellulose, gelatin, and hydroxypropyl cellulose.

4. The deucravacitinib compound external gel preparation according to claim 2, characterized in that: The gel matrix is ​​selected from at least one of the following: carbomer 940, carbomer 980, polyvinyl alcohol PVA-124, and methylcellulose.

5. The method for preparing the Deucravacitinib compound external gel preparation according to any one of claims 1 to 4, comprising the following steps: 1) stirring the thickener, gel matrix and glycerin to be uniformly wetted, and soaking them in water until they are fully swollen to obtain a swelling liquid; 2) adding a pH adjuster to the swelling solution and stirring evenly until the pH reaches 7-9; 3) Add the deucravacitinib and borneol in sequence, stir, and oscillate with an ultrasonic oscillator until the gel is uniform.

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