CN114748463A - Application of Remetinostat in preparation of medicine for treating psoriasis - Google Patents

Abstract

The invention belongs to the field of pharmacy, and particularly relates to application of Remetinostat in preparation of a medicine for treating psoriasis. The invention provides a method for preparing a medicine for treating psoriasis by using Remetinostat, wherein Remetinostat and an external gel matrix or an external ointment matrix are prepared into an external gel or an external ointment for treating psoriasis, so that skin damage, stratum corneum thickening and interferon (INF-gamma) expression can be reduced, the use is more convenient, the toxic and side effects are less, and a new way is provided for effectively treating psoriasis.

Description

Application of Remetinostat in the preparation of medicine for treating psoriasis

technical field

The invention relates to the field of pharmacy, in particular to the application of Remetinostat in the preparation of a medicine for treating psoriasis.

Background technique

Psoriasis is a common chronic inflammatory skin disease, and its histopathological changes are mainly manifested as hyperproliferation of keratinocytes and parakeratosis, significant thickening of the spinous layer, accompanied by inflammatory cells such as lymphocytes and histiocytes. infiltration. Psoriasis has an incidence of 0.1%-2.9% in the natural population and affects about 2% of the global population. There are about 6 million psoriasis patients in my country, and the number is increasing year by year. The etiology of psoriasis is complex, the course of disease is long, and it is easy to recur, which seriously affects the physical and mental health and quality of life of patients.

At present, there are many drugs for the treatment of psoriasis vulgaris. Most of the commonly used oral drugs are immunosuppressive drugs and tretinoin drugs. These drugs require long-term oral treatment, with large side effects and unsatisfactory efficacy. Commonly used topical drugs include glucocorticoids, retinoic acid, vitamin DR derivatives, dithranol, tar preparations, and calcineurin inhibitors. Dithranol, tar preparations and glucocorticoids are limited in their use due to their large side effects. The therapeutic effects of tretinoin, calcineurin inhibitors and vitamin DR derivatives are not very satisfactory, and biological preparations such as monoclonal antibodies are expensive. , increasing the burden of life of patients. Therefore, it is of great significance to find new effective and low-cost psoriasis drugs.

Remetinostat is a hydroxamic acid-based inhibitor of histone deacetylase (HDAC), which blocks the cell cycle and induces apoptosis by inhibiting the activity of HDAC 1, 3 and 6 isoforms. Treatment of cutaneous T-cell lymphoma, a rare chronic blood cancer in which the main symptoms appear in the skin tissue. Remetinostat is a unique topical histone deacetylase inhibitor that is rapidly degraded in the blood after systemic administration, but is effective in topical application to the skin to avoid the adverse effects associated with systemic HDAC inhibitors.

Psoriasis is a common chronic inflammatory skin disease, and its histopathological changes are mainly manifested as hyperproliferation of keratinocytes and parakeratosis, significant thickening of the spinous layer, accompanied by inflammatory cells such as lymphocytes and histiocytes. infiltration.

SUMMARY OF THE INVENTION

In view of the above-mentioned deficiencies existing at present, the present invention provides an application of Remetinostat in the preparation of a medicine for the treatment of psoriasis. For psoriasis, it can reduce skin lesions, stratum corneum thickening, and the expression of interferon (INF-γ), and is more convenient to use, with less toxic and side effects, and provides a new way for effective treatment of psoriasis.

In order to achieve the above object, the present invention provides a kind of application of Remetinostat such as formula I in the preparation of a medicine for the treatment of psoriasis:

According to one aspect of the present invention, the medicament is mainly prepared from pharmaceutically acceptable excipients and the Remetinostat as an active ingredient.

According to one aspect of the present invention, the adjuvant is an external gel base or an external ointment base, and the drug is an external gel or an external ointment.

According to one aspect of the invention, the concentration of Remetinostat in the medicament is 0.05%-0.5%.

According to one aspect of the present invention, the external gel base is a combination of carbomer, propylene glycol, polysorbate 80, triethanolamine, ethylparaben, and water.

According to one aspect of the present invention, the external ointment base is a combination of white petrolatum, liquid paraffin, lanolin, propylene glycol and propylene carbonate.

According to one aspect of the present invention, the gel for external use comprises, in parts by weight, 0.05-0.5 parts of Remetinostat, 0.25-1 parts of carbomer, 5-20 parts of propylene glycol, and 800.5-2 parts of polysorbate , 0.1-1 part of triethanolamine, 0.1-0.5 part of ethyl paraben, and 80-99 parts of water.

According to one aspect of the present invention, the external ointment is 0.05-0.5 parts by weight of Remetinostat, 70-90 parts of white petrolatum, 5-20 parts of liquid paraffin, 2 parts of lanolin and 1-2 parts of propylene glycol , prepared from 1 to 2 parts of propylene carbonate.

According to one aspect of the present invention, dissolve Remetinostat in a mixed solution of water, propylene glycol, polysorbate 80, triethanolamine and ethyl paraben to obtain solution A; mix carbomer with an appropriate amount of water, stir and swell overnight , to obtain a gel matrix; add solution A to the gel matrix and stir evenly to obtain a gel for external use.

According to one aspect of the present invention, the preparation method of the external ointment comprises the following steps: dissolving Remetinostat in a mixed solution of propylene carbonate and propylene glycol to obtain solution B; heating white petrolatum, liquid paraffin, and lanolin to form a molten matrix ; The solution B was slowly added to the molten matrix, stirred until naturally cooled to obtain an external ointment.

Beneficial effects of the present invention:

The present invention is the first application of Remetinostat shown in formula I in the preparation of medicines for the treatment of psoriasis. Remetinostat and external gel base or external ointment base are used to make external gel or external ointment for the treatment of silver For psoriasis, it can reduce skin lesions, stratum corneum thickening, and the expression of interferon (INF-γ), and is more convenient to use, with less toxic and side effects, and provides a new way for effective treatment of psoriasis. This application provides a new use for Remetinostat and a new drug for the treatment of psoriasis. Remetinostat has obvious efficacy, broad application prospects, and has great promotion and application value; and because Remetinostat is an existing drug, Its toxicology and pharmacology are relatively clear, and it also reduces the cost of research and development.

Description of drawings

1 is a photo of the fifth day of the back skin of each group of mice in animal experiment 1 in Example 5 of the present invention;

Fig. 2 is the trend line made by the PASI scores of 5 groups of mice in animal experiment 1 in Example 5 of the present invention;

3 is a bar graph made of PASI scores on the fifth day of five groups of mice in animal experiment 1 in Example 5 of the present invention;

Fig. 4 is the electron microscope picture of skin magnified 100 times after the execution of 5 groups of mice in animal experiment 1 in Example 5 of the present invention;

5 is a bar graph showing the expression levels of the inflammatory cytokine INF-γ detected by fluorescence quantitative PCR in five groups of mice in Animal Experiment 1 in Example 5 of the present invention;

6 is a photo of the fifth day of the back skin of each group of mice in animal experiment 2 in Example 5 of the present invention;

Fig. 7 is the trend line made by the PASI scores of 5 groups of mice in animal experiment 2 in Example 5 of the present invention;

Figure 8 is a bar graph made of PASI scores on the 5th day of 5 groups of mice in Animal Experiment 2 in Example 5 of the present invention;

Fig. 9 is the electron microscope picture of skin magnified 100 times after the execution of 5 groups of mice in animal experiment 2 in Example 5 of the present invention;

10 is a bar graph showing the expression levels of the inflammatory cytokine INF-γ detected by fluorescence quantitative PCR in five groups of mice in animal experiment 2 in Example 5 of the present invention.

Detailed ways

In order to make the present invention easier to understand, the present invention will be further described below with reference to specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention. Unless otherwise defined, the professional terms used below have the same meaning as understood by those skilled in the art; unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or can be obtained through prepared by existing methods. The Remetinostat was purchased from Shanghai Taoshu Biotechnology Co., Ltd.

Example 1

Gel for external use in the treatment of psoriasis, prepared from 0.1 part of Remetinostat, 0.5 part of carbomer, 5 parts of propylene glycol, 802 parts of polysorbate, 0.65 part of triethanolamine, 0.5 part of ethylparaben, and 91.25 parts of water made. The preparation method includes the following steps: dissolving Remetinostat in a mixed solution of water, propylene glycol, polysorbate 80, triethanolamine and ethylparaben to obtain solution 1. The carbomer is mixed with an appropriate amount of water, stirred and swollen overnight to obtain a gel matrix. The solution 1 was added to the gel base and stirred well to obtain a 0.1% Remetinostat topical gel.

Example 2

External gel for the treatment of psoriasis, prepared from 0.5 parts of Remetinostat, 0.5 parts of carbomer, 5 parts of propylene glycol, 802 parts of polysorbate, 0.65 parts of triethanolamine, 0.5 parts of ethylparaben, and 90.85 parts of water made. The preparation method includes the following steps: dissolving Remetinostat in a mixed solution of water, propylene glycol, polysorbate 80, triethanolamine and ethylparaben to obtain solution 2. The carbomer is mixed with an appropriate amount of water, stirred and swollen overnight to obtain a gel matrix. The solution 2 was added to the gel base and stirred well to obtain a 0.5% Remetinostat topical gel.

Example 3

The external ointment for treating psoriasis is prepared from 0.1 part of Remetinostat, 1 part of propylene carbonate, 1 part of propylene glycol, 75.9 parts of white petrolatum, 20 parts of liquid paraffin and 2 parts of lanolin. The preparation method includes the following steps: dissolving Remetinostat in a mixed solution of propylene carbonate and propylene glycol to obtain solution 3. White petrolatum, liquid paraffin, and lanolin were heated to 65° C. (melted base), solution 3 was slowly added to the melted base, and stirred until naturally cooled to obtain 0.1% Remetinostat topical ointment.

Example 4

The external ointment for treating psoriasis is prepared from 0.5 parts of Remetinostat, 1 part of propylene carbonate, 1 part of propylene glycol, 75.5 parts of white petrolatum, 20 parts of liquid paraffin and 2 parts of lanolin. The preparation method includes the following steps: dissolving Remetinostat in a mixed solution of propylene carbonate and propylene glycol to obtain solution 4. White petrolatum, liquid paraffin, and lanolin were heated to 65° C. (melted base), the solution 34 was slowly added to the melted base, and stirred until naturally cooled to obtain 0.5% Remetinostat topical ointment.

Example 5

Establishment of a psoriasis-like mouse model: external application of imiquimod, an agonist of Toll-like receptor 7/8, to the skin of mice can induce psoriasis-like skin lesions and histological changes in the skin of mice. The proliferation of keratinocytes and the infiltration of immune cells produce psoriatic dermatitis, which is very similar to the pathological features of human psoriatic lesions. This animal model has been widely used for psoriasis drug screening and mechanism research.

animal experiment 1

Forty 8-week-old female BALB/c mice were randomly divided into 5 groups according to body weight, with 8 mice in each group. Divided into normal control group (group A), psoriasis-like mice control experimental group (group B), psoriasis-like mice blank gel group (group C), psoriasis-like mice 0.1% Remetinostat gel Group 1 (Group D) (Example 1), psoriasis-like mice 0.5% Remetinostat gel group (Group E) (Example 2). Group A was the blank control group, and no other treatment was performed during the experiment; group B was continuously smeared with imiquimod cream on the back on days 1-4; group C was continuously smeared with imiquimod on the back on days 1-4 Cream, blank gel base was applied on the back after an interval of 6 hours; group D was applied with imiquimod cream on the back continuously on days 1-4, and 0.1% Remetinostat gel was applied on the back after an interval of 6 hours. Group E applied imiquimod cream on the back continuously on days 1-4, and applied 0.5% Remetinostat gel on the back after a 6-hour interval. On day 5, the severity of psoriatic lesions on the back of the mice was evaluated.

The PASI (Psoriasis Area and Severity Index) score is the abbreviation of the psoriasis skin lesion score, which is an internationally accepted objective method for evaluating the area and severity of psoriasis skin lesions. The skin lesions on the back of the mice were scored by PASI every day, and the skin lesions on the back of the mice were photographed and recorded, as shown in Figure 1. It can be seen from Figure 1 that there was no erythema, scaling or thickening of the skin of the mice in group A; 2 and 3 days after imiquimod was applied to the back skin of mice in group C, erythema and a small amount of scales began to appear, which gradually increased with time, and the skin thickened, reaching a peak on the 5th day; The phenotypic characteristics of the disease in the groups were basically the same; the erythema of the back skin of the mice in the D and E groups was lighter than those in the C and B groups, and the scales were reduced. obvious. After the 5 groups of experiments were completed (day 5), the mice were sacrificed, and the skin tissue of the skin lesions on the back of the mice was taken for inflammatory cytokine detection and embedded sections, and HE staining was performed to observe the pathological manifestations of the skin lesions, and fluorescence quantitative PCR was used. The expression level of inflammatory cytokine INF-γ was detected.

The PASI scores of the 5 groups of mice were made into trend lines, and the PASI scores of the 5 groups of mice on the 5th day were made into histograms, and statistical analysis was performed, as shown in Figure 2 and Figure 3, groups D and E The difference between group B and C group was statistically significant (P<0.0001).

Referring to Figure 4, at a magnification of 100 times, HE staining found that the back skin lesions of mice in group B and group C showed hyperkeratosis with parakeratosis, acanthosis, superficial dermis vasodilation and congestion on the 6th day. The peripheral sparse lymphocyte infiltration was basically consistent with the pathological changes of psoriasis; the HE staining of the back skin of the mice in group A did not have the above changes, indicating that the psoriasis-like mouse model was successfully constructed. Compared with group A, group D and group E had hyperkeratosis and parakeratosis, but the thickness of spinous layer was significantly lighter than group B. As shown in Figure 5, the expression levels of interferon (INF-γ) in the skin lesions of groups D and E were significantly higher than those of groups B and C (P<0.0001).

It can be seen that Remetinostat gel can relieve psoriasis-like skin lesions by topical treatment, and achieve the effect of treating psoriasis by inhibiting the proliferation of keratinocytes, and has a significant therapeutic effect on psoriasis.

Animal experiment 2

Forty 8-week-old female BALB/c mice were randomly divided into 5 groups according to body weight, with 8 mice in each group. Divided into normal control group (group A), psoriasis-like mice control experimental group (group B), psoriasis-like mice blank ointment base group (C group), psoriasis-like mice 0.1% Remetinostat ointment group 1 (D group) (Example 3), psoriasis-like mice 0.5% Remetinostat ointment group (E group) (Example 4). Group A was the blank control group, and no other treatment was performed during the experiment; group B was continuously smeared with imiquimod cream on the back on days 1-4; group C was continuously smeared with imiquimod on the back on days 1-4 Cream, blank ointment base was applied on the back after an interval of 6 hours; group D was applied with imiquimod cream on the back continuously on days 1-4, and 0.1% Remetinostat ointment was applied on the back after an interval of 6 hours. Group E applied imiquimod cream on the back continuously on days 1-4, and applied 0.1% Remetinostat ointment on the back after an interval of 6 hours. On day 5, the severity of psoriatic lesions on the back of the mice was evaluated.

The skin lesions on the back of the mice were scored by PASI every day, and the skin lesions on the back of the mice were photographed and recorded. As shown in Figure 6, there was no erythema, scaling or thickening of the skin of the mice in group A; the back of the mice in groups B and C were not found. After 2 to 3 days of imiquimod application on the skin, erythema and a small amount of scales began to appear on the skin, which gradually increased with time, and the skin thickened, reaching a peak on the 5th day; the phenotypic characteristics of the disease in groups C and B Basically the same; the erythema of the back skin of the mice in the D group and the E group was reduced, and the scales were reduced. After the 5 groups of experiments were completed (day 5), the mice were sacrificed, and the skin tissue of the skin lesions on the back of the mice was taken for inflammatory cytokine detection and embedded sections, and HE staining was performed to observe the pathological manifestations of the skin lesions, and fluorescence quantitative PCR was used. The expression level of inflammatory cytokine INF-γ was detected.

The PASI scores of the 5 groups of mice were made into trend lines, and the PASI scores of the 5 groups of mice on the 5th day were made into histograms, and statistical analysis was performed, as shown in Figure 7 and Figure 8, groups D and E The difference between group B and C group was statistically significant (P<0.0001).

Referring to Figure 9, under 100x magnification, HE staining found that the back skin lesions of mice in group B and group C showed hyperkeratosis with parakeratosis, hypertrophic acanthosis, dilation and congestion of superficial dermis blood vessels on day 6 of mice in group B and group C. The peripheral sparse lymphocyte infiltration was basically consistent with the pathological changes of psoriasis; the HE staining of the back skin of the mice in group A did not have the above changes, indicating that the psoriasis-like mouse model was successfully constructed. Compared with group A, group D and group E had hyperkeratosis and parakeratosis, but the thickness of spinous layer was significantly lighter than group B. As shown in Figure 10, the expression levels of interferon (INF-γ) in the skin lesions of groups D and E were significantly higher than those of groups B and C (P<0.0001).

It can be seen that Remetinostat ointment can relieve psoriasis-like skin lesions by topical treatment, and achieve the effect of treating psoriasis by inhibiting the proliferation of keratinocytes, and has a significant therapeutic effect on psoriasis.

The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited to this. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, All should be included within the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims (10)

1. The use of Remetinostat as shown in formula I in the preparation of a medicament for treating psoriasis:

2. the use according to claim 1, wherein the medicament is prepared mainly from pharmaceutically acceptable adjuvants and said Remetinostat as an active ingredient.

3. The use of claim 2, wherein the excipient is a topical gel base or a topical ointment base and the medicament is a topical gel or a topical ointment.

4. The use of claim 2, wherein the concentration of Remetinostat in the medicament is 0.05% -0.5%.

5. The use of claim 3, wherein said topical gel base is a combination of carbomer, propylene glycol, polysorbate 80, triethanolamine, ethylparaben, and water.

6. The use of claim 3, wherein said topical ointment base is a combination of white petrolatum, liquid paraffin, lanolin, propylene glycol, and propylene carbonate.

7. The use according to claim 5, wherein the external gel is prepared from 0.05-0.5 part of Remetinostat, 0.25-1 part of carbomer, 5-20 parts of propylene glycol, 800.5-2 parts of polysorbate, 0.1-1 part of triethanolamine, 0.1-0.5 part of ethylparaben and 80-99 parts of water in parts by weight.

8. The use according to claim 6, wherein the external ointment is prepared from, by weight, 0.05 to 0.5 parts of Remetinostat, 70 to 90 parts of white vaseline, 5 to 20 parts of liquid paraffin, 2 parts of lanolin, 1 to 2 parts of propylene glycol, and 1 to 2 parts of propylene carbonate.

9. The use according to claim 7, wherein the preparation method of the external gel comprises the following steps: dissolving Remetinostat in a mixed solution of water, propylene glycol, polysorbate 80, triethanolamine and ethylparaben to obtain a solution A; mixing carbomer with appropriate amount of water, stirring, swelling, and standing overnight to obtain gel matrix; adding the solution A into the gel matrix, and uniformly stirring to obtain the external gel.

10. The use according to claim 8, wherein the topical ointment is prepared by a process comprising the steps of: dissolving Remetinostat in a mixed solution of propylene carbonate and propylene glycol to obtain a solution B; heating white vaseline, liquid paraffin and lanolin to obtain molten matrix; slowly adding solution B into molten matrix, stirring, and naturally cooling to obtain topical ointment.

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