Compositions containing berberine or its analogues for treating skin diseases related to rosacea or blush

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a local pharmaceutical composition for treating rosacea containing at least 0.02% berberine or a biologically equivalent berberine analogue, such as palmatine, and an ingredient specified in a group consisting of water, methanol, ethanol and dimethylsulphoxide, wherein berberine or the biologically equivalent berberine analogue represents the major pharmaceutically active ingredient.

EFFECT: invention provides extending the range of products for treating rosacea.

4 cl, 6 ex, 2 dwg

 

BACKGROUND of INVENTION

1. Rosacea, its symptoms

Rosacea is a chronic skin disease that is manifested by redness and swelling, primarily on the face and especially in the Central part of the face. Others affected by this disease areas include the scalp, neck, ears, chest, back and eyes. Rosacea is manifested by redness of the face, erythema, telangiectasia, episodes of inflammation with papules and pustules, and in severe cases, rhinophyma. It is essential that there are no comedones1.

For patients with rosacea mainly characterized by increased sensitivity of the skin and dryness, scaly dermatitis, swelling of the face and persistent granulomatosis populonia sites2. Clinical and histopathological characteristics of this disease can be classified into four subtypes: (a) erythematotelangiectatic, b) papulopustular, c) femality and (d) eye, where each of these subtypes on the severity of the condition is characterized by three degrees (mild, moderate, severe)3. The disease mainly occurs as chronic with remissions and repeated exacerbations.

2. Other skin disorders, manifested by redness of the face

Rosacea is the most common skin the Sam is eusto, manifested by redness of the face. Other skin disorders, manifested by redness of the face and having similar symptoms and, possibly, similar pathological causes include common acne, seborrheic dermatitis, photodermatitis and contact dermatitis. These conditions associated with redness of the face, can vary from a feeling of warmth and sensitivity of the skin to redness or strong feeling the heat4. Patients with rosacea and other skin disorders associated with redness of the face, often exhibit an increased sensitivity to environmental factors and to locally introduce tools5. Induced by steroids rosacea-like dermatitis (or steroid rosacea) is a lesion occurring in the form of papules or pustules with erythematous or edematous base, in the presence or in the absence of telangiectasia, which is called prolonged use of local steroids on the face or manifests itself in the form of the phenomenon of cancellation that occurs after discontinuation of local steroids6,7(Chen AY Zirwas MJ, 2009; Lee DH, Li K, Suh DH 2008). Inhibitors of EGFR, such as cetuximab, erlotinib, gefitinib cause acneform dermatitis on the face or other area of the skin, including papulopustular reaction, erythema, telangiectasia and hyperemia in 30-90% of patients, and in this case can also be superin is under bacteria, such as Staphylococcus aureus8,9(Wollenberg A, Kroth J et al., 2010; Lacouture ME, Maitland ML, et al., 2010).

3. The pathogenesis of rosacea

The etiology of rosacea is not entirely clear. On a number of different factors it has been suggested their participation in the development and manifestation of rosacea. However, the role of any of these factors has not been confirmed.

3.1. The role of genetic factors

Earlier studies showed the presence of genetic predisposition in humans to congestion, representing the earliest symptom of rosacea on the face10. Additionally, it was shown that the null genotype for glutathione-S-transferase MU-1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) is associated with an increased risk of developing rosacea11.

3.2. Inflammation and the innate immune system

With progression of rosacea appear inflammatory lesions. Rosacea unlike common acne is a bacterial disease pilosebaceous complex. In this case, the comedones are usually absent in skin samples taken from patients with rosacea, identified only normal bacterial flora12. Inflammatory stage of rosacea can be viewed as a form of chronic sterile cellulite13. Although the presence of microorganisms was considered as a possible factor influencing the development of the roses is highly significant, the study results were inconclusive1. TicksDemodex folliculorumare optional and do not play an important role in the pathogenesis of rosacea, although the inflammatory reaction to the mites can worsen symptoms14.

Yamasakiet al.discovered an abnormally high level of cathelicidin with histopathological staining of the lesion in patients with rosacea. It has been shown that epidermal keratinocytes stimulated cathelicidin peptides, increase the release of IL-8. Injection cathelicidin peptides in the skin of mice caused inflammatory changes with increased infiltration of neutrophils and formation of microvessels, typical skin disorder rosacea in people15. It is possible that cathelicidin play a dual role in the immune system, because they can destroy microorganisms, and to stimulate the inflammatory response of the host body, such as the induction of the release of IL-816. Other inflammatory cytokines, the level of which increases with rosacea include IL-1 alpha and transforming growth factor beta-217,18.

3.3. Vascular mediators

Inflammatory mediators may be responsible for the vasodilatation observed in patients with rosacea. For example, this assumption was expressed relative to substance P, histamine, with whom rotonen, bradykinin or prostaglandins19. Smithet al.showed increased expression of growth factor vascular endothelial and its receptors in rosacea20.

4. Current approaches to the treatment of patients with rosacea

For the treatment of rosacea has been used many antibiotics, such as tetracycline and doxycycline. It has been suggested that these antibiotics have, rather, anti-inflammatory, not an antimicrobial effect. However, other anti-inflammatory agents were not effective in the treatment of rosacea. Immunosuppressants, such as corticosteroids, often worsen inflammation in rosacea1.

Input locally metronidazole and some systemic antibiotics are often used as first-line drugs for the treatment of rosacea. Primarily for the treatment of rosacea was used tetracycline, doxycycline and minocycline, are entered in the oral mode. It is believed that the effectiveness of oral antibiotics mainly related to their anti-inflammatory effect, but not with antibiotic action. 15% gel azelaic acid was allowed by the Federal Agency for supervision of medication administration (FDA) of the USA in 2002 for the local treatment of rosacea, expressed in degree from "weak" to "moderate". Other standard local means that p is manalishi not registered indication, include clindamycin, sulfacetamide and sulfur, but the mechanism of action is poorly understood.

5. The use of berberine for disorders that are not associated with skin

Berberine (natural yellow 18, 18,6-dihydro-9,10-dimethoxybenzo)(g)-1,3-benzodioxole (5,6-a)finalizing) is an isoquinoline alkaloid present in herbal plants, such as coptis (A rhizome Coptidis),philodendron,Scutellaria baicalensis, Mahonia aquifoliumand barberry23. It was shown that berberine and its derivatives have antimicrobial and antimalarial activity. He can act against different types of pathogens, such as fungi, Saccharomyces cerevisiae, parasites, bacteria and viruses24. It was shown that berberine has other potentially useful properties. For example, it can be used to reduce the high level of blood cholesterol, cardiovascular disease, diabetes and tumors25.

Berberine also has anti-inflammatory action, although the exact mechanism of its action is unknown. Recently a number of researchers found that the anti-inflammatory mechanism of action of berberine is associated with the metabolism of cyclooxygenase-2 (COX-2), since COX-2 plays a key role in the synthesis of prostaglandins, which increases inflammation26. Berberine was used as ingr dient in the solutions of some eye drops or eye ointment, used to treat trachoma27.

6. The use of berberine in disorders of the skin

In U.S. patent No. 6440465 described containing berberine composition for topical application to the skin, including glucosamine in softening basis for psoriasis treatment28. In the application for U.S. patent No. 20050158404 describes a food product, dietary Supplement or pharmaceutical composition, which contains vitamin a, vitamin E, selenium, vitamin B6, zinc, chromium and herbal source of berberine, for the treatment of acne in the mode of oral administration29. In U.S. patent No. 6974799 describes the local composition containing Tripeptide (N-Palmitoyl-Gly-His-Lys) and tetrapeptide (N-Palmitoyl-Gly-Gln-Pro-Arg), to treat visible signs of aging, including wrinkles, creases and dark circles30. This composition may contain additional ingredients, including berberine. In these inventions berberine is included as one of many ingredients and its concentration is not specified.

In the patent application No. 20040146539 describes local nutraceutical composition, the slimming and rejuvenating action related to improving body tone, which was used to treat aging skin, reduce wrinkles, flaky skin, acne, rosacea and other skin problems31. The song is about the present invention includes an antimicrobial agent, selected from several substances, including berberine. The composition of these nutraceutical compositions berberine was included as one of many ingredients and its concentration was not specified. Was offered a cream with 10% content of Mahonia aquifolium (Relieva™, Apollo Pharmaceutical Canada Inc) for the treatment of psoriasis32that contained 0.1% berberine.

Therapeutic effect of berberine in the treatment of rosacea and other skin disorders associated with redness of the face, is unknown. To date there has been no direct evidence to support the fact that berberine can improve the symptoms of rosacea.

Description of the INVENTION

Currently, there is a need for an effective strategy for the treatment of rosacea and other skin disorders, which would be characterized by minimal side effects. The present invention relates to local pharmaceutical compositions that are effective and safe in case of their use for the treatment of rosacea and other skin disorders associated with redness of the face, such as acne, seborrheic dermatitis, contact dermatitis and photodermatol. The present invention takes into account the inadequacy of currently available local pharmaceutical compositions of the investigated compositions containing berberine as one of its components, and eliminates et is t deficiency.

There are a number of data obtained in animal studies and in clinical trials on humans that berberine is an active pharmaceutical ingredient, which used purified berberine or used compositions containing herbal extract containing berberine. In the treatment of many diseases, such as bacterial and fungal infections and cardiovascular disease, sometimes achieved statistically significant efficacy of berberine. Were also obtained good results in tests of compositions containing enriched with berberine extract, psoriasis, although the effectiveness of berberine in psoriasis is still not confirmed. These results suggest that berberine may act on molecular targets and to cause modification of a number of molecular pathways and cellular functions, such as described in the introductory part of this patent application.

Pharmacological studies of a large number of pharmaceutical compounds showed that the pharmaceutically active compound should be present in the body or the affected tissues in excess of the threshold concentration for this medicinal compounds, so that was achieved significant biological and pharmacological effect and, accordingly, therapeutic EF is known, the subject that is being treated. In herbal medicines that contain extracts one or many plants, there are many active medicinal ingredients. In most cases, the treatment using herbal preparations, administered in oral or local mode, selected medicinal ingredients present in subparagraph concentrations in the body or diseased tissue or a subject to be treated. However, multiple connections from the same plant or different plants can act on the same molecular target, or multiple connections from the same plant or different plants can act on different molecular targets in the same biological pathway. As a result of various compounds, acting in combination, cause significant biological and pharmacological response, and eventually and therapeutic response.

In the case when the herbal pharmaceutical drug does not cause a therapeutic effect in the subject that is being treated, it is likely that this pharmacologically active compound contained in this preparation is present in too low concentrations in the body of the subject, and that in this connection the connection, by itself or in combination with other available drug soy is inanami, not able to cause significant biological and pharmacological effect. In fact, the plant was identified many important medicinal compounds (certain chemicals, which are used in herbal preparations. In case of using such pure compounds achieved therapeutic efficacy is often more than the efficiency observed in herbal preparations containing these compounds.

Local herbal pharmaceutical compositions that include enriched with berberine plant extracts, has been used for centuries to treat a variety of diseases, including many skin disorders such as psoriasis, acne, eczema, etc., However, the results of the application of such local herbal preparations is largely varied. In some such preparations containing berberine extract comprises about 10% of various components included in the composition. It was found that berberine connection in such local drugs is about 0.1 wt.% from all of the finished composition32.

Based on the above data, the authors undertook a study of thein vitroeffect of berberine in different concentrations on the biological pathways that may be involved in the pathogenesis of rosacea. Based on the results and the above data, the authors developed the Ali chemically defined local pharmaceutical composition, which contain berberine installed in percentage concentration exceeding the concentration of berberine in standard herbal pharmaceutical compositions of berberine. The authors investigated the effect of the compositions on the affected skin of patients with rosacea. The results showed that the local pharmaceutical composition containing berberine in amounts above 0.1 wt.%, effective and well tolerated in the treatment of patients with rosacea and related disorders of the skin, prone to redness.

Analogues of berberine

The structure of berberine (5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxole (5,6-a) chinoline) is shown below.

Can be obtained several protoberberine alkaloids, which have varying biological activity similar to berberine, such as atralin, palmatine, coptisine, 9-dimethylbenzene, 9-dimethylpyrimidin, 13-hydroboration, berberovic, palmtran, 9-O-ethylbarbituric, 9-O-ethyl-13-ethylbarbituric, N-methyl Sol 13-methyldihydromorphine, tetrahydroprotoberberine and their N-methyl salt, 13-exillerating, 13-hexylamine and 9-lauroylsarcosine chloride33,34.

Palmatin present in the plants belonging to different families, and especially noticeable in quantities in rhizomes is Fibrarurea Tinctoria Lour.Palmatin is an isoquinoline alkaloid, and compositions containing palmatin, was widely used in China for the treatment of gynecological inflammation, bacillary dysentery, enteritis, respiratory infections and urinary tract infections. Additionally, palmatin possesses antiarrhythmic function, is antiseptic, has bacteriostatic and antiviral activity. Palmatin can also be used as compounds useful for screening antitumor drugs35. Was also described pharmaceutical composition containing palmatin, which was used as a topically applied inhibitor of hair growth (Keramene, Divine Skin Solutions D S Laboratories Keramene Body Hair Minimizer).

Coptisine is an alkaloid found in plants of coptis three leaf Chinese(Coptis chinensis).It has been used in Chinese herbal medicine along with the related barberinum compound to treat disorders of the digestive tract bacterial infections. Coptisine also has some significant inhibitory effect on tumor growth. As shownin vitro, coptisine has a cytotoxic effect on the cell line tumor cells of human colon36cell cell line human hepatoma jakosky cell line 37.

In research conducted by the authors, were studiedin vitroandin vivoeffects of different concentrations palmatine and coptisine on biological pathways that may be involved in the pathogenesis of rosacea. Based on these results and the above data, the authors also developed a chemical specific local pharmaceutical compositions that contain palmatin or coptisine in the specified concentrations. These compositions can provide an effective and well-tolerated by patients results in the treatment of rosacea and similar disorders associated with the tendency of the skin to redness.

Example 1: Effects of berberine on the inhibition of secretion by human keratinocytes cytokine-induced cathelicidin peptides (testin vitro)

In thein vitrothe study of berberine (Sigma, St. Louis, MO, USA) was dissolved in water, methanol, ethanol or dimethyl sulfoxide (DMSO). Normal human keratinocytes (Invitrogen, CA, USA) were grown in EpiLife medium (Invitrogen, CA, USA) with the addition of 0.06 mm Ca+2that 1% growth supplements EpiLife and 1% penicillin/streptomycin (Invitrogen, CA, USA). Cells were grown at 37°C in humidified atmosphere containing 5% CO2and 95% air. Human keratinocytes were cultured to confluence and treated synthetic cathelicidin peptides (LL-37) (6.4 µm) during the 16 hours for the induction of the inflammatory response, similar to the responses observed in rosacea. Some of the cultures of keratinocytes treated with cathelicidin, incubated with berberine at concentrations of 1.25 μg/ml to 12.5 μg/ml Culture of keratinocytes treated with cathelicidin or cathelicidin with 1% ethanol, and not treated with berberine, were used as negative controls. Supernatant collected and placed in sterile wells of 96-well plate to conduct, within IFTTA, analysis of interleukin-8 (IL-8), interleukin-1 alpha (IL-1 alpha) and growth factor venous epithelial cells (VEGF), according to manufacturer's instructions (R&D Systems, MN, USA).

In the result, it was shown that cathelicidin can induce the release of IL-8, IL-1 alpha and VEGF from cultured human keratinocytes. Inhibitory effect of berberine on the release of IL-8 (Fig. 1A), IL-1 alpha (Fig. 1B) and VEGF (Fig. 1C) investigated adding to the culture medium at various concentrations (0~12.5 µg/ml) of berberine. There was a decrease in the release of IL-8, IL-1 alpha and VEGF by 31.4%, 24,9% and 29.1%, respectively, when stimulated cathelicidin keratinocytes were treated with berberine at concentrations of 1.25 μg/ml, in comparison with the treatment option cathelicidin peptide with 1% ethanol-investigated as a control (P<0,05). These results showed that berberine could largely the ore to inhibit induced cathelicidin inflammatory response in a dose-dependent mode, when the concentration of berberine was higher than at 6.25 µg/ml, indicating that berberine has anti-inflammatory activity against induced cathelicidin release of cytokines associated with rosacea.

Example 2: Retrieving local pharmaceutical compositions containing the purified berberine and palmatine installed in percentage concentrations

On the basis of the above data were obtained from local pharmaceutical composition containing berberine, according to the present invention, which contain one key feature: they included the purified berberine in the established percentage concentrations where these concentrations were higher than the concentrations that have been achieved in the standard, previously used compositions with the use of plant extracts, enriched with berberine. Investigated different concentrations, taken in a certain range, in animal models and in clinical trials on humans.

For research on animal models and in testing on humans according to the present invention purified berberine was dissolved in 100% ethanol and then added water to achieve the desired concentration of berberine in the finished solution. In the case of a gel composition berberine, for example, 0.1% or 0.2% concentration, were made in 10% ethanol. RA the solution or gel composition was closed with a cap and stored at 4°C until use. The results of the research of the authors in animal models and in trials with people with rosacea show that the concentration of berberine in the compositions should be 0.1% or higher, in order to achieve a stable satisfactory results. Moreover, these concentrations exceed the concentrations that were present in the local compositions containing berberine, produced using enriched with berberine plant extract.

Currently, experiments are being conducted on the production of compositions in the form of ointments, gels, creams, lotions or spray means, which would be more suited for their application in clinical conditions of patients. In the local pharmaceutical compositions of the present invention berberine or biologically equivalent analogue of berberine (for example, palmitin and coptisine) is the only or the main active drug compound. Purified palmatin used in the research of the authors of the present invention was dissolved in 100% water and then diluted so that in the finished solution or ready gel composition was achieved concentrations palmatine comprising, for example, of 0.02%, 0.1% or 0.2 percent.

However, improved or modified compositions may contain additional ingredients, imposed for the purpose of the appreciation is of the solubility of berberine or its equivalent, to improve the emulsifying, sliding properties, antibiotic activity or hydration.

One of the preferred embodiments of the present invention associated with increased solubility of berberine or a biologically equivalent analogue of berberine and includes the addition of glycerol in the composition. One way of implementing the present invention relates to improved antibiotic activity of the composition and is associated with the addition of herbal extracts, which are known to possesses antibiotic activity. One variant of implementation of the present invention associated with increased hydrating properties of the local composition of the present invention and includes the addition of hyaluronic acid.

Example 3: Effects of local pharmaceutical preparation of the present invention to model rosacea in mice

Animal model rosacea: an animal model of rosacea was adapted from previous studies18. In General, the experiment consisted in the fact that BALB/c mice and C57BL/6 shaved 24 hours before the experiment and twice a day they were injected with subcutaneously in the back 40 ál cathelicidin peptide (320 µm). Forty-eight hours after the initial injection (just after four injections) at the injection site was marked erythema and edema that mimic the clinical signs of roses is highly significant.

In the authors conducted experiments with mice, which were injected with cathelicidin, were treated by the local composition of berberine twice a day or not was treated with this composition, to evaluate the effect of berberine on reducing inflammation. The results showed that mice who had subcutaneous injection cathelicidin peptides, 48 hours developed erythema and vascular Gelateria on the skin, which were similar to the clinical signs of rosacea. Mice after injection of cathelicidin were divided into two groups, where one of the groups of animals were treated with berberine (n=3), and the other group did not enter berberine (n=3; control), respectively, over the next 2 days. Local composition containing 0.1% berberine, were applied to the induced cathelicidin skin 2 times a day. Erythematous or inflammatory lesions lasted more than 7 days in the control group. On the 4th day of erythema and vasodilation was significantly reduced in the treatment group by berberine in comparison with the control. These results showed that the local introduction of berberine may reduce the inflammatory reaction induced cathelicidinin vivo.

Example 4: a Clinical trial on humans conducted to assess the effectiveness of local pharmaceutical compositions of the present invention in patients with rosacea

the method : A clinical trial with an open label conducted to assess the effectiveness of local compositions of berberine according to the present invention for the treatment of rosacea and related skin disorders. Patients included in this trial were diagnosed by dermatologists as having clinically definite manifestation of rosacea. All patients were given 0.1% of barbarisovyj gel twice a day for 6 weeks. At certain time points after the start of treatment and after 2 weeks and 6 weeks after completion of treatment, patients were examined for signs and symptoms of rosacea. Patients were not allowed to use other drugs, including antibiotics used in such skin disorders. Were permitted only oral antihistamines to relieve symptoms of itching.

To assess the effectiveness of treatment was used a standard ranking system symptoms of rosacea, developed by the National Expert Committee on the study of rosacea (National Rosacea Society Expert Committee on the Classification and Staging of Rosacea)3. Additionally, we used parameters such as the overall score researcher (IGA) and a General assessment of the severity of erythema in patients on a scoring system in the following time points: 0 weeks, 2 weeks and 6 weeks, during Barberino therapy. Figure IGA expressed on a 7-point system by shriramana of scores from 0 (clear skin) to 6 (severe condition). The weight of the total erythema of the face and telangiectasia, respectively, ranged from the use of such terms as "none", "weak", "moderate" or "severe", which corresponded to scores from 0 to 3. The ranking system used to assess the severity of the overall erythema of the skin, has been described previously38.

Results: this study included 20 patients with rosacea (18 women and 2 men). The average age in the study population were as follows : 43.3 (19-85) years. The average duration of rosacea before treatment with berberine was 4 (1-24) years. Among 20 patients with rosacea there were 13 cases erythematotelangiectatic type (65%), 7 cases papulopustular type (35%) and 5 cases (25%) timatanga type.

According to the 7-digit system ranking IGA score assessment rosacea at a basic level (start of treatment) was 4.1±1,3. The specified parameter is decreased to 2.6±0,9 2 week and then reached a value of 1.6±0.8 to 6 week. Differences in scores IGA between week 0, week 2 and week 6 were statistically significant (W2 W0 against: paired t-testP<0,0001; W6 W0 against: paired t-testP<0,0001). At the beginning of treatment, the severity of the condition of most patients (95%) were estimated from "weak" to "moderate" (3) to "severe" (6). By the end of treatment, 19 of 20 patients (95%) was characterized by an index of severity from "weak" (2) to the standing of "clean skin" (0).

The overall severity of erythema, evaluated by the researcher, was 2,35±0.6 at the beginning of the study, 1,5±0,5 2 week and 0.95±0.4 6 week. Improvement in week 2 or week 3 was statistically significant (W2 W0 against: paired t-testP<0,0001; W6 W0 against: paired t-testP<0,0001). In the beginning of treatment, the severity of erythema in most patients (95%) ranged from "moderate" (2) to "severe" (3). By the end of treatment, 19 of 20 patients (95%) was characterized by erythema in degree from "weak" (1) to its "no" (0).

Safety and tolerability: not observed serious side effects during the test. Only in 2 cases (10%) was noted tingling in the field of local application of the drug, but all of them passed without interrupting the test.

Example 5: the Local composition of berberine was effective for the treatment of steroid-induced rosacea-like dermatitis and acneform dermatitis induced by EGFR inhibitors

The authors investigated the gel containing 0.1% berberine, in the mode of its introduction twice a day for 6 weeks, 10 patients with rosacea-like dermatitis, steroid induced, and 5 patients with acneform dermatitis induced by the EGFR inhibitor. All 15 patients showed improvement of symptoms and was well tolerated by local treatment, as b is lo can be seen on the signs of rosacea.

Example 6: Palmatin demonstrated efficacy in the treatment of rosacea or disorders associated with reddening face

The authors also investigated the local composition comprising palmatin at a concentration of 0.02 wt.%, in 10 patients with rosacea and related disorders associated with redness of the face. All 10 patients showed improvement in symptoms and was well tolerated by local treatment, as noted in the situation of berberine.

Conclusions the results described examples:

Studies using culturein vitroshowed that berberine has anti-inflammatory effect through inhibition induced cathelicidin production of IL-8, IL-1 alpha and VEGF in human keratinocytes. Because inflammation is involved in the pathogenesis of rosacea and related disorders of the skin, anti-inflammatory effect of berberine may be responsible for clinically significant beneficial effects in rosacea and related inflammatory skin disorders.

The results of the authors of the clinical trials showed that local pharmaceutical compositions of the present invention, containing the purified berberine at concentrations of more than 0.1% or palmatin in a concentration of more than 0.02%, can be an effective, safe and well tolerated n is the patients in the treatment of rosacea and related disorders associated with redness of the skin, such as acne, contact dermatitis, seborrheic dermatitis and photodermatitis, rosacea-like dermatitis induced by steroids, and acneform dermatitis induced by EGFR inhibitors.

BRIEF DESCRIPTION of DRAWINGS

Fig. 1. Berberine inhibited induced cathelicidin peptide (LL-37) the release of IL-8, IL-1 alpha and VEGF from human keratinocytes. Keratinocytes stimulated cathelicidin peptide (LL-37) and the release of IL-8 (Fig. 1A), IL-1 alpha (Fig. 1B) and VEGF (Fig. 1C) by keratinocytes was investigated by the method of IFTTA.

Fig. 2. A. Overall assessment by the researcher conducted at the beginning of treatment with berberine and in week 2 and week 6 of treatment, in accordance with the ranking system. B. a composite score of severity of erythema at the beginning of treatment by local drug berberine and at 2 week and 6 week after the start of treatment.

The LIST of references

1. Local pharmaceutical composition for treating rosacea, containing at least 0.02% berberine or biologically equivalent analogue, berberine, such as palmatine, and a component selected from the group consisting of water, methanol, ethanol and dimethyl sulfoxide, where berberine or biologically equivalent analogue Berber is on is a basic pharmaceutically active component.

2. Local pharmaceutical composition under item 1, characterized in that the concentration of berberine or a biologically equivalent analog berberine is from about 0.05 wt.% to about 2 wt.%.

3. A method for the treatment of rosacea, including local application on the affected skin a therapeutically effective amount of a pharmaceutical composition containing at least 0.02 wt.% berberine or its biologically equivalent analogue, such as palmatine, and a component selected from the group consisting of water, methanol, ethanol and dimethyl sulfoxide, where berberine or biologically equivalent analogue of berberine is a basic pharmaceutically active component.

4. The method according to p. 3, characterized in that the pharmaceutical composition contains from about 0.05 wt.% to about 2 wt.% berberine or biologically equivalent analogue of berberine.



 

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SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: invention relates to molecular pharmacology and particularly to a peptide which is an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound. The invention shows that when bound with an alpha subunit of the receptor (IL-15Rα) the peptide inhibits T cell proliferation induced by IL-15, tumour necrosis factor α (TNFα) induction caused by IL-15, and expression of IL-8 and IL-6 caused by IL-15Rα. The invention also relates to use of the peptide in treating pathologies where anomalous expression of IL-15 or IL-15Rα is associated with the course of a disease such as rheumatoid arthritis (AR) and prostate cancer.

EFFECT: obtaining an interleukin-15 (IL-15) sequence derivative which is optimised for inhibiting biological activity of said compound.

18 cl, 6 dwg, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method relates to medicine, particularly to dermatology, and may be used in treating localised forms of psoriasis. That is ensured by administering 1% glutoxim 0.1 ml along the perimetre of a psoriasis patch at 1.0-1.5 cm once a day for 7-12 procedures.

EFFECT: effective treatment ensured by no side effects, and reduced length of treatment.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely - to dermatology. A method involves the ointment application and the ultrasound exposure. The ointment is methylprednisolone aceponate. The ultrasound exposure has an intensity of 0.7-1.0 Wt/cm2. The exposure length is 2-5 minutes per one field. The duration of a procedure is 12 minutes. The therapeutic course is 7 procedures.

EFFECT: method reduces the side effects and complications provides achieving the immediate clinical effect and prolongs the remission length.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to a method of treating psoriasis by introducing an antibody or an antigen-binding determinant thereof able to bind to the IL-12 and/or IL-23 subunit p40 in a dose of approximately 0.1 5.0 mg/kg under therapeutic regimen into an individual. The antibody or antigen-binding determinant thereof can be introduced once every two weeks, once a week or once in various doses depending on the patient's state. The method is applicable for treating chronic psoriasis. The therapeutic course is cyclic; each cycle makes at least 12 weeks, i.e. the first long-term cycle which involves introducing the antibody; then the introduction of the antibody or determinant thereof is terminated for at least 12 weeks that is followed by another long-term cycle of at least 12 weeks that involves introducing the antibody or fragment thereof. A dose of the antibody or determinant thereof to be introduced makes approximately 100 mg to 200 mg. The treatment is controlled by a psoriasis area and severity index (PASI).

EFFECT: using the method enables higher clinical effectiveness in chronic psoriasis.

40 cl, 35 dwg, 12 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically dermatology, and may be used for treating the patients with psoriatic erythroderma. For this purpose, detoxification hormone therapy combined with external ointment therapy is preceded by prescribing Galavit in a therapeutic dose of 100 mg intramuscularly every day within the course of 10 procedures.

EFFECT: method provides higher clinical effectiveness ensured by a shorter length of therapy, no side effects and prolonged remission.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to dermatology, and can be used for treating such diseases, as rosacea, psoriasis, topic dermatitis or acne. That is ensured by a local application on an individual's skin area of a topical composition, which can be an ingredient of a kit and contains a therapeutically effective amount of an α2-adrenergic receptor agonist, wherein the α2-adrenergic receptor agonist is specified in a group consisting of: a compound of formula (Ia) wherein each of R1, R2 and R3 independently means hydrogen, halogen, (C1-C8)alkyl or alkoxy; each of R4 and R5 independently means hydrogen, (C1-C8)alkyl or alkoxy; each of R6 and R7 independently means hydrogen, nitro, (C1-C8)alkyl or alkoxy; alkoxy is specified in methoxy, ethoxy, n-propoxy, sec-butoxy, tret-butoxy, n-hexyloxy; and a therapeutically effective amount of the non-steroid anti-inflammatory agent diclofenac and a pharmaceutically acceptable carrier, wherein the skin area is subject to or can be injured by an inflammatory skin disease or a symptom related to the above disease. The α2-adrenergic receptor agonist can be presented by, e.g. brimonidine.

EFFECT: ensuring the synergetic effect when using the declared combination which shows the synergetic effect by improving the anti-inflammatory action of diclofenac that leads to the complete relief of any symptoms of the inflammatory disease.

21 cl, 3 ex, 6 tbl, 2 dwg

FIELD: medicine.

SUBSTANCE: topical cosmetic composition effective for stimulating each of SIRT1, Gadd45b and SOD2, which contains a senna alata leaves extract, a great morinda leaves extract and a melon flesh extract taken in certain proportions. A method for the protection against or recovery of an oxidative injury involving administering the topical composition containing the senna alata leaves extract, the great morinda leaves extract and the melon flesh extract taken in certain proportions. The topical cosmetic or dermatological composition for stimulating each of SIRT1, Gadd45b and SOD2. Using the above composition for producing a drug preparation for treating the oxidative injury.

EFFECT: composition is effective for stimulating each of SIRT1, Gadd45b and SOD2.

8 cl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a polymer conjugate of an indolocarbazole compound of formula (I), where R1, R2, R3, W1 and W2 represent hydrogen, X represents methoxy-polyethyleneglycol. The method includes the interaction of a polymer compound of formula (II) with an indolocarbazole compound of formula (III), where Y stands for a methoxygroup. The nvention also relates to a polymer conjugate of formula (I), a pharmaceutical composition, containing the conjugate of formula (I) as an active ingredient, and to the application of the polymer conjugate of formula (I).

EFFECT: obtaining the polymer conjugate of the formula with a high output, the polymer conjugate of the formula for treatment of skin pathologies and HMGB1-associated pathologies.

48 cl, 7 dwg, 7 tbl, 15 ex

FIELD: pharmacology.

SUBSTANCE: method involves preparing a liquid composition containing a pharmaceutical active ingredient, a mixture of solvents containing water, isopropanol in an amount of 5 wt % to 20 wt % and propylene glycol in an amount of 2 wt % to 25 wt %, and a phospholipid foaming agent in an amount of 2 wt % to 25 wt %, foaming the liquid composition mechanically with no propellant used, and measuring the foam volume and stability. That is followed by transforming the nature and/or changing the concentration of the pharmaceutically active ingredient and/or the phospholipid foaming agent and/or changing the concentration of one of the solvents to produce 250 ml of the liquid composition. The above liquid composition is expected to produce foam in the volume of 400 ml and with the stability so that 50% of an initial foam volume is observed so far after the 10-minute hold-up and measured by the standard SITA procedure. The invention also relates to a composition applicable for topical use and prepared by the method described above.

EFFECT: preparing the composition presented by the stable foam.

22 cl, 18 dwg, 1 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I: cis-COOR-XCH-(CH2)a-CH=CH-(CH2)b-CH3, wherein (a) and (b) can take any value from 0 to 14, (X) is specified in: OH, NH2, CH3, F, F3C, HS, O-CH3, PO4(CH2-CH3)2 and CH3COO, and (R) represents sodium (Na) applicable for preventing and/or treating obesity, hypertension and/or cancer. Also, the invention refers to using the compounds of formula I for preparing a pharmaceutical and/or nutrient composition, to the pharmaceutical and/or nutrient composition based on the compounds of formula I, to a cosmetic, non-therapeutic method for improving skin manifestations and to a method for preventing and/or treating the diseases in humans and animals with using the compounds of formula I.

EFFECT: preparing the new compounds.

18 cl, 22 dwg, 5 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a group of inventions containing a combination of the avermectine compound specified in ivermectine, invermectine, avermectine, abamectine, doramectine, eprinomectine and selamectine, aversectine B, AB or C, emamectine B1a, emamectine B1b and their derivatives, or latidectine, and the alpha-2 adrenergic receptors agonist compound specified in apraclonidine, brimonidine, clonidine, dexmedetomidine, guanabenze acetate, lidamidine, lofexidine, methyldopa, rilmenidine, talipexole, tiamenidine, tizanidine, tolonidine or salts thereof, to be used as a therapeutic agent in treating and/or preventing rosacea, including eye rosacea, using the above combination for preparing the therapeutic agent applicable for treating and/or preventing rosacea, a product in the form of a kit and a pharmaceutical composition of the same formulation and application both, using the above product for preparing the therapeutic agent for treating and/or preventing rosacea.

EFFECT: what is shown is the synergetic effect of the combination in treating rosacea and eliminating the withdrawal effect usually observed at the end of treatment with alpha-2 adrenergic receptor agonists.

20 cl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a water-soluble complex of β-cyclodextrine-histochrome initiation with a molar ratio of the said components from 1:1 to 3:1. To obtain an initiation complex at the first stage performed are: mixing of dry β-cyclodextrine with bidistilled water (DDH2O), shaking the solution at a temperature of 55-65°C until total dissolution, after which cooling of the solution to 37-45°C is realised, at the second stage a 1% solution of histochrome in a volume, necessary for obtaining the necessary concentration is added to the obtained solution, after which the solution is subjected to shaking at 25-45°C for 1.5-2 hours.

EFFECT: prolonged antioxidant action.

2 cl, 4 dwg, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, namely to an extract of Nerium oleander in aloe. A method of obtaining the extract of Nerium oleander in aloe includes mixing vegetable material, which contains leaves and stems of the Nerium oleander plant, with vegetable mucus of aloe with obtaining an extraction mixture, conditioning the said extraction mixture with obtaining the extract of Nerium oleander in aloe. The composition of cardiac glycosides and aloe for treatment of a pathological state of skin, selected from sun-damaged skin, ageing skin, acne, age spots, liver spots, sunburn and herpes. A pharmaceutical composition for treatment of the pathological state of skin. A method of treating the pathological state of skin. A method of the cosmetic composition application.

EFFECT: described above extract and based on it preparations are efficient.

14 cl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically dermatology, and can be used for treating patients with pemphigus vulgaris. That is ensured by prescribing prednisolone in a dose of 1 mg/kg/day for 7 days. On the 7th day, Metoject is administered subcutaneously in a dose of 7.5 mg once a day for 3-4 weeks. On the following day of the above administration, the dose of prednisolone is reduced by 1/3, after the following injections, the dose of prednisolone is reduced by 5-10 mg after each following injection.

EFFECT: invention enables providing higher clinical effectiveness in the patients with pemphigus vulgaris with a lower risk of complications.

2 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to therapy, and can be used for treatment of scleroderma. For this purpose, a therapeutically efficient quantity of type I interferon (IFN) antagonist, where the said antagonist is represented by an antibody, is introduced to a patient in need. The group of inventions also relates to a method of reducing intensity of one or more symptoms, associated with scleroderma.

EFFECT: application of type I interferon antagonist, namely the antibody, makes it possible to suppress transmission of IFN signal with the participation of άIFN receptor, which substantially reduces the probability of development and severity of inflammatory disease of skin and contributes to skin recovery.

20 cl, 8 ex, 9 dwg

FIELD: medicine.

SUBSTANCE: invention represents eye drops containing a pharmaceutically acceptable additive acid salt and methylethylpyridinole, taurine and a composition of group B vitamins.

EFFECT: creating the combined preparation for treating traumatic and dystrophic eye injuries causing no irritant action and possessing improved pharmacological properties.

5 cl, 6 ex, 2 tbl

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