Using alpha 2 adrenergic receptor agonists for treating or preventing psoriasis

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a method of treating psoriasis or a related symptoms, in an individual, involving the local administration of a local composition containing a therapeutic effective amount of an α2 adrenergic receptor agonist and a pharmaceutically acceptable carrier on an individual's skin area, wherein the skin area is subject to psoriasis or the related symptom, or prone thereto, and wherein the α2 adrenergic receptor agonist is brimonidine.

EFFECT: invention provides developing the effective and safe method for treating or preventing psoriasis with no side effects or small side effects.

10 cl, 1 tbl, 2 ex

 

The level of technology

Psoriasis is a common, chronically recurring state characterized by a rash of well-defined, isolated and confluent, reddish, silvery-scaly macular papules that appear mainly on the elbows, knees, scalp scalp and torso. The skin is growing rapidly and is accumulated in the form of psoriatic plaques, i.e., red scaly spots. Psoriasis varies in severity from minor localized patches to complete coverage of the body. Common forms of the disease include, for example, psoriasis vulgaris, guttate psoriasis, psoriasis skin folds, erythrodermic psoriasis, General pustular psoriasis and local pustular psoriasis. The cause of psoriasis is unknown, but it is believed that it is internal. It can burden ourselves with many factors, such as stress, discontinuation of systemic corticosteroids, excessive alcohol consumption and Smoking.

To treat psoriasis is difficult. Currently available treatment of psoriasis has limited effectiveness for many patients and, as a rule, can only be used for a limited time. For example, local treatment with tar, dithranol (intraline), corticosteroids like desoximetasone (Topicort), fluocin what nidom, vitamin D analogues (for example, calcipotriol), retinoids, argan oil, and the like, often irritate normal skin, can not be used for extended periods of time and can cause aggressive recurrence of the condition when the treatment is terminated. Phototherapy, such as daily, short-term, not causing burns exposure to sunlight or ultraviolet B (UVB) (315-280 nm), helps to get rid of psoriasis or to improve the condition in some, but not all patients. Photochemotherapy, that is, concomitant therapy with psoralen and phototherapy with ultraviolet A (PUVA), is also used for the treatment of psoriasis. However, PUVA is associated with nausea, headache, fatigue, burning, itching. Long-term treatment with PUVA is associated with carcinoma samawah cells. Psoriasis can also be treated with systemic treatment, for example by injection or oral administration of drugs, such as methotrexate, cyclosporine and retinoids. However, these drugs are known to have toxic side effects and, thus, cannot be used too often. Patients with systemic treatment should undergo regular research functions of the liver and blood, and pregnancy should be excluded for great is nsta these treatments. Most people experiencing a relapse of psoriasis after termination of the treatment system. Biological drugs, such as Amevive®, Enbrel®, Humira® and Remicade®, Raptiva®, are a relatively new therapy tools that focus on specific aspects of immune function, leading to psoriasis. However, long-term biological effects of drugs on immune function is unknown. Raptiva® was withdrawn by the manufacturer from the U.S. market in April 2009. They are very expensive and only suitable for a very small number of patients with severe psoriasis.

Agonists of α2 adrenergic receptors used therapeutically for a number of conditions including hypertension, congestive heart failure, angina, muscle spasticity, glaucoma, diarrhea, and to suppress the symptoms of the discontinuation of opiates (J. P. Heible and R. R. Ruffolo Therapeutic Applications of Agents Interacting with α-Adrenoreceptors, p. 180-206 inProgress in basic and Clinical PharmacologyVol. 8, P. Lomax and E. S. Vesell Ed., Karger, 1991). Agonists adrenergic receptors such as clonidine, are used primarily oral, although known and the preparation is in the form of a patch.

Published patent application US US20050276830 describes the agonists of α2 adrenergic receptors and their use for the treatment or prevention of inflammatory disorders of the skin.

There is still a need for new effective the active and safe methods and compositions for the treatment or prevention of psoriasis and related symptoms. Such methods and compositions described in this application.

The invention

It was found that the agonist of α2 adrenergic receptors is effective in the treatment or prevention of psoriasis without side effects, or minor side effects.

In one General aspect, embodiments of the present invention relate to a method of treating or preventing psoriasis or a symptom associated therewith, the subject. The method includes the local introduction to an area of skin of the subject compositions for local administration, containing a therapeutically effective amount of α2 agonists adrenergic receptor and a pharmaceutically acceptable carrier, where the area of skin exposed to the effects of psoriasis or a symptom associated with it, or prone to it.

In another General aspect, embodiments of the present invention relate to a kit for treating or preventing psoriasis or symptoms associated with it.

Set contains:

(1) the composition of the input local image containing a therapeutically effective amount of α2 agonists adrenergic receptor and a pharmaceutically acceptable carrier; and

(2) instructions for the local introduction of the composition introduced local way to an area of skin of a subject for the treatment or prevention of psoriasis or the sympto is s, associated with it, where the area of skin exposed to the effects of psoriasis or a symptom associated with it, or prone to it.

In a preferred embodiment, the agonist of α2 adrenergic receptors used in the variants of implementation of the present invention is brimonidine.

Other aspects, features and advantages of the present invention will become apparent from the following further description, including a detailed description of the present invention and its preferred embodiments and the accompanying claims.

Detailed description of the invention

Various publications, articles and patents cited or described in the description of the current level of technology in the present description, each of these references is incorporated herein by reference in its entirety. Discussion of documents, acts, materials, devices, products or anything like that, which is included in the present description, is intended to provide context for the present invention. Such a discussion is not an admission that any of these descriptions or they are all part of modern technology in relation to any of the described or claimed inventions.

If not defined otherwise, all technical and scientific terms used herein, and out the same value as commonly understood by a specialist in the field that applies the present invention. Otherwise, certain terms used herein have the meanings as given in the description. All patents, published patent applications and publications cited herein are incorporated as reference, as if fully cited herein. It should be noted that as used herein and in the appended claims, the singular number shall include references to the plural, unless the context clearly dictates otherwise.

As used herein, "psoriasis or symptoms associated with it, as it is assumed that encompasses any type or classification of psoriasis and any symptom associated with it. For example, the term "psoriasis or a symptom associated therewith" includes plaque-like psoriasis, pustular psoriasis, guttate psoriasis (small spots like drops) and psoriasis in skin folds, nail psoriasis, psoriatic arthritis and erythrodermic psoriasis, and related symptoms. This term also includes pustulezny psoriasis, such as ordinary psoriasis (chronic stationary psoriasis, plaque-like psoriasis), psoriatic erythroderma (erythrodermic psoriasis and pustular psoriasis, such as total p shall stoletny psoriasis (pustular psoriasis von Cumbuka) (fluid-filled yellowish small bubbles), pustular psoriasis of the palms and soles (palmoplantar pustules (acting primarily on the palms and soles), pustular psoriasis type Barbera, pustular psoriasis of the extremities), annular pustular psoriasis, persistent acrodermatitis and impetigo herpetiformis, and related symptoms. The term also covers drug psoriasis, inverse psoriasis (in the folds, such podpiska, navel, and buttocks), diaper psoriasis and seborrheic psoriasis, and related symptoms.

The degree or severity of psoriasis can vary. The degree of severity, as a rule, is based on the proportion of the surface area of the body that is exposed to the disease activity (the degree of redness, thickness and exfoliate plaques), response to previous therapy and the impact of the disease on the individual.

The term "psoriasis or a symptom associated" encompasses mild (affecting less than 3% of the area of the body), moderate (affecting 3-10% of the area of the body) or severe (more than 10% of the area of the body) psoriasis and its symptoms.

Psoriasis usually looks like red or pink areas of thickened, serving and dry skin. In the classic version it affects the areas above the elbows, knees and on the hairy scalp. Essentially any area of the body can b the th involved. There is a trend toward a greater prevalence in the areas of trauma, repetitive friction, use, or abrasion. Psoriasis can have a varied appearance. It can be a small flattened bumps, large thick plaques protruding skin, red spots and pink slightly dry skin to big flakes of dry skin that is flaking off. Sometimes snagging one of these little dry white flakes of skin causes a small bloody spots on the skin. This is referred to in medicine as a specific diagnostic sign ofpsoriasis, called a sign of Auspice.

Common are genital damage, in particular, at the head of the penis. Psoriasis on moist areas, like the navel or the area between the buttocks (miyakodani folds), may look like a flat red spots. This unusual appearance can be confused with other skin conditions like fungal infections, yeast infections, skin irritation or bacterial infections of the Stuff.

On the nail it may look like very small pits (indentations as from the pin pricks or white spots on the nail) or as a separate yellowish-brown patches on the nail bed of the big sizes, called "oil spots". Nail psoriasis may be confused with a fungal infection n is GTA and mistakenly be diagnosed as such.

On a hairy part of the scalp it may look like a strong dandruff with dry scales and red patches of skin.

From the point of view of the present description, the area of skin affected by psoriasis or inclined to be affected by psoriasis may be identified using any of the diagnostic signs or means known in this field, and can be treated using the methods in accordance with the variants of implementation of the present invention.

As used herein, "agonist at α2-adrenergic receptors or agonist of α2 adrenergic receptors" means a compound which binds to the subclass α2 alpha adrenergic receptors selectively stimulates them. Such compounds can have a strong vasoconstrictor effects when injected into mammals, in particular humans.

As used herein, the term "alkyl" means saturated, monovalent, unbranched or branched hydrocarbon chain. Examples of alkyl groups include, but are not limited to, (C1-C3) alkyl groups such as methyl, ethyl, propyl, isopropyl, and (C4-C8) alkyl groups such as 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-what until, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like. The alkyl group can be unsubstituted or substituted by one or more appropriate substituents.

As used herein, the term "alkoxy" means oxygen radical simpleOlkiluoto ether. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, n-hexyloxy and the like. The alkoxy group can be unsubstituted or substituted by one or more appropriate substituents.

When a particular group is "substituted" (e.g., alkyl, alkoxy), this group may have one or more substituents, preferably from one to five substituents, more preferably one to three substituents, most preferably from one to two substituents independently selected from the above substituents.

At the mention of the substituents, the term "independently" means that when there are a number of such substituents, such substituents may be the same or different.

As used herein, the term halogen means fluorine, chlorine, bromine or iodine. Accordingly, the term "halogen" means the group of fluorine, chlorine, bromine and iodine.

As used herein, a connection name, as expected, covers all possible existing isomeric forms (e.g., optical isomer, enantiomer, diastereoisomer, racemate or racemic mixture), esters, prodrugs, metabolic forms or pharmaceutically acceptable salts of the compounds. For example, "brimonidine" can be a compound (5-bromo-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)amine, and any pharmaceutically acceptable salt of the compound, such as brimonidine tartrate.

The phrase "pharmaceutically acceptable salt (salt)", as used herein, means those salts of the considered compounds that are safe and effective when topically applied to mammalian and that have the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in these compounds. Pharmaceutically acceptable acid additive salts include, but are not limited to, cleaners containing hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, hydrophosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantat the room, bitartrate, ascorbate, succinate, maleate, gentianaceae, fumaric, gluconate, glucuronate, sahabatnya, formiate, benzoate, glutamate, methanesulfonate, econsultancy, benzosulfimide, p-toluensulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout) salt. Certain compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids. The corresponding basic salts include, but are not limited to, salts of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine. On review pharmaceutically acceptable salts see BERGE ET AL., 66J. PHARM. SCI.1-19 (1977), incorporated in this document by reference.

The term "hydrate" means the considered compound or its pharmaceutically acceptable salt, which further comprises a stoichiometric or non-stoichiometric amount of water associated with non-covalent intermolecular forces.

The term "composition, local input," "trackfor local introduction or preparation for local injection" as used herein means any substance or composition that is pharmaceutically and/or cosmetically acceptable for local delivery of these compounds ACC is accordance with the variants of implementation of the present invention. Illustrative forms of the drug that can be used for local injection in the variants of implementation of the present invention include, but are not limited to, sprays, misty, aerosols, solutions, lotions, gels, creams, ointment, paste, ointments, emulsions and suspensions. Song select, input local image will depend on several factors, including the nature of the symptoms that must be treated or prevented, the physico-chemical characteristics of a particular connection, which must be entered, and others attending the fillers, their stability, in preparation, available production equipment and limitations on costs.

The term "composition", as expected, covers the product containing the specified ingredients in the specified amounts, as well as any product which arises, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term "carbomer" according to USP (USP) is the designation for various polymeric acids, which are dispersible but not soluble in water. When the dispersion of the acid is neutralized with base, formed stable transparent gel. Carbomer 934P is physiologically inert and is not a primary irritant or sensitizer. Other carbomer include 910, 940, 941 and 1342.

T is pmin "subject" means any animal, preferably, a mammal, most preferably human, which will be introduced or injected compounds or agents for local injection in accordance with the variants of implementation of the present invention. The term "mammal" as used herein covers any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, Guinea pigs, monkeys, humans, and the like, more preferably, humans. Preferably, the subject needs observation or experiment, treatment or prevention of psoriasis and the symptoms associated with it, or is their object.

The term "instruction", when used in the context set, includes a publication, a recording, a diagram, or any other medium for storing information that can be used to communicate the usefulness of the collection for the use for which it is intended. The instructions may, for example, be affixed to the container for a set or contained in it.

In one of the embodiments, "treatment" or "cure" refers to the alleviation, prevention or treatment course of disease or disorder or at least one discernible symptom, for example, for treatment of psoriasis by reducing redness and/or scales is atih spots on the skin. In another embodiment, "treatment" or "cure" refers to the alleviation, prevention, or treatment of stroke at least one measurable physical parameter related to the disease or disorder that is treated, not necessarily distinct from a mammal or to themselves. In another embodiment, "treatment" or "cure" refers to inhibition or slowing of a disease or disorder, either physically, e.g., to stabilize discernible symptom, or physiologically, e.g., stabilization of a physical parameter, or both ways together. In another embodiment, "treatment" or "cure" refers to the slow onset of the disease or disorder.

In certain embodiments of the implementation of the considered compounds are introduced as a preventive measure. As used herein, "prevention" or "preventing" refers to the reduction in the risk of the disease or disorder. In a preferred mode of implementation, the following compounds are introduced as a preventative measure to a subject having a predisposition to psoriasis, internal disease, even if the symptoms of psoriasis do not exist or are minimal.

As used herein, "therapeutically effective the number of α2 agonists adrenergic receptors" means the number of agonists of α2 adrenergic receptors, which causes the biological or medical response system tissue from an animal or human, according to the judgment of the researcher, veterinarian, medical doctor or other Clinician, which includes alleviation of the symptoms of the disease or disorder is treated. In a preferred embodiment, a therapeutically effective amount of α2 agonists adrenergic receptors is effective in the treatment, better treatment or prophylactic prevention of psoriasis or symptoms associated with it.

In one General aspect, the present invention relates to a method of treating or preventing psoriasis or a symptom associated therewith, the subject. The method includes the local introduction to an area of skin of a subject a composition containing a therapeutically effective amount of α2 agonists adrenergic receptor and a pharmaceutically acceptable carrier, where the area of skin exposed to the effects of psoriasis or a symptom associated with it, or inclined to it, in the treatment or prevention.

In one of the embodiments of the present invention, agonists of α2 adrenergic receptors include, but are not limited to, agonists of α2 adrenergic receptors, are described in published patent application U.S. US20050276830, which is incorporated herein by reference in saee fullness.

In one of the embodiments of the present invention, the agonist of α2 adrenergic receptors is a compound of formula (I):

where each of R1, R2and R3independently represents hydrogen, halogen, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy; each of R4and R5independently represents hydrogen, alkyl, preferably unsubstituted alkyl or alkoxy, preferably unsubstituted alkoxy; and each of R6and R7independently represents hydrogen, nitro, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy.

In the preferred embodiment, as R6and R7are hydrogen in formula (I).

In another preferred embodiment, as R4and R5are hydrogen in formula (I).

In one of the embodiments of the present invention, the agonist of α2 adrenergic receptors is a compound of formula (Ia):

where each of R1, R2and R3independently represents hydrogen, halogen, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted ALCO is si; each of R4and R5independently represents hydrogen, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy; and each of R6and R7independently represents hydrogen, nitro, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy.

In the preferred embodiment, as R6and R7are hydrogen in formula (Ia).

In another preferred embodiment, as R4and R5are hydrogen in formula (Ia).

In another preferred embodiment, as R2and R3represent hydrogen, and R1is a group of halogen, preferably a bromine group, in the formula (Ia).

In one of the embodiments of the present invention, the agonist of α2 adrenergic receptors is a compound of formula (Ib):

where each of R1, R2and R3independently represents hydrogen, halogen, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy.

In the preferred embodiment, as R2and R3represent hydrogen, and R1is a group of halogen, before occhialino, the group of bromine, in the formula (Ib).

In one of the embodiments of the present invention, the agonist of α2 adrenergic receptors is a compound of formula (Ic):

where R1represents hydrogen, halogen, alkyl, preferably unsubstituted alkyl or alkoxy, preferably unsubstituted alkoxy.

In a preferred embodiment, R1is a group of halogen, more preferably, a bromine group; and each of R4and R5independently represents hydrogen, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably, unsubstituted alkoxy, in formula (Ic).

In a preferred embodiment, at least one of R4and R5represents a hydrogen in the formula (Ic).

In one of the embodiments of the present invention, the agonist of α2 adrenergic receptors is a compound of formula (Id):

where R1represents hydrogen, halogen, alkyl, preferably unsubstituted alkyl, or alkoxy, preferably unsubstituted alkoxy.

In a preferred embodiment, R1is a group of halogen, more preferably, a bromine group, in the formula (Id).

In another embodiment, n is standing of the invention, agonist at α2-adrenergic receptors is a compound of formula (II):

where each of A1, A3and A4independently represents hydrogen or alkyl; and A2independently represents hydrogen or hydroxy.

In another embodiment of the present invention, the agonist of α2 adrenergic receptors is a compound of formula (III):

where each of B1B2and B3independently represents hydrogen, hydroxy or alkoxy, preferably methoxy; and each of B4and B5independently represents hydrogen or alkyl.

Representative agonists of α2 adrenergic receptors, which can be used in the present invention include, but are not limited to, compounds listed in Table 1.

Table 1
Representative agonists of α2 adrenergic receptors
The formula of the compoundThe connection name
(5-Bromo-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine (Brimonidine)
(8-Bromo-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine

(8-Bromo-cinoxacin-5-yl)-(4,5-dihydro-1H-imidazol-2-yl)Amin
(5-Bromo-3-methyl-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)Amin
(5-Bromo-2-methoxy-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)Amin
(4,5-dihydro-1H-imidazol-2-yl)-(8-methyl-cinoxacin-6-yl)-amine
(4,5-dihydro-1H-imidazol-2-yl)-cinoxacin-5-yl-amine
Tetrahydrozoline
The nafazolina

Oxymetazoline
Xylometazoline
Epinephrine
Norepinephrine
Phenylephrine
Methoxyamine

The most preferred agonist of α2 adrenergic receptors is brimonidine, (5-bromo-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine and its pharmaceutically acceptable salts such as tartrate salt.

In a preferred embodiment, the method according to the present invention includes a local introduction on the skin of the subject composition containing a pharmaceutically acceptable carrier and a therapeutically effective amount of brimonidine.

The person skilled in the art will recognize that a therapeutically effective amount of α2 agonists adrenergic receptors, which should be used in this invention may vary with various factors such as a specific subject, such as age, diet, health status, and the like, severity, and complications, and the types of psoriasis, which are supposed to be treated or prevented, used the drug, and the like.

T is his view of the present description, can be standard procedures for assessing the impact of the introduction of the composition for local administration subject, allowing, thus, to determine a therapeutically effective amount of α2 agonists adrenergic receptors. For example, clinicallythe observed beneficial effects introduced by local image of an agonist of α2 adrenergic receptors can be observed or monitored directly on the subject, for example, by measuring the severity index square of psoriasis (PASI) before and after treatment. PASI combines the assessment of the severity of damage and the area affected, as a single score ranging from 0 (no disease) to 72 (maximal degree of the disease).

Clinically observable beneficial effects may be a situation in which, when the composition of the present invention is administered to the subject after you experience symptoms associated with psoriasis, prevents further progression or worsening symptoms, or they develop to a lesser extent than without the introduction of specified composition in accordance with the variants of implementation of the present invention. Clinically observable beneficial effect can also be concluded that, when the composition of the present invention is administered to the subject before they become for the maintain symptoms associated with psoriasis, the symptoms will be prevented, or they subsequently occur to a lesser extent than without the introduction of the compositions of the present invention.

In one of the embodiments, a therapeutically effective amount of α2 agonists adrenergic receptors will reduce the syndrome or a condition of discomfort of the subject associated with psoriasis or a symptom associated with at least about 20%, for example at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100%.

In another embodiment, a therapeutically effective amount of α2 agonists adrenergic receptors will prevent the emergence of a syndrome or a condition of discomfort associated with psoriasis or a symptom associated with him, the subject, or to reduce the probability of occurrence of at least about 20%, for example at least about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100%.

Dosage and frequency of dosing will be determined by a health care worker depending on the activity of the compounds used, the characteristics of a specific product for local administration and the specific type and severity of the dermatological disorders the STS, which is treated or prevented.

In one of the embodiments of the present invention, the composition is introduced by local image, contains 0.01% to 5% of the mass. agonists of α2 adrenergic receptors. For example, the composition may contain 0,01%, 0,05%, 0,1%, 0,2%, 0,3%, 0,4%, 0,5%, 0,6%, 0,7%, 0,8%, 0,9%, 1%, 2%, 3%, 4% or 5%, mass. agonists of α2 adrenergic receptors.

In a preferred embodiment, the composition is introduced by local image contains 0.05 to 0.5%, 0.07 per cent of-0.7%, or 0.1 to 0.6% of the mass. agonists of α2 adrenergic receptors.

For the treatment or prevention of psoriasis or a symptom associated with it, from the point of view of the present description, the composition for local injection of the present invention can be applied to local image directly on the area affected by any conventional method known in this field, for example, in the form of drops or by using a tube of the applicator, in the form of Myst, using an aerosol applicator, using intradermal or transdermal patch or by means of a simple distribution of the drug of the present invention on the area affected, using your fingers. Typically, the amount of the drug for the local introduction of the present invention, applied to the affected skin area is in the range of from about 0.1 g/cm2square the square the skin surface to about 5 g/cm 2preferably from 0.2 g/cm2approximately 0.5 g/cm2the surface area of the skin. As a rule, during the period of treatment recommended from one to four applications per day.

The methods of the present invention can be used in combination with one or more other therapies and medicines psoriasis or symptoms associated with it.

Another medication or treatment may be administered to the subject simultaneously with the introduction of α2 agonists adrenergic receptors, consistently with him and within a certain time interval, so that the active ingredients or agents can act together to treat or prevent psoriasis and symptoms associated with it. For example, another medication or treatment and the agonist of α2 adrenergic receptors can be administered in the same or in separate preparations at the same time or at different points in time.

Any suitable method of administration can be used to deliver additional treatment or drugs including, but not limited to, oral, intra-oral; rectal, parenteral, local, cutaneous, transdermal, subcutaneous, intramuscular, intranasal, sublingual, buccal, an intradural, intraocular, intra is respiratory or nasal inhalation.

In one of the embodiments, the agonist of α2 adrenergic receptors in accordance with the variants of implementation of the present invention is used in conjunction with local treatment with tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort), fluocinonide, analogues of vitamin D (for example, calcipotriol), and retinoids, argan oil, and the like.

In another embodiment, the agonist of α2 adrenergic receptors in accordance with the variants of implementation of the present invention used in combination with phototherapy, such as daily, short-term, does not cause burns, exposure to sunlight, or by ultraviolet light B (UVB) (315-280 nm).

In another embodiment, the agonist of α2 adrenergic receptors in accordance with the variants of implementation of the present invention is used in combination with photochemotherapy, that is, with combined therapy with psoralen and phototherapy using ultraviolet A (PUVA).

In another embodiment, the agonist of α2 adrenergic receptors in accordance with the variants of implementation of the present invention is used in combination with systemic treatment, for example by injection or oral administration of drugs, such as methotrexate, cyclosporine is retinoids (synthetic form of vitamin A).

In another embodiment, the agonist of α2 adrenergic receptors in accordance with the variants of implementation of the present invention is used in combination with a biological agent such as Amevive®, Enbrel®, Humira® and Remicade®.

Another aspect of the present invention relates to a kit for treating or preventing psoriasis or symptoms associated with it. Set contains:

(1) the composition of the input local image containing a therapeutically effective amount of an agonist of α2 adrenergic receptor and a pharmaceutically acceptable carrier; and

(2) instructions for the local introduction of the composition introduced local way to an area of skin of a subject for the treatment or prevention of psoriasis or a symptom associated therewith, where the area of skin exposed to the effects of psoriasis or a symptom associated with it, or inclined to it, in the treatment or prevention.

In one of the embodiments of the present invention, the composition introduced local image contained in a single usable container, such as a pipette, a vessel or a tube with a corresponding small holes, such as a tube with an elongated tip, made from any pharmaceutically acceptable material. The preparations for the local introduction of the present invention can be filled and Packed plastikowy bottle or tube, where they can be squeezed out. Suitable for use in the system of containers and wrappers for packaging drugs for the local introduction of the present invention are commercially available, for example, from Wheaton Plastic Products, 1101 Wheaton Avenue, Millville, N J. 08332.

Preferably, the instructions Packed with the preparations of the present invention, for example, as a sheet of paper with the description or label on the package. The instructions on the label explain how to enter the preparations for the local introduction of the present invention, in sufficient quantity and for a sufficient period of time for treating or preventing psoriasis or symptoms associated with it. Preferably, the label contains instructions on dosage and introduction, composition of the preparation for local administration, clinical pharmacology, resistance to drugs, pharmacokinetics, absorption, bioavailability and contraindications.

The song entered the local way, which can be used in embodiments implementing the present invention contains a pharmaceutically acceptable carrier and a therapeutically effective amount of α2 agonists adrenergic receptors. Carriers suitable for local delivery of these compounds in accordance with the variants of implementation of the present invention can be submitted is ü any media, known in local introduction of pharmaceuticals, including, but not limited to, pharmaceutically acceptable solvents, such as polisport or water; the emulsion or emulsions of the type oil-in-water or type water in oil), such as creams or lotions; micro-emulsions; gels; adjustment; liposomes; powders and aqueous solutions or suspensions. Pharmaceutically acceptable carrier includes necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspendresume agents, lubricants, flavorings, preservatives, dyes and coatings.

The song entered the local way, is prepared by mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of α2 agonists adrenergic receptors in accordance with methods known in this field, for example, with the methods described in standard reference texts, such as REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1577-1591, 1672-1673, 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUG DILEVERY SYSTEMS (1997), both of them are thus included in the present document by reference.

In one variant of implementation, the song entered the local way, is in the form of an emulsion. Emulsions, such as creams and lotions, are the preparations for matnog the introduction, suitable for use in the present invention. Emulsion is a dispersed system containing at least two immiscible phases, one phase dispersed in the other as droplets within, in diameter from 0.1 μm to 100 μm. To improve stability, usually included emulsifiable agent. When the water is the dispersed phase and oil is the disperse medium, the emulsion is the emulsion type water in oil. When the oil is dispersed as droplets in the aqueous phase, in the form of droplets, the emulsion is the emulsion of the type oil-in-water. Emulsions, such as creams and lotions that can be used as carriers for local administration, and their preparation are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 282-291 (Alfonso R. Gennaro ed. 19th ed. 1995), which thereby is incorporated herein by reference.

In another embodiment, the composition is introduced by local image is in the form of a gel, for example, two-phase or gel-phase gel. Gels are semisolid systems consisting of suspensions of small inorganic particles or large organic molecules, permeable to liquid. When the mass of gel contains a grid of small individual inorganic particles, it is classified as a two-phase gel. Single-phase gel consists of organic macrom is of the molecules, uniformly distributed in the liquid so that there are no visible boundaries between dispergirovannykh macromolecules and fluid. Suitable for use in the present invention gels are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1517-1518 (Alfonso R. Gennaro ed. 19th ed. 1995), which thereby is incorporated herein by reference. Suitable for use in the present invention gels are described in U.S. patent No. 6387383 (issued may 14, 2002); U.S. patent No. 6517847 (issued February 11, 2003) and U.S. patent No. 6468989 (issued October 22, 2002), each of these patents thus is incorporated herein by reference.

In one of the embodiments, the composition is introduced by local image contains a water-based gel containing water and a gelling water quantity pharmaceutically acceptable gelling agent selected from the group consisting of carbomer, glycerin polyacrylate and mixtures thereof, and composition for local injection has a physiologically acceptable pH.

Polymeric thickeners (gelling agents), which can be used in compositions in accordance with the variants of implementation of the present invention include agents known to specialists in this field, such as hydrophilic and water-alcohol gelling agents, often used in cosmetic and Pharma is eticheskoi industry. Preferably, the hydrophilic or hydroalcoholic gelling agent includes "CARBOPOL®" (B. F. Goodrich, Cleveland, Ohio), "HYPAN®" (Kingston Technologies, Dayton, N. J.), "NATROSOL®" (Aqualon, Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington, Del.) or "STABILEZE®" (ISP Technologies, Wayne, N. J.). Preferably, the gelling agent is in the range between about 0.2 per cent - about4% of the massof the composition. More specifically, the preferred mass range of interest for "CARBOPOL®" is in the range between about 0.5% and about 2%, while the preferred mass range of interest for "NATROLSOL®" and "KLUCEL®" is in the range between about 0.5% and about 4%. The preferred range of mass percent composition for "HYPAN®" and "STABILEZE®" is in the range between 0.5% and approximately 4%.

"CARBOPOL®" is one of many transverse cross-linked polymers of acrylic acid, which has received the common name carbomer. These polymers dissolve in water and form a clear or slightly turbid gel by neutralizing with caustic material such as sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases. "KLUCEL®" is a cellulose polymer, which is dispersed in water to form a homogeneous gel at full hydration. Other preferred gelling polymers include hydroxyethyl cellulose, cellulose is maul, crosspolymer MVE/MA decadiene copolymer (PVM/MA or a combination thereof.

In another preferred embodiment, the composition is introduced by local way, is in the form of grinding. The adjustment represents an oily semi-solid foods that contain little water, if any contain. Preferably, the basis for the adjustment is a hydrocarbon, such as wax, vaseline, or gel-like mineral oil. Suitable for use with the adjustment in the present invention are well known in this field and are described in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1585-1591 (Alfonso R. Gennaro ed. 19th ed. 1995), which thereby is incorporated herein by reference.

In the embodiment of the present invention, the composition is introduced by local image comprises at least one material from the cream and ointment, containing agent selected from the group consisting of stearic acid, stearyl alcohol, cetyl alcohol, glycerin, water, and mixtures thereof, and composition for local injection has a physiologically acceptable pH.

In another embodiment, the composition is introduced by local way, is in the form of an aqueous solution or suspension, preferably an aqueous solution. Water agents for local injection, suitable for use in the present invention include the materials described in REMIGTON: THE SCIENCE AND PRACTICE OF PHARMACY 1563-1576 (Alfonso R. Gennaro ed. 19th ed. 1995), which thereby is incorporated herein by reference. Other utilizable water system media for local injection include the materials described in U.S. patent No. 5424078 (issued June 13, 1995); U.S. patent No. 5736165 (issued April 7, 1998); U.S. patent No. 6194415 (issued February 27, 2001); U.S. patent No. 6248741 (issued June 19, 2001); 6465464 (issued October 15, 2002), all of these patents are thus included in this document as a reference.

the pH of the preparations for the local introduction of the present invention is preferably within a physiologically acceptable pH, for example, in the range from about 6 to about 8, more preferably from about 6.3 to about 6.5. To stabilize the pH, preferably included an effective amount of a buffer. In one of the embodiments, a buffering agent present in the aqueous preparation for local administration in the amount of about 0.05 to about 1 percent of the mass of the preparation. Acids or bases can be used for pH adjustment.

Agents to adjust toychest can be included in aqueous agents for local injection for use in embodiments implementing the present invention. Examples suitable for use agents to adjust toychest include, but are not ogran Chivas this, sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. The amount of agent to adjust toychest may vary within wide limits depending on the desired properties of the drug. In one of the embodiments, the agent to adjust toychest present in the aqueous preparation for local administration in the amount of about 0.5 to about 0.9 percent of the mass from the drug.

Preferably, the aqueous preparations for the local introduction have a viscosity in the range from about 15 CP to about 25 CP. The viscosity of aqueous solutions of the present invention can be adjusted by adding agents to adjust the viscosity, for example, but not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamers, carboxymethyl cellulose or hydroxyethyl cellulose.

In a preferred embodiment, an aqueous preparation for the local introduction of represents an isotonic saline solution containing a preservative, such as benzylaniline or chlorine dioxide agent to adjust the viscosity, such as polyvinyl alcohol, and a buffer such as sodium citrate and citric acid.

The composition of the input local image may contain pharmaceutically acceptable excipients, such as those listed in EMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995; Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUG DILEVERY SYSTEMS (1997), which are thus included in this document as a reference, including, but not limited to, protective agents, adsorbents, tools, reducing irritation, softeners, preservatives, antioxidants, humectants, buffering agents, solubilizing agents, agents for increasing the permeability of the skin and surface-active substances.

Suitable for use by protective agents and adsorbents include, but are not limited to, dust-raising powders, zinc stearate, collodion, Dimethicone, silicone, zinc carbonate, aloe Vera gel and other products aloe oil, vitamin E, allantoin, glycerin, petrolatum and zinc oxide.

Suitable for use tools that reduce irritation include, but are not limited to, benzoin, hydroxypropylcellulose, hypromellose and polyvinyl alcohol.

Suitable for use softeners include, but are not limited to, animal and vegetable fats and oils, ministerului alcohol, aluminum alum and aluminum acetate.

In one of the embodiments of the present invention, the composition is introduced by local image, further comprises one or more agents selected from the group consisting of a preservative, a local anesthetic and the humidifier to the I.

Suitable preservatives include, but are not limited to, Quaternary ammonium compounds, such as benzylaniline, benzenehexachloride, cetrimide, dequalifled and cetylpyridinium; agents on the basis of mercury, such as finalstate nitrate, finalstate acetate, and thimerosal; alcoholic agents, for example, chlorobutanol, phenethyl alcohol and benzyl alcohol; antibacterial esters, for example, esters with parahydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chlorocresol, benzoic acid and polymyxin.

Chlorine dioxide (ClO2),preferably, the stabilized chlorine dioxide is a preferred preservative for use with the preparations for the local introduction of the present invention. The term "stabilized chlorine dioxide" is well known in the industry and experts in this field. Stabilized chlorine dioxide includes one or more precursors of chlorine dioxide, such as one or more complexes containing chlorine dioxide and/or one or more chlorite-containing components and/or one or more other compounds that can decompose or dissolve in water with the formation of chlorine dioxide. U.S. patent No. 5424078 (issued June 13, 1995), thus includes the first in this document as a reference, describes the form of stabilized chlorine dioxide and a method of its production, it can be used as preservatives for aqueous ophthalmic solutions and is suitable for use in the preparations for the local introduction of the present invention. Production or receiving certain stable products of chlorine dioxide is described in U.S. patent No. 3278447, thereby to be included herein as reference. Commercially available stabilized chlorine dioxide, which can be used in the practice of the present invention is a stabilized accordingly chlorine dioxide from BioCide International, Inc. Norman, Okla., sold under the trade name Purogene™ or Purite™. Other usable products of stabilized chlorine dioxide include the products sold under the trade name DuraKlor Rio Linda Chemical Company, Inc., and sold under the trade name Antheium Dioxide International Dioxide, Inc.

Suitable antioxidants include, but are not limited to, ascorbic acid and its esters, sodium bisulfite, bottled hydroxytoluene, bottled hydroxyanisole, Tocopherols and chelating agents like EDTA and citric acid.

Suitable humectants include, but are not limited to et is m, glycerin, sorbitol, polyethylene glycols, urea and propylene glycol.

Buffering agents suitable for use with the present invention include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, the buffers on the basis of lactic acid and borate buffers.

Suitable for use solubilizing agents include, but are not limited to, chlorides Quaternary ammonium compounds, cyclodextrins, benzyl benzoate, lecithin and Polysorbate.

Suitable agents for increasing the permeability of the skin include, but are not limited to, ethyl alcohol, isopropyl alcohol, octylphenoxypolyethoxyethanol, oleic acid, polyethylene glycol 400, propylene glycol, N-decylmethacrylate, esters of fatty acids (for example, isopropylmyristate, meilleur, glycerolphosphate and propilenglikolmonostearata) and N-organic.

In a preferred embodiment, the composition is introduced by local image, in accordance with the variants of implementation of the present invention further comprises titanium dioxide (TiO2), preferably in a quantity sufficient to mask the color of brimonidine or other colored ingredient in the drug, but would not cause skin irritation. TiO2may cause slight irritation and pokrasnenie the eyes, so eye contact with TiO2-containing composition is introduced by local image should be excluded.

The song entered the local way, in accordance with the variants of implementation of the present invention may contain pharmaceutical agents or their pharmaceutically acceptable salts, such as agonist at α2-adrenergic receptors, and, optionally, one or more other pharmaceutically active ingredients, including, but not limited to, tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort), fluocinonide, vitamin D analogues (for example, calcipotriol), retinoids, argan oil, psoralen, methotrexate, cyclosporine, retinoids or other synthetic forms of vitamin A, Amevive®, Enbrel®, Humira® and Remicade®.

The song entered the local way, in accordance with the variants of implementation of the present invention may additionally include local anesthetics and analgesics, such as camphor, menthol, lidocaine, and dibucaine, and pramoxine; fungicides, such as ciclopirox, chloroxylenol, triacetin, sulconazole, nystatin, undecylenoyl acid, tolnaftate, miconazole, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconazole and amphotericin B; antibiotics and anti-infective agents such as mupirocin, erythromycin, clindamycin, gentamicin, polymyxin, Bakar the Qing and sulfadiazine; and antiseptics such as iodine, povidine-iodine, benzylaniline, benzoic acid, chlorhexidine, nitrofurazone, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol and cetylpyridinium.

The present invention will be better understood by reference to non-limiting examples that follow, but the person skilled in the art will recognize that the examples are only illustrations of the present invention, as described more fully in the claims which follows.

Example 1

The drug gel

Illustrative preparation of the gel prepared using methods known in this field, for example, by mixing the following ingredients at the indicated concentrations:

IngredientThe percentage mass
Brimonidine tartrate0,18%
Carbomer 934P1.25%
Methylparaben0,3%
Phenoxyethanol0,4%
Glycerin5.5%
10% titanium Dioxide of 0.625%
Propylene glycol5.5%
10% NaOH solution6.5%
Deionized waterOn demand
Only100%

Example 2

The research experiment is performed with the use of Alpbagan®-P (0,15% of brimonidine tartrate) as a researched solution for the treatment of psoriasis in the subject person.

The subject, a woman aged 52 years, demonstrates severe psoriasis on both elbows on the back and on the leg. During the initial period of 30 days, it was not treated with any drug against psoriasis, and she's got the skin treatment, limited only soap and water. Then, she received a 10-day treatment with Alphagan®P 0.15 per cent of brimonidine tartrate), by applying 1 ml of Alphagan®-P twice a day on skin with psoriasis, approximately 3 inches by 6 inches (7.5 to 15 cm) on the left elbow. This deposition is carried out using not absorbing cotton swab in a way that thoroughly wets the plot with psoriasis, and then let him air dry. As a control, her right elbow continues to receive treatment only through soap ibody. Full forty-day Protocol was repeated twice.

Two desirable effects observed at the site of psoriasis, which is treated with Alphagan®P: (1) redness around psoriatic plaques is greatly reduced, and (2) the itchy sensation completely disappears, although the size of the plaque is not reduced significantly. When treatment ceased, redness and itching returned. The results are reproducible when repeated studies.

The results of this experiment show that local application of agonist of α2 adrenergic receptors, such as brimonidine on the skin area affected by psoriasis is effective in the relief of symptoms of psoriasis, for example, reduces redness and eliminate itching.

Having no desire to be limited by theory, it is assumed that the agonist of α2 adrenergic receptors, such as brimonidine, can reduce the blood flow to the skin area affected by psoriasis, and slows the rapid growth of skin on the affected area of skin with the treatment or prevention of psoriasis and its symptoms.

Specialists in this field will understand that changes may be made in the implementation options described above without deviating from the concepts of the present invention in a broad sense. For this reason, it is clear that this is General the invention is not limited to the specific options described implementation, but is intended to cover modifications within the spirit and scope of the present invention, as defined by the attached claims.

1. A method of treating psoriasis or symptoms associated with it, the subject, including local introduction to an area of skin of the subject local composition comprising a therapeutically effective amount of an agonist of α2 adrenergic receptor and a pharmaceutically acceptable carrier, where the skin surface is exposed to psoriasis or a symptom associated with it, or are prone to this, and where an agonist of α2 adrenergic receptors is brimonidine

2. The method according to p. 1, where the composition contains 0.01%-5% of the mass. agonist α2 adrenergic receptors.

3. The method according to p. 2, where the composition is introduced to the skin from about 0.1 g/cm2to about 5 g/cm2the area of the skin, from one to four applications per day.

4. The method according to p. 1, further comprising introducing at least one additional treatment and medicines against psoriasis or symptoms associated with it.

5. The method according to p. 1, where the medicinal product further comprises titanium dioxide.

6. The method according to p. 1, where the local composition is in a form selected from the group consisting of sprays, mistou, aerosols, solutions, lotions, gels, creams, ointments, pastes, ointments, emuls the th and suspensions.

7. The method according to p. 1, where the local composition contains 0.05 to 0.5%, 0.07 per cent of-0.7%, or 0.1 to 0.6% of the mass. agonist α2 adrenergic receptors.

8. The method according to p. 1, where the local composition is an aqueous gel containing water, and a gelling water quantity pharmaceutically acceptable gelling agent selected from the group consisting of carbomer, glyceryltrinitrate and mixtures thereof, and the drug has a physiologically acceptable pH.

9. The method according to p. 1, where the local composition is at least one of the cream and ointment, each of them contains an agent selected from the group consisting of stearic acid, stearyl alcohol, cetyl alcohol, glycerin, water and mixtures thereof, and the drug has a physiologically acceptable pH.

10. The method according to p. 1, where the local composition further comprises a preservative, a local anesthetic and skin moisturizer.



 

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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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and describes a non-aqueous ointment containing a compound of vitamin D, corticosteroid and ester of N,N-di(C1-C8)alkylamino-substituted (C4-C18)alkyl(C2-C18)carboxylic acid in Vaseline, optionally containing mineral oil and tocopherol.

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23 cl, 4 dwg, 5 tbl, 3 ex

FIELD: medicine, pharmaceutics.

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EFFECT: preparing new cyclosporine derivatives.

5 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of (R)-5-[3-chloro-4-(2,3-dihydroxypropoxy)benz[2]ylidene]-2-([2]-propylimino)-3-ortho-tolylthiazolidin-4-one (compound 1) or its salt for obtaining a medication for prevention and/or treatment of a disease or disorder, associated with the immune system activation, where the medication represents a set of Compound 1 doses; with the dose inducing the heart desensitisation in an initial phase of treatment and being lower than the final dose; with the said initial phase of treatment the dose is introduced with a frequency ensuring support of the heart desensitisation until the next acute reduction of heart rate occurs, after which the dose is titrated with increase to the final dose of Compound 1; a corresponding method of treatment and the set of doses.

EFFECT: invention ensures reduction and minimisation of undesirable side effects of Compound 1 (acute reduction of heart rate, atrioventricular conduction, or fatigue and dizziness) aimed at increase of Compound 1 tolerance and safety, as well as minimises problems, associated with monitoring at the initial phase of treatment or after interruption of treatment in the period of repeated treatment.

22 cl, 1 tbl

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15 cl, 1 tbl, 3 ex

FIELD: biotechnologies.

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

,

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10 cl, 2 tbl, 202 ex

FIELD: chemistry.

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18 cl, 6 dwg, 6 ex

FIELD: medicine, pharmaceutics.

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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).

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40 cl, 35 dwg, 12 tbl, 8 ex

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, pharmaceutics.

SUBSTANCE: what is presented is a group of inventions involving a pharmaceutical composition for preventing or treating diabetes mellitus, diseases related to diabetes mellitus, or complications of diabetes mellitus containing a combination of (A) (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol, or its salt, hydrate or hydrate salt, and (B) metformine or an agent intensifying insulin secretion, and a combination of the same formulation and for the same application.

EFFECT: in addition to the pronounced blood plasma glucose reduction, the synergetic effect is ensured in inhibiting the plasma insulin level; what is also shown is inhibiting the side effect of glimepiride that is a body weight increase.

16 cl, 20 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, represented by formula (I) where represents α-configuration; represents β-configuration; and represents α-configuration, β-configuration or their arbitrary mixture, its salt, or its mixture with diastereomer in an arbitrary ratio, or its cyclodextrin clathrate. The invention relates to a pharmaceutical composition for the prevention, treatment and/or reduction of intensity of the urinary bladder contraction dysfunction and/or urethral relaxation dysfunction, which contains the compound, represented by formula (I) as an active ingredient. The invention also relates to a compound, represented by formula (I-a) where R1 represents C1-C4-alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; represents α-configuration; represents β-configuration; and represents α-configuration, β-configuration or their arbitrary mixture, its salt, or its mixture with diastereomer in an arbitrary ratio, or its cyclodextrin clathrate.

EFFECT: compound in accordance with the claimed invention is suitable as an excellent agent for the prevention, treatment and/or improvement of the insufficiently active urinary bladder.

8 cl, 3 tbl, 8 dwg, 24 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: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and deals with a pharmaceutical composition for enhancing the efficiency of treatment of liver cancer by Sorafenib, with the said composition containing an anti-glypican 3-antibody as an active ingredient.

EFFECT: invention provides an improved anti-cancer effect and reduction of the side effect, in particular loss of the body weight.

14 cl, 9 dwg, 2 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a method for the suppression of physiological disorders related to abnormal angiogenesis, specified in retinopathy, diabetic retinopathy, macular degeneration, retinopathy of prematurity, age-related macular degeneration, pancreatic tumour and glioma, involving the administration of an effective amount of 3-[(5-(2,3-dimethoxy-6-methyl-1,4-benzoquinolinyl)]-2-nonyl-2-propenoic acid (E3330) or its pharmaceutically acceptable salts or solvates. The decreased EHF-1α, NFKβ, AP-1 activity by E3330 and the suppression thereby of the growth, survival. Migration and metastasis of tumour cells are accompanied by the absence of the major suppression of the growth of normal cells (hemopoietic embyo cells or CD34+ human progenitors). Besides, E3330 has enhanced the therapeutic effect of other cytotoxic preparations.

EFFECT: reducing the amount of VGEF and proliferation of retinal endothelial cells by E333O even in the presence of a fibroblast growth factor, both in the normal oxygen conditions, and in the hypoxia by the inhibition of the oxidation-reduction activity of Apel/Ref-1.

12 cl, 35 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: using hyaluronidase for preventing and/or treating arterial hypertension, a related method of treating or preventing arterial hypertension. There are also presented a formulation, a combined preparation and a pharmaceutical composition for preventing and/or treating arterial hypertension, containing hyaluronidase and at least one antihypertensive additive, and a method of preventing and/or treating arterial hypertension using them.

EFFECT: what is shown is achieving the declared application after the independent administration of hyaluronidase intensifying the hypotension action of angiotensine II inhibitors, a calcium channel antagonist, an ATP antagonist and combinations of anti-hypertension agents.

16 cl, 10 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination for treating a proliferative disease containing (a) the phosphoinositide3-kinase inhibitor 5-(2,6-dimorpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethylpyridin-2-ylamine (compound B) or a pharmaceutically acceptable salt thereof and (b) a compound that modulates the Ras/Raf/Mek pathaway specified in a group consisting of (i) a compound that modulates Raf kinase activity that is Raf265, SB590885, XL281 or PLX4032; (ii) a compound that modulates Mek kinase activity that is PD325901, PD-181461, ARRY142886/AZD6244, ARRY-509, XL518, JTP-74057, AS-701255, AS-701173, AZD8330, ARRY162, ARRY300, RDEA436, E6201, RO4987655/R-7167, GSK1120212 or AS703026, wherein the active ingredients in each case present in a free form or as a pharmaceutically acceptable salt or a hydrate thereof, and used simultaneously, separately or sequentially, a respective pharmaceutical composition or a combination drug, and a method of treating a proliferative disease in a homoithermic animal, principally a human.

EFFECT: what is shown is a synergism of the antineoplastic action of the declared combinations.

11 cl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to a method for preparing a therapeutic hydrogel material involving mixing an aqueous solution of sodium alginate and a drug preparation, dispersing a cross-linking agent that is presented by calcium sulphate in glycerol in the concentration of 0.8-2.5%, mixing the dispersion with the prepared mixture of sodium alginate with the drug preparation in ratio 1-2:4-6, placing the prepared product into a tiling pattern and keeping it till form-stable, conducting gamma sterilisation; the formation process involves the mechanical stability measurements with the diametral compression of the formed hydrogel; the hydrogel is considered to be formed once a thickness of the formed hydrogel varies with the diametral compression by 10-30%.

EFFECT: invention provides the wider medical variation of the drug concentrations, preparing high-thixotropy soft hydrogel materials (tablets) easy to administer, including through rectum, preparing the materials that preserve its all their physical-technical and mechanical properties after the gamma sterilisation along with the sterility.

4 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: group of inventions relates to veterinary and medicine and specifically to compositions which include one or more long-chain polyunsaturated fatty acids, one or more compounds which release nitrogen monoxide, and one or more medium-chain triglycerides, and methods of using such compositions to enhance cognitive function, reduce or prevent deterioration of social behaviour, reduce or prevent age-related behavioural changes, enhance learning capability, maintain optimum brain functioning, facilitate learning and memory, reduce memory loss, slow down brain ageing, prevent or treat stroke and prevent or treat dementia in humans and pets.

EFFECT: group of inventions improves effectiveness of enhancing cognitive function.

113 cl, 5 tbl, 1 ex

Jak inhibitors // 2538204

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I wherein R means C1-6alkyl, C1-6halogenalkyl, hydroxy-C1-6alkyl, hydroxygroup or halogen; m, n is equal to 0 or 1; Z1 means CH or NH; Z2 means CH or N; Z3 means CR1, N or NR2; R1 means H, C1-6alkyl, C3-7cycloalkyl, cyanogroup, cyano-C1-6alkyl or halogen; R2 means H or C1-6alkyl; X means CH, CR' or N; X' means CH, CR' or N; r is equal to 1; Y means CH or CR'; R' means R'a or R'b; R'a means a halogen or cyanogroup; R'b means C1-6alkyl, heterocycloalkyl specified in piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, OR", SR", S(=O)2R" or NR"R", optionally substituted by one or more R'c; R'c means a hydroxygroup, oxogroup, cyanogroup, C1-6alkyl, pyridinyl, carboxy-C1-6alkyl, aminocarbonyl-C1-6alkylaminogroup, C1-6alkylaminogroup, C1-6dialkylaminogroup or C1-6alkoxygroup; R" means H, C1-6alkyl, hydroxy-C1-6alkyl, piperidinyl, C3-7cycloalkyl or pyridinyl; Q means S(=O)2Q1, C(=O)Q2, C(=O)OQ3 or Q4; Q1 means C1-6alkyl, C3-7cycloalkyl-C1-6alkyl, C1-6alkylaminogroup or C1-6dialkylaminogroup optionally substituted by one or more Q1'; each Q1' independently means C1-6alkyl or cyanogroup; Q2 means C1-6alkyl optionally substituted by one or more Q2'; each Q2' independently means a cyanogroup; Q3 means C1-6alkyl; Q4 means C1-6alkyl, oxetanyl optionally substituted by one or more Q4'; each Q4' independently means a halogen, cyanogroup, cyano-C1-6alkyl; p is equal to 0, 1 or 2; q is equal to 1 or 2; each means a single bond or a double bond; provided one of Z1 and Z2, and Z3 and Z3 bonds are double and single.

EFFECT: compounds of formula I as JAK inhibitors.

23 cl, 2 tbl, 121 ex

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