The use of cgrp antagonist for treatment of herpes and poonsuk (prurigo), the composition and method of treatment

 

(57) Abstract:

The invention relates to the use of CGRP antagonist in a cosmetic, pharmaceutical or dermatological compositions, especially for topical application, for the treatment (processing) herpes, poonsuk, pruriginous of taxidermy and heavy Zudov, as well as to the new specified compositions based on it. When this composition in addition to the antagonist CGRP contain at least one antagonist selected from the antagonists of substance P and antagonists mediator of inflammation. The invention expands the Arsenal of tools specified destination. 2 S. and 19 C.p. f-crystals.

The invention relates to the use of CGRP antagonist (a peptide derived from the gene calcitonin: Calcitonin Gene Related Peptide) in or for the preparation of cosmetic, pharmaceutical or dermatological compositions, especially for topical application, for the treatment of certain skin diseases.

Mostly this composition makes it possible to treat topical way, by introducing into the stomach or through injection, lichens, especially red flat lichens and retinitis herpes: prurigo and especially astenicheskii of prurigo (prurigo), prurigo Besnier, or prurigo Gebrs, or hives, or the node is in; cholestasis or biliary Judy. Pruriginous toksidermii are primarily the result of the absorption of the medication; these diseases are very different from urticaria and do not give any contact reactions.

Up to the present time red flat scab and pigment psoriasis treated with local corticoids or puva therapy. Corticoide certainly very effective for "calm" symptoms, but, unfortunately, they have secondary effects, are often very aggravating, as atrophy; infection, especially fungal or bacterial. Puva therapy is a local irradiation of the patient's skin using UV-a radiation, after absorbing the photosensitizing substance (psoralen). This method has serious drawbacks, which consists in photoaging, which often may result in skin cancer. Moreover, this treatment is not ambulatory; in this treatment, patients should be usually in a specialized center for the treatment, which is very limits of their professional activities.

Of prurigo also treated with local corticoids, puva-therapy or thalidomide. Local corticoid and puva therapy have vysheukazannoe stvie which prohibit its use for pregnant women. Moreover, it is very regulated prescription (limited treatment in the hospital) limits its application.

Pruriginous toksidermii currently treated with local corticoids and/or antihistamines: their treatment, therefore, has the same drawbacks as mentioned above.

Heavy sudi also treated with local corticoids with the same disadvantages mentioned above.

Therefore, there is a need in the treatment of these skin diseases with the exception of these shortcomings.

The subject of the present invention is the use, in a cosmetically, pharmaceutically and/or dermatologically acceptable medium, one or more antagonists of CGRP that can effectively treat some diseases of the skin, completely avoiding the above disadvantages.

CGRP is a polypeptide chemical element, produced and released a nervous finish. CGRP is particularly involved in respiratory and inflammatory diseases, allergic diseases and in some dermatological diseases such as eczema or prurigo (prurigo).

However, until segodnyashniy antagonists of CGRP.

Therefore, the object of the present invention is the use of at least one CGRP antagonist and/or for the preparation of cosmetic, pharmaceutical and/or dermatological compositions for the treatment of herpes, poonsuk, pruriginous of taxidermy and heavy Zudov.

The applicant determines the CGRP antagonist as any molecule organic or inorganic origin, can cause inhibition (suppression) receptor commit CGRP or cause suppression of the synthesis and/or release of CGRP sensitive nerve fibers.

In order substance has been recognized as a CGRP antagonist, it must meet the following characteristics:

- it must have pharmacological, antagonistic towards CGRP, activity, i.e. inductivity coherent pharmacological response, especially in one of the following tests:

substance antagonist should reduce vasodilatation caused by capsaicin; and/or

substance antagonist should cause suppression of the release of CGRP sensitive nerve fibers; and/or

substance antagonist should reduce the inhibition of contraction of smooth muscle of the spermatic cord, called for scienists CGRP in the invention can be used, for example, CGRP 8-37, anti-CGRP-antibody.

In the compositions according to the invention, the CGRP antagonist is used preferably in the amount of 0,000001 - 10 wt.% calculated on the total weight of the composition, especially in the amount of 0.0001 - 5 wt.% calculated on the total weight of the composition.

Preferably the antagonist CGRP is possible to combine one or more antagonists of another neuropeptide, as antagonists of substance P and/or one or more antagonists of a mediator of inflammation, as antagonists histamine antagonists of interleukin-I (IL-I) and antagonists factor tumor necrosis (Tumor Necrosis Factor alpha; TNF-).

Therefore, the object of the invention is also the cosmetic, pharmaceutical and/or dermatological composition containing in a cosmetically, pharmaceutically and/or dermatologically acceptable medium, at least one CGRP antagonist and at least one antagonist of another neuropeptide and/or at least one antagonist of a mediator of inflammation.

The subject of the invention is therefore the cosmetic, pharmaceutical and/or dermatological composition for treating herpes and poonsuk, characterized in that it contains a cosmetically, pharmaceutically and/or dermatologica and/or at least one antagonist of a mediator of inflammation.

An antagonist of a neuropeptide, a non-CGRP is preferably an antagonist of substance P.

Substance P is a polypeptide chemical element, produced and released a nervous finish. It is included in the family of tachykinins, which derive from the free nerve endings of the epidermis and dermis (skin). Substance P is involved especially in the transmission of pain and diseases of the Central nervous system such as anxiety, schizophrenia; in respiratory and inflammatory diseases, diseases of the gastrointestinal tract, rheumatic diseases, and in some dermatological diseases such as eczema, psoriasis, urticaria and contact dermatitis.

As antagonists of substance P, used in the invention, it is possible to call any substance, organic or inorganic, capable of causing inhibition (suppression) receptor fixing substance P or inhibition (suppression) synthesis and/or release of substance P sensitive nerve fibers.

In order that the substance was recognized as the antagonist of the substance P, it must meet the following characteristics:

it must be the village of the political in relation to substance P, activity, i.e., to indoctrinate coherent pharmacological response, especially in one of the following two tests:

substance antagonist should reduce the radiolabeled plasma through the vessel wall induced by capsaicin or by nerve stimulation, propagate nerve impulses on axona in the direction opposite to normal; or

substance antagonist should cause the suppression of the reduction of smooth muscles, caused by introduction substances P.

The antagonist of the substance P is preferably receptor antagonist substance P.

The receptor antagonist of the substance P may be a peptide or ones derived, including heteroatom, and more specifically, the connection comprising a heterocycle or heteroatom connected directly or indirectly to the benzene cycle.

As a peptide, which is an antagonist of the receptor for substance P, can be used, for example, sanded or candid-II.

As the peptides of the invention it is also possible to use the peptides described in U.S. patent A-4472305; U.S. patent A-4839465; European patents NN A-101929, A-333174, A-336230, A-394989, A-443132, A-498069, A-515681, A-517589; WIPO-A-92/22569 and the United Kingdom patent A-2216529.

Receptor antagonists (p the NGOs heterocyclic compounds, mainly sulphur-, nitrogen - or oxygen-containing heterocyclic compounds, or compounds containing a nitrogen atom linked directly or indirectly to the benzene cycle.

As the heterocyclic compounds of the invention can be used compounds described in the following documents: European patents NN A-360390, A-429366, A-430771, A-499313, A-514273, A-514274, A-514275, A-514276, A-520555, A-528495, A-532456, A-545478, A-558156; WIPO-A-90/05525, WIPO-A-90/05729, WIPO-A-91/18878, WIPO-A-91/18899, WIPO-A-92/12151, WIPO-A-92/15585, WIPO-A-92/17449, WIPO-A-92/20676, WIPO-A-93/00330, WIPO-A-93/00331, WIPO-A-93/01159, WIPO-A-93/01169, WIPO-A-93/01170, WIPO-A-93/06099, WIPO-A-93/09116, WIPO-A-94/08997. In particular, a compound containing at least one nitrogen-containing heterocycle is derived 2-tricyclic-2-amino-ethane, derived spirolactone, derived hinoklidina, azollaceae derived, derived aminopyrrolidine, a derivative of piperidine, aminoazo-heterocycle, isoindole derivative.

As compounds containing a nitrogen atom linked directly or indirectly to the benzene nucleus can be called compounds described in the following documents: European patent EP-A-522808, WIPO-A-93/01165.

As antagonists mediator of inflammation used in the invention, it is possible to call tripolidine); the phenothiazines (alimemazine, promethazine); auranofin; lipophilin; A802715; sulfasalazine; cetirizine HCl; loratidine; abatin; setaction HCl.

As an example, antagonists of substance P and antagonists mediator of inflammation can be used in the quantity constituting 0,000001 - 10 wt.% calculated on the total weight of the composition and better still of 0.0001 - 5 wt.%.

The composition according to the invention can be applied to either a local path, i.e., by topical or by subcutaneous and intradermal injections, or system or shared path, i.e., orally and/or by intramuscular injection.

The object of the present invention is a method for the cosmetic, pharmaceutical and/or dermatological treatment of herpes, poonsuk, pruriginous of taxidermy and/or heavy Zudov, characterized in that on the skin, hair and/or mucous membranes applied composition comprising at least one CGRP antagonist in a cosmetically, pharmaceutically and/or dermatologically acceptable medium.

The composition of the invention intended for topical application contains a cosmetically, pharmaceutically or dermatologically acceptable medium, i.e. a medium compatible with the skin, nails, seem on the face, neck, hair, mucous membranes and nails, large folds or on any other area of body skin.

Compositions according to the invention can be any commonly used, galenical forms depending on the route of administration (injection, oral, tapicerki).

For topical application, the composition may be in any galenical form normally used for this application, especially in the form of aqueous, aqueous-alcoholic or oily solutions, dispersions of the type of lotion or serum, an aqueous gel, an anhydrous gel, or lipophilic gels, emulsions of liquid or semi-liquid consistency of the type of milk, obtained by dispersion of a fatty phase in an aqueous phase (oil-in-water) and Vice versa (water-in-oil), suspensions or emulsions of soft, semi-solid or solid consistency of the type of cream or gel, or microemulsions, of microcapsules, microparticles or vesicular (bubbly) dispersions of ionic and/or nonionic type. These compositions are prepared in the usual way.

These compositions can also be used for the hair in the form of aqueous, alcoholic or aqueous-alcoholic solutions, or in the form of creams, gels, emulsions, foams, and also in the form of aerosol compositions also containing the buoyancy of the lotion or serum.

Compositions used orally, can be in the form of capsules, gelatin capsules, syrups or tablets.

The amounts of the various components of the compositions according to the invention is a composition, usually used in the fields.

These compositions are especially creams for protection, treatment and care for the skin of the face, hands, feet, large anatomical folds or for the body; cleansing milk for the protection or care of the skin; lotions, gels or foams for caring for the skin and mucous membranes, as lotions for cleaning or disinfection; compositions for the bath; compositions containing a bactericidal agent.

The composition can also be in the form of solid preparations constituting Soaps or bars for cleansing.

The number of different components of the compositions according to the invention are those which are commonly used in the fields.

Method of cosmetic treatment according to the invention can be realized particularly by applying hygienic or cosmetic compositions, such as described above, according to the usual technique of using these compositions, for example, as applying to the and composition according to the invention is an emulsion, the proportion of the fatty phase can reach 5-80 wt.% and is preferably 5-50 wt. % calculated on the total weight of the composition. The oils, emulsifiers and simulatory used in the composition in the form of an emulsion, choose among commonly used in the cosmetic field. Emulsifier and simulator present in the composition in an amount of 0.3 to 30 wt.% and preferably 0.5 to 20 wt.% calculated on the total weight of the composition. The emulsion can also contain lipid vesicles.

When the composition of the invention is an oil solution or an oily gel, the fatty phase may represent more than 90 wt.% calculated on the total weight of the composition.

Cosmetic, pharmaceutical or dermatological composition according to the invention may also contain conventional in the areas of additives such as hydrophilic or lipophilic gelation agents, hydrophilic or lipophilic active start, preservatives, antioxidants, solvents, fragrances, fillers, filters, bactericides, odor absorbers and colorants. The amounts of these various additives are those which are commonly used in the areas under review, and are, for example, from 0.01 to 20 wt. % calculated on the total mednyi balls.

As used in the invention oils can be called mineral oil (liquid paraffin), vegetable oils (liquid fraction of the oil tallow tree, sunflower oil), animal oils (perhydrosqualene), synthetic oils (porcelanowe oil), silicone oils (cyclomethicone) and fluorinated oils (simple parfocality). As fatty materials (substances) it is also possible to use fatty alcohols, fatty acid series (stearic acid), waxes (paraffin wax, Carnauba wax, beeswax).

As used in the invention emulsifiers include, for example, glycerol stearate, a simple 3-ministerului ether polypropylenglycol and satellitecontrol.

As used in the invention solvents can be called lower alcohols, especially ethanol and isopropanol, propylene glycol.

As hydrophilic agents, gelation can be called carboxyvinyl polymers (carbomer), acrylic copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural vegetable gums and clays, and lipophilic agents, gelation can be called mixed silicon, or another ethylcellulose, polyethylene.

As hydrophilic active principles it is possible to use proteins or protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and derivatives of sugars, water-soluble vitamins, starch and plant extracts, especially from Aloe Vera.

As lipophilic active principles can be used retinol (vitamin A) and its derivatives, tocopherol (vitamin E) and its derivatives, volatile fatty acid number, ceramide, volatile oil.

By the way, you can combine antagonists of CGRP with the applicable principles, designed especially for protection and/or for the treatment of skin diseases. As an example of these active principles can be called:

agents, modulating the differentiation and/or proliferation, and/or skin pigmentation, such as retinoic acid and its isomers, retinol and its esters, vitamin D and its derivatives, oestrogens such as oestradiol, kojic acid or hydroquinone;

- antibacterial agents, such as clindamycine, erythromycin or antibiotics of the class tetracycline;

- antiparasitic agents, in particular metronidazole, crotamiton or pyrethrinoid;

- Econazole or miconazole or their salts; polyene compounds such as amphotericin B, compounds of the family of allylamines, such as terbinafine, or else octopirox;

anti - inflammatory agents, steroids such as hydrocortisone, betamethasone-valerate or clobetasol-propionate, or anti-inflammatory agents, non-steroidal type, such as ibuprofen and its salts, diclofenac and its salts, acetylsalicylic acid, acetaminophen or glycyrrhetinic acid;

- anesthetic agents, such as hydrochloride lidocaine and its derivatives;

- antiproteinase agents, as analgin, trimeprazine or cyproheptadine;

- antiviral agents such as acyclovir;

- keratolytic agents such as alpha - and beta-hydroxycarbonate acids or beta-ketocarboxylic acids, their salts, amides or esters, and preferably hydroxy acids such as glycolic acid, lactic acid, salicylic acid, citric acid and, in General, fruit acids, and n-octanoyl-5-salicylic acid;

agents against free radicals, such as alphatocopherol or its esters, peroxydisulfate, some agents education ORGANOMETALLIC chelate compounds or ascorbic acid and airox or zinc pyrithione;

agents against acne as retinoic acid or benzoyl peroxide.

The following compositions illustrate the invention; these number represent weight percents.

Example 1. Disinfecting lotion for the face and mucous membranes:

CGRP 8-37 - 0,50

Antioxidant - 0,05

Isopropanol - 40,00

Preservative - 0,30

Water Enough to 100%

This song is also good to use for processing red flat lichen or pigment herpes, as well as pruriginous of taxidermy.

Example 2. Gel for the face or body to process red flat lichen:

Hydroxypropylcellulose (Klucel H, available in the sale by the company Hercules) - 1,00

CGRP 8-37 - 0,0001

Salicylic acid - 1,00

Antioxidant - 0,05

Isopropanol - 40,00

Preservative - 0,30

Water Enough to 100%

Example 3. Cream (emulsion oil-in-water) for the treatment of severe Zudov:

Anti-CGRP-antibody - 0,05

Glitzenstein - 2,00

Lactic acid/acetic acid - 1,00

Polysorbate 60 (tween 60, manufactured in the sale by the company ICI) - 1,00

Stearic acid - 1,40

Triethanolamine - 0,70

Carbomer - 0,40

Silicone oil - 12,00

Parhedros is 00%

Example 4. The gel.

Example 4 is identical to example 3, except that the gel contains additional 0.3% of Candida.

Example 5. Gel for treatment of herpes:

Candid - 1,00

Anti-CGRP-antibody - 0,10

Hydroxypropylcellulose (Klucel H) - 1,00

Antioxidant - 0,05

Isopropanol - 40,00

Preservative - 0,30

Water Enough to 100%

Example 6. Cream (emulsion oil-in-water) for the treatment of itching of the anus:

Anti-CGRP-antibody - 2,00

Satellitecontrol - 2,50

NaCl - 0,60

NaOH is Sufficient to obtain a pH = 5

Cyclomethicone - 18,00

3-ministerului simple ether polypropylenglycol - 6,00

Glycerin - 3,00

Preservative - 0,20

Water Enough to 100%with

1. Use as active principle, at least one CGRP antagonist in the pharmaceutical composition for treatment of herpes, poonsuk (prurigo), pruriginous of taxidermy and heavy Zudov.

2. Application under item 1, characterized in that the CGRP antagonist is a molecule selected among CGRP 8 - 37 and anti-CGRP antibodies.

3. Application under item 1 or 2, characterized in that the CGRP antagonist use in quantity 0,000001 - 10 wt.%, calculated on the total m is the number of 0.0001 - 5 wt.%, calculated on the total weight of the composition.

5. The use according to any one of paragraphs.1 to 4, characterized in that the composition additionally contains at least one agent chosen among the antagonists of substance P, antagonists mediator of inflammation, antibacterial agents, antiparasitic agents, antifungal agents, anti-inflammatory agents, antiproteinuric agents, anesthetic agents, antiviral agents, keratolytic agents, agents against free radicals, antiseborrheic agents, agents dandruff agents, anti-acne and/or agents, modulating the differentiation and/or proliferation and/or pigmentation of the skin.

6. The use according to any one of paragraphs.1 to 5, characterized in that the composition additionally contains at least one antagonist of the substance P antagonist of the histamine antagonist of interleukin-1 and/or TNF antagonist.

7. Application under item 6, wherein the antagonist is used in the quantity constituting of 0.0001 - 5 wt.%, calculated on the total weight of the composition.

8. The use according to any one of paragraphs.1 to 7, characterized in that the composition additionally contains at least one active principle chosen among proteins or getically extracts, volatile fatty acid number, ceramides, volatile oils, hydroxyacids.

9. The use according to any one of paragraphs.1 to 8, characterized in that the composition is a suitable form for topical application, application in the form of injection or by introduction into the stomach.

10. The use according to any one of paragraphs.1 to 9, characterized in that the composition provides a water -, oil-or water-alcohol solution, emulsion oil-in-water emulsion, water-in-oil microemulsion, an aqueous gel, an anhydrous gel, a serum, a dispersion of vesicles, microcapsules or microparticles.

11. The use according to any one of the preceding paragraphs, characterized in that the composition is a cosmetic and/or dermatological composition.

12. Pharmaceutical composition for the treatment of lichen, prurigo, pruriginous of taxidermy and heavy Zudov, characterized in that it contains, in a pharmaceutically acceptable medium, at least one CGRP antagonist and at least one other antagonist selected from the antagonists of substance P and antagonists mediator of inflammation.

13. The composition according to p. 12, wherein the CGRP antagonist is a molecule selected among CGRP 8 - 37 and anti-CGRP antibodies.

15. Composition according to any one of paragraphs.12 to 14, characterized in that the CGRP antagonist is used in amounts of 0.0001 - 5 wt.%, calculated on the total weight of the composition.

16. Composition according to one of paragraphs.12 to 15, characterized in that the antagonist of the substance P is an antagonist of the receptor for substance P.

17. Composition according to one of paragraphs.12 to 16, characterized in that the antagonist mediator of inflammation choose among histamine antagonists, antagonists of Il-1 and TNF antagonists-.

18. Composition according to any one of paragraphs.12 to 17, characterized in that R antagonist or antagonist of a mediator of inflammation used in the quantity constituting of 0.0001 - 5 wt.% calculated on the total weight of the composition.

19. Composition according to any one of paragraphs.12 to 18, characterized in that it further comprises at least one agent chosen among antibacterial, antiparasitic, antifungal, anti-inflammatory, antiseptic, antiproteinase, anesthetic, antiviral, keratolytic, anti-free radicals, antiseborrheic, dandruff, anti-acne agents, and agents modulating the differentiation and/or proliferation and/or pigmentation of the skin.

20. Composition according to any one of paragraphs.12 - 19, otlichayas the water-in-oil emulsion oil-in-water microemulsion, an aqueous gel, an anhydrous gel, a serum, a dispersion of bubbles.

21. Composition according to any one of paragraphs.12 to 20, characterized in that it is cosmetic and/or dermatological composition.

 

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