The use of at least one peptide in a cosmetic composition or for medicines

 

(57) Abstract:

The invention relates to medicine and to the use of at least one peptide containing the C-end of the Tripeptide Lysine-Proline-Valine, in which a Proline residue is in the form of programalso optical isomer for the local treatment of inflammation. The invention improves the efficiency of treatment of inflammation. 2 S. and 6 C.p. f-crystals, 4 PL.

The present invention relates to the use as an active agent in a physiologically acceptable medium, in a cosmetic composition or for drugs, an effective amount of at least one peptide containing the Tripeptide Lys-Pro-Val, or any functional biological equivalent, in which a Proline residue is present in the form of his programalso optical isomer, intended for the treatment of inflammation.

Inflammation is a complex biological reactions that occur throughout the animal Kingdom. In humans, two of the three diseases have signs of inflammation. Inflammation may be localized.

It can manifest as a primary response to any local impact near especily and tissue fibrosis.

Swelling, pain, redness, burning are manifestations of localized inflammation. They usually occur due to infiltration of damaged tissues, swelling and/or expansion of capillary vessels.

The symptoms of inflammation can reach fever, General malaise and/or increase the concentration of some proteins in the blood plasma.

This phenomenon, which among other things involves a number of local cellular responses and secretion of cytokines and other mediatorov, such as substance P, prostaglandins, histamine or alternative serotonin.

It manifests itself as a change in blood flow increasing, level of inflammation, vascular permeability, leading to leakage of plasma proteins and cells in the extracellular fluid, as well as extravasation of white blood cells, mainly polymorphonuclear leukocytes and macrophages to the inflammation.

In fact, these phenomena are the result of the action of inflammatory mediators.

Among the factors involved in these inflammatory phenomena, can be called cytokines, in particular interleukin-1-, inter-Lakin-1, interleukin 6, tumor necrosis, and (TNF -), chemokines, such as interleukin 8 or hamot olnine lymphocytic cells, monocytic cells, Langerhans cells or basophils in the site of inflammation or other factors involved in the inflammatory cascade, such as arachidonic acid, or prostaglandins, particularly prostaglandin E2.

Inflammation is associated with numerous pathologies. As examples, solar erythema, pruritus, erythema nodosum, urticaria, systemic mastocytosis, psoriasis, insect bites, and other dermatological diseases, such as acrotiri polyhedric, eriteria, necrobiosis lipoidica. You can also call disseminated erythematous lupus, spondyloarthropathy or joint diseases like chronic enteropathy.

For many years in the pharmaceutical industry are looking for substance, which allows to treat inflammation.

In this regard, it has recently been suggested to use a sufficient number of derived melanocytestimulating hormone type (-MSH), or Melanotropin, and in particular peptides containing the Tripeptide Lys-Pro-Val (us patents 5028592 and 5157023).

However, it was shown that the optical form of the isomers used in the composition of Tripeptide, is of great importance. Thus, it was shown that cogged or peptide, containing Tripeptide, completely loses its effectiveness in the treatment of inflammation (Hiltz et al. Peptides, vol. 12, pp. 767-771, 1991).

However, after research in this direction, it was found that the peptide containing the Tripeptide Lys-Pro-Val, in which a Proline residue is present in the Tripeptide in the form of his programalso optical isomers (D-Pro) or any functional biological equivalent, active in the treatment of inflammation.

Under functional biological equivalent to mean a peptide functionally equivalent in terms of biological function, in which at least one of the amino acid residues may be substituted with amino acid residue having a similar hydropathicity index.

Thus, the invention relates to the use in cosmetic compositions and/or in receipt of a medicinal product intended for the treatment of inflammation, at least one peptide containing the Tripeptide Lys-Pro-Val, in which a Proline residue is present in the form of his programalso optical isomers (D-Pro) or any functional biological equivalent.

In the field of amino acids geometry of the molecules is such that toconfigure amino acids(AA), which rejects the plane of polarized light to the right (programada configuration or D-aa) and molecular configuration amino acids (AA), which rejects the plane of polarized light to the left (levogyrate configuration or L-aa).

Amino acids occurring in nature, have only levogyrate configuration. Accordingly, the peptide of natural origin will consist of the amino acid L-aa.

Laboratory chemical synthesis allows to obtain amino acids, with two possible configurations. From this original product during the synthesis of peptides can be entered amino acids in them as levogyrate, and programada optical isomers.

Thus, in the synthesis of peptides, in addition to the rest of D-Proline (D-Pro), you can enter the amino acid residues Lysine or Valine, regardless of their type D-lysine (D-Lys), L-lysine (L-Lys), D-valine (D-Val) or L-valine (L-Val).

Thus, the invention relates, more specifically, to the use of an effective amount of the above peptide, in which the remains of Lysine or Valine of Tripeptide Liz-(D)-Pro-Val can be in the form as programada and levogyrate optical isomers.

Below is the l

L-Lys-D-Pro-D-Val

L-Lys-D-Pro-L-Val

Preferably, the Tripeptide was at the s-end of the peptide.

Preferably, when the peptide of the present invention is a Tripeptide Lys-Pro-Val, in which a Proline residue is present in the form of his programalso optical isomers (D-Pro).

Also preferred is a peptide containing the Tripeptide Lys-Pro-Val, in which residues of Lysine, Proline and Valine are in the form of programada optical isomers (D-Lys-D-Pro-D-Val).

According to the invention can be used more than one peptide. In this case, the mixture of peptides may be one of the possible combinations of the peptides described above.

In the description the following terms are used. Under the Proline understand the Proline residue in the form of his programalso isomer (D-Pro), and the term "peptide" refers to as a "peptide containing the Tripeptide Lysine-Proline-Valine or any functional biological equivalent" and contained "the Tripeptide Lysine-Proline-Valine", in which a Proline residue is in the form of his programalso optical isomers (D-Pro).

It is possible that to make the peptide resistance razlozheny Biologicheskie compatible. Can be considered numerous biologically compatible form of protection, as, for example, acylation or acetylation of amine end or amidation of carboxyl end.

Thus, the invention discloses the use of a peptide in which the peptide is shishisenkou or unprotected form.

Preferably, according to the invention, use protection either by acylation or acetylation of amine end, or by amidation of carboxyl end or both reactions.

The effective amount of active agent corresponds to the quantity necessary to obtain the desired result.

More specifically, in the cosmetic composition, the peptide is present in such quantity that the concentration of Tripeptide Lys-Pro-Val range from 10-12M to 10-3M and preferably from 10-9M to 10-4M

More specifically, upon receipt of the medicinal product peptide is present in such quantity that the Tripeptide Lys-Pro-Val can be used in a concentration of from 10-12M to 1 M and preferably from 10-6M to 10-1M

The quantity of product varies depending on whether you are using a peptide containing the CLASS="ptx2">

The composition according to the invention may be introduced parenterally, interline or locally. Preferably the composition is applied locally.

The physiologically acceptable medium in which the use of a peptide according to the invention may be anhydrous or aqueous. Under anhydrous environment understand the environment of the solvent containing less than 1% water. This environment may consist of a solvent or mixture of solvents, selected in particular from lower alcohols containing 2-4 carbon atoms, for example, ethyl alcohol, alkalophile, for example propylene glycol, and simple alilovic esters of alkalophile or dialkylglycerol, in which alkyl or alkylene radicals contain 1-4 carbon atoms. Under the water environment understand the medium consisting of water or a mixture of water and other physiologically acceptable solvent, selected especially among the organic solvents mentioned above. In the latter case, these other solvents, when they are present, approximately 5-95% by weight of the composition.

It is possible that the physiologically acceptable medium may contain other adjuvants normally used in the cosmetic or pharmaceutical field, such as surface-active is acidifying agents, well known in the art, in amounts sufficient to obtain the desired species, especially more or less thick lotion, gel, emulsion or cream.

If necessary, the product can be applied as an aerosol under pressure, or in the form of vapour from the bottle with the pump.

Can also be used in combination with a peptide of the above-described compounds as having anti-inflammatory activity.

Can more specifically be called glucocorticoids, vitamin D and its derivatives and non-steroidal anti-inflammatory compounds.

The peptide of the present invention can be applied by topical application of a cosmetic composition containing an effective amount of at least one peptide containing the Tripeptide Lys-Pro-Val, in which a Proline residue is in the form of his programalso optical isomers (D-Pro), on the part of the body, with symptoms of inflammation.

Thus, the subject of the present invention equally is a method of cosmetic treatment in which the skin, hair and/or mucous membranes skin areas with symptoms of inflammation, causing cosmetic composition comprising effectivenessthe in the form of his programalso optical isomers (D-Pro).

Method of cosmetic treatment according to the invention can be carried out, preferably, by applying the cosmetic compositions described above, in accordance with the usual method of using these compositions. For example: application of creams, gels, serums, lotions, milk makeup remover or sunscreen compositions to the skin or hair, shampoos or even the application of toothpaste to the gums.

The following are examples which illustrate the invention without limiting its scope. The contents of the components in the compositions listed in mass% relative to the total weight of the composition.

Example 1: activity dose-response Tripeptide Ac-LPV-NH2* in relation to the production of interleukin-1 in the supernatant remote hair taken in inflammatory alopecia:

Hair is removed from volunteers from the crown area heads in place of inflammatory alopecia. They are placed in the environment of survival Williams E (supplied by the company Gibco BRL) containing penicillin G (100 units/ml), streptomycin-S (100 μg/ml), amphotericin b (250 ng/ml) in the presence or in the absence (control) of Tripeptide Ac-LPV-NH2* synthesized by order of the company Neosystem S. A. (Strasbourg) specified in the ri 14000 rpm/min (Eppendorf centrifuge, model S). Then the supernatant transferred to a clean tube and stored at a temperature of 4oC.

The concentration of interleukin-1 is then determined in 100 μl of the supernatant using an ELISA kit Biotrak, released firm Amersham, in accordance with the instructions of the supplier (see tab.1).

Example 2: Inhibition of expression of messenger RNA Pro-inflammatory and inflammatory cytokines in response to the Tripeptide Ac-LPV-NH2*.

Ten remote hair is collected from volunteers from the crown area of the head in the place of inflammatory alopecia. They are placed in the environment of survival Williams E. (sold by Gibco BRL) containing penicillin G (100 units/ml), streptomycin-s (100 μg/ml), amphotericin b (250 ng/ml) in the presence (treated part) or in the absence (control part) Tripeptide Ac-LPV-NH2* synthesized by order of the company Neosystem S. A. (Strasbourg).

After 3 hours and 30 minutes incubation messenger RNA corresponding to these two parts, is purified by means of a set of "quick prep mRNA purification Kit (cleaning kit mRNA fast food) included in the sale by the company of Pharmacia. DNA, complementary to that of the mRNA, then get with the set for reverse transcription, postassembly (PCR) using primers specific for mRNA of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), IL-1 receptor IL-1 type 1 receptor IL-1 type 2. The number of amplified DNA appreciate then by electrophoresis in 1.5% agarose gel in the presence of ethidium-bromide. The intensity of the bands determine when irradiated with ultraviolet light using a video camera and analysis software (Bioprofil TM) supplied in the sale of the company Vilbert-Lourmat. The intensity of the bands obtained with primers IL-1, IL-L, IL-R, divided by the intensity of the bands obtained with primers amplificating internal standard GAPDH (see tab.2).

Example 3: the Inhibitory activity of Ac-LPV-NH2* on the expression of mRNA of IL-1, calculated through the ratio of IL-1/GAPDH

Two different donors remove 5 hair and then incubated them for 20 hours at 37oWITH 5% CO2in environment E. Williams, which added antibiotics and glutamine, in the presence of Ac-LPV-NH2* in the specified concentrations. Exercise control, in which the added peptide is absent. The results are expressed in % relative to the control (see table.3).

Example 4: Measurement of the inhibition of the production of PGE2 (prostaglandin E2) papillary catagen cell is firm GIBCO in the presence of amniotic calf serum and antibiotics. 20 hours later Wednesday to replace an identical medium containing tripeptides, which determines in a final concentration of 10 μm. Five hours add interleukin-1 at a final concentration of 10 ng/ml After 20 hours, the levels of PGE2 produced cultivated papillary cells, assessed using the Biotrak kit supplied in the sale of the company Amersham, following the supplier's instructions. This method allows to assess the inhibitory effect of these tripeptides on the production of PGE2 induced by Pro-inflammatory cytokines: interleukin-1 (see tab.4).

From these results it is seen that the tripeptides containing either the form (D)-Pro, either in the form of (L)-Pro occurring in nature, comparative anti-inflammatory activity.

Example 5: Examples of compositions containing the Tripeptide Ac-LPV-NH2*.

These compositions are obtained by known methods, in particular, by a simple mixing of the ingredients.

Composition 1: Aerosol, 2:

Ac-LPV-NH2* - 510-6< / BR>
Minoxidil - 0.5 g

Ethanol 95o- 55,1

Propylene glycol - 22,8

Odorant - sufficient.

Water demineralized - a sufficient number to 100.

Dyes - sufficient.

Water demineralized - a sufficient number to 100

Composition 3: Liposomal gel, g:

Natipide II(or 2 g of phospholipids) - 10

Ac-LPV-NH2* - 510-5< / BR>
Carbomer - 0,25

Triethanolamine is a sufficient amount of pH 7.

Preservatives - sufficient.

Water demineralized - a sufficient number to 100.

(Natipide II - a Mixture of water/alcohol/lecithin company Nattermann)

Track 4: Nissany gel, g:

Chimexane NS - 1,8

Staroignat of moonacre - 0,2

Ac-LPV-NH2* - 7,5-10-4< / BR>
Carbomer - 0,2

Triethanolamine is a sufficient amount for pH=7.

Preservatives - sufficient.

Perfumes - sufficient.

Water demineralized - a sufficient number to 100.

(Chimexane NS - non-ionic surfactant, supplied by the firm Simex)

Composition 5: Nissany lotion, g:

Chimexane NL value (0.475)

The cholesterol value (0.475)

Staroignat of moonacre - 0,05

Ac-LPV-NH2* - 10-3< / BR>
Preservatives - sufficient.

Color is I - a sufficient number to 100.

(Chimexane NL - non-ionic surfactant, supplied by the firm Simex)

Track 6: care Cream: emulsion M/g:

Cetylstearyl alcohol/acetyltyrosine cetylstearyl alcohol containing 33 mol of ethylene oxide (80/20) - 5

Glycerol monostearate - 1,5

Cetyl alcohol - 0,75

Vaseline oil - 10

The polydimethylsiloxane - 0,75

Glycerin - 4

Preservatives - Sufficient.

Ac-LPV-NH2* - 510-3< / BR>
Water demineralized - a sufficient number to 100.

Track 7: the Solution for subcutaneous injection:

Ac-LPV-NH2* - 0.7 mg

Saline solution (NaCl 9 g/N2About a sufficient amount to 100 ml) is sufficient to 1 ml.

*: Acetyl-(D)Lys-(D)Pro-(D)Val-NH2< / BR>
**: Acetyl-(L)Lys-(L)Pro-(D)Val-NH2< / BR>
***: Acetyl-(L)Lys-(D)Pro-(L)Val-NH2:

1. The use of at least one peptide containing the C-end of the Tripeptide Lysine-Proline-Valine, in which a Proline residue is in the form of programalso optical isomer (Dpro) as an active ingredient of a medicinal product for the treatment of inflammation by topical application or the bottle: the zine-Proline-Valine, in which a Proline residue is present in the form of his programalso optical isomers (D-Pro).

3. Application under item 1 or 2, characterized in that the peptide is a Tripeptide Lysine-Proline-Valine, in which residues of Lysine, Proline, Valine are in the form of programada optical isomers (D-Lysine-D-Proline-D-Valine).

4. The use according to any one of paragraphs. 1-3, characterized in that the peptide is in protected or unprotected form.

5. Application under item 4, characterized in that the protection is carried out either by acylation or acetylation of amine end, or by amidation of carboxyl end or both reactions.

6. Application in the cosmetic composition according to any one of paragraphs. 1-5, characterized in that the Tripeptide Lysine-Proline-Valine, in which a Proline residue is in the form of his programalso optical isomers (D-Pro), used in concentrations from 10-12up to 10-3M, and preferably from 10-9up to 10-4M

7. The application for obtaining a medicinal product according to any one of paragraphs. 1-5, characterized in that the Tripeptide Lysine-Proline-Valine, in which a Proline residue is in the form of his programalso optical isomers (D-Pro), the FDS cosmetic treatment, characterized in that on the skin, hair and/or mucous membranes, with symptoms of inflammation, causing cosmetic composition comprising an effective amount of at least one peptide containing the Tripeptide Lysine-Proline-Valine, in which a Proline residue is in the form of his programalso optical isomers (D-Pro).

 

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3 cl, 16 tbl, 9 ex

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