Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-23
2002-04-16
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S018700, C514S887000, C514S928000, C530S333000, C530S335000, C530S337000, C530S343000, C530S345000, C436S085000, C436S086000, C436S089000
Reexamination Certificate
active
06372717
ABSTRACT:
The skin is the largest organ of the body, but also the most exposed to various sources of harm: irritation due to the environment (pollution, allergies), to the weather (wind, rain, cold, solar radiation, drying), to physical treatments (shaving, epilation, abrasions, shocks). Whilst being a protective member of the whole organism against dehydration, against bacterial or molecular invasion, the skin serves also to communicate with the environment and to register sensations of touch. It is therefore completely provided with nerves, the sensations of pain or discomfort or quite localized in the epidermis of the entire body.
Anatomical, histological and physiological analyses have shown cells connected to the nervous system which could be the cells responsible, at least partially, for the trans- mission of the sensations of touch, and above all of pain. These cells are called “Merkel cells”.
Recent studies have shown by immunoreactivity, the presence of a certain number of neuropeptides at the level of the epidermis, adjacent the Merkel cells. Among these neuropeptides are enkephaline, a peptide of the sequence Tyr-Gly-Gly-Phe-Leu(Seq ID No:1), whose activity known at present is suppression of pain (analgesic effect) by action on the receptor of morphine in the brain. This peptide has been discovered, apart from cerebral tissue, in other places in the body, at the periphery, and hence also in the skin. Its role is not yet known. Other studies have shown that the release of the peptide in the brain, upon an inherent need with an analgesic effect, takes place by means of another peptide of the sequence Tyr-Arg. This peptide is not connected to the morphine receptor itself, but it induces the synthesis or the release of enkephaline and thereby provokes a rapid—but fleeting—suppression of pain. This peptide has until now only been found in the brain, and its activity has not been described other than by direct intracerebral administration.
The object of the present invention is the discovery that this peptide, and above all the lipophile derivatives of the peptide, have a calming, antalgic activity when applied to the human skin in a suitable cosmetic or dermopharmaceutical preparation.
The peptides correspond to the general formula: R1-L-Tyr-L-Arg-R2 in which R1=a group R3-C=O wherein R3 is an alkyl chain of C1 to C20, linear or branched, saturated or unsaturated, hydroxylated or not, or with R3=an aryl, aryl-alkyl, or alkyloxy, group, and in which R2=a group O-R4 wherein R4 is an alkyl chain of C1 to C20, or R2 equals an NH2 or NHX or NXX group wherein X is an alkyl chain of C1 to C4.
The non-lipophilic peptide H-L-Tyr-L-Arg-OH has only a slight activity by topical application, because it penetrates through the corneal layer only with difficulty. The modification which consists in attaching by an amide linkage a fatty chain (alkyl) or an aromatic residue (aryl) or their alkyloxy or aryloxy or arylalkyloxy variants on the NH of tyrosine, and/or attaching by ester linkage a fatty alcohol (alkyl) or by amide linkage a group NH2 or NHX or NXX wherein X=an alkyl chain of C1 to C4, confers on the peptide a substantially greater affinity for the skin and an increased power of penetration which increases very greatly the biological activity of the peptide.
The peptide can be obtained by conventional peptidic syntheses or by enzymatic route.
By way of example, arginine can be esterified with a short chain alcohol (butyl) by acid condensation, then Boc-tyrosine is attached to the ester of arginine by the conventional method of activated ester (ethyl chloroformate or DCC), then palmitic acid is attached by the acid chloride method to obtain N-palmitoyl-L-Tyr-L-Arg-O-butyl. The synthesis by enzymatic route uses enzymes of the chymotrypsin or trypsin type in a preferably anhydrous medium to couple the aminated acids Tyrosine and Arginine, then the tyrosine is acylated to obtain N-acyl-L-Tyr-L-Arg.
Those skilled in the art of peptide synthesis know how to prepare derivatives of the general formula indicated by the known methods.
The peptides and its derivatives, which are the objects of the present application, must be carried in a suitable cosmetic or dermopharmaceutical preparation. According to the nature of the residues R1 and R2 and X, it can have variable solubility. The preferred embodiment of the invention is constituted by peptides of the nature N-acyl
A
-L-Tyr-L-Arg-O-alkyl
B
, wherein acyl
A
is an alkyl chain of C1 to C18, preferably C1 to C4, and alkyl
B
is an alkyl chain of C1 to C18, preferably C8 to C16. A particularly preferred embodiment is constituted by the peptide N-Acetyl-L-Tyr-L-Arg-O-hexadecyl. It is obtained by synthesis in the following way:
300 ml of toluene is heated 100° C., then there is added 20 g of hexadecanol and 34 g of PTSA (paratoluene sulfonic acid), then there is gradually added 17 g of L-Arginine.HCl. A sterification is effected by refluxing overnight. Precipitation is effected with TEA, followed by filtration and drying of the precipitate (hexadecyl ether of L-arginine). Then 5.6 g of N-acetyl-L-tyrosine is prepared in 75 ml of THF, to which is added 3 g of N-hydroxysuccinimide in 20 ml of THF. There is added a solution of 5.3 g DCC (Dicyclohexylcarbodiimide) in 20 ml of dichloromethane. After quantitative formation of DCU and filtration, there is added a solution of the ester of L-Arginine in THF (14 g in 200 ml of THF) and this is allowed to react for 48 hours at ambient temperature. The solvent is evaporated and it is crystallized in water, then filtered and dried. The obtained product (18 g) is characterized by thin layer chromatography, HPLC, infrared and melting point (140-143° C.).
These peptides are generally not soluble in water, but can be dissolved in conventional cosmetic or dermopharmaceutical solvents such as ethanol, propanol or isopropanol, propylene glycol, glycerin, butylene glycol, ethoxydiglycol, polyethylene glycol, methyl or ethyl ethers of diglycols, cyclic polyols, ethoxylated or propoxylated glycols or any mixture of these solvents. Those skilled in the art know methods of preliminary solubilization of this type of molecule. The peptides can also be previously incorporated in cosmetic vectors such as liposomes, chylomicrons, macro-, micro- and nanoparticles as well as macro-, micro- and nanocapsules, or be adsorbed on powdered organic polymers, talcs, bentonites and other mineral supports. These solutions or preparations can then be used in creams, lotions, pomades or other cosmetic and dermopharmaceutical preparations.
REFERENCES:
patent: 4489062 (1984-12-01), Lowe et al.
patent: 4540682 (1985-09-01), Hardy et al.
patent: WO 94/09750 (1994-05-01), None
Fidler,Eur. J. Biochem.,vol. 163, pp. 303-312, 1987.*
Kaschet et al.,Biotechnology and Bioengineering,vol. 45, pp. 261-267, 1995.
Low Christopher S. F.
Mohamed Abdel A.
Sederma S.A.
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