Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2000-06-16
2004-04-06
Criares, Theodore J. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S450000, C514S002600, C514S063000, C514S506000, C514S579000, C514S740000, C514S886000, C514S909000, C514S912000, C514S937000, C514S944000, C514S945000, C514S914000
Reexamination Certificate
active
06716436
ABSTRACT:
The present invention concerns a new cosmetic composition for slimming containing L-arginine, an L-arginine analogue, or one of their derivatives, for topical application.
Cosmetic industry is continuously searching for new performing and really efficient active ingredients to fight localised adipose overloads.
Adipose tissue is mainly constituted of adipocytes, which are metabolically very active cells maintaining the energetic balance in the organism by two antagonist metabolic pathways:
lipogenesis, i.e. biosynthesis from glucose and fatty acids, of triglycerides stored into the adipocytes.
lipolysis, which is the hydrolysis of the triglycerides to glycerol and free fatty acids.
Amoung the slimming cosmetic products commercially available are compositions acting by inhibition of lipogenesis, containing inhibitors of glucose uptake or binding which is necessary for the triglycerides synthesis.
Other slimming products aim to stimulate lipolysis by acting on the AMPc level which stimulates the lipase activating the hydrolysis of triglycerides; most of these products contain xanthic bases, especially caffeine, usually associated with vegetal extracts which increase their activity. Some products contain active ingredients which have an action on &agr; and &bgr; adrenergic receptors which respectively inhibit and stimulate lipolysis.
The influence of sexual hormones and catecholamines on &bgr;-receptors was recently shown, but their use in cosmetic is forbidden.
Recent improvements in understanding the mechanisms of regulation of the adipocyte lead to consider new cosmetic strategies concerning slimming products for topical use.
The new approach described in this patent is the use of a topical lipolytic active ingredient acting on the adipocyte by inducing the release of a cellular mediator.
A researchers team has recently identified a potential regulator of lipolysis: the nitric oxide radical (NO
o
) or its related redox forms (Modulation of White Adipose Tissue Lipolysis by Nitric Oxide, Gaudiot et Coll., J.Biol. Chem., 1998, 273, 13475-13481). It arises from this work that, in an appropriate environment, NO
o
radical can act as a lipolysis stimulation factor.
Nevertheless, nitric oxide itself or a NO-donor use are not suitable for cosmetic applications.
Actually, nitric oxide radical has many physiologic properties because it is a cellular mediator acting particularly on vascular and neuronal systems.
Nitric oxide is also a potential cellular toxin involved in the immune response. In the skin, NO
o
takes part in the inflammatory response (for instance during photoinduced stress), modulates melanocytes activity or cellular proliferation in wound healing process.
Furthermore, in some cases, nitric oxide radical can generate in vivo toxic by-products such as peroxinitrous anion.
Thus, one of the aim of the present invention is to solve a part of the above mentioned problems providing a cosmetic composition for slimming, which contains a cosmetic active ingredient able to generate nitric oxide radical in an endogenous way.
L-arginine is the natural substrate of NO-synthase, the enzyme that metabolises arginine to release nitric oxide radical. This enzyme is naturally present in the adipose tissue and maintains a basal level of NO
o
.
Is was shown that an extracellular supply of L-arginine led to NO
o
production.
Although this enzyme is very specific, it was proved recently that it could accept other substrates, particularly an analogue of L-arginine, homo-L-arginine.
In the scope of this new cosmetic approach, the topical application of the active ingredient was taken in account, which raises the question of its bioavailability that is to say its ability to act on its main biological target: the adipocyte. This kind of cell is not localised in the direct vicinity of the active ingredient application area, but in a deep layer of the skin, hypodermis.
That is why an important aim of the invention is increasing the bioavailability of the cosmetic active ingredient according to the invention.
Thus, one of the characteristics of the cosmetic composition according to the invention is to reduce L-arginine (or its analogue) degradation (by arginases) or metabolisation in skin's upperlayers, or to improve its cutaneous penetration.
NO-synthase is also present in the cells of the upperlayers of the skin, as keratinocytes and fibroblasts.
So an other characteristic of the invention is to avoid any possible side effects that may result from NO
o
production by skin's upperlayers.
A positive consequence of NO-synthase presence in skin's upperlayers is that the lipolytic composition containing NO
o
precursor will be able to produce a lipolytic signal which may be transmitted to a deeper layer as hypodermis.
Furthermore, endothelial cells, which form the wall of microvessels irrigating dermis and hypodermis, also have NO-synthases and may contribute to the lipolytic effect. Moreover, they can also help decreasing excess adipose tissue by a special mechanism: NO
o
can induce a vasodilatation which can promote adipose tissue's draining.
At last, a possible mode of action of nitric oxide radical, suggested by new experimental data, could result from its ability to act against preadipocytes multiplication. Preadipocytes are precursor cells which differentiate in mature adipocytes, able to store fat. This property could fight very efficiently against adipose tissue increase.
The present invention consists in the use of L-arginine, an L-arginine annalogue, or one of their derivatives (or any of their salts) as an endogenous precursor of NO
o
, in cosmetic compositions for slimming with topical application.
So far, L-arginine, L-arginine analogue or their derivatives had never been used as NO
o
precursor for slimming.
The patent N
o
FR-A-2.758.724 provides a composition against cellulite and adipose tissue's excess, said composition comprising protamine, a protein containing among other aminoacids arginine. Thus, protamine may have an inhibitory action on fatty acids captation by adipocytes in the subcutaneous adipose tissue. Protamine may act by inhibition of lipogenesis, which is not the effect described in the present invention.
Arginine is also used in the patent N
o
FR-A-2.745.498 which describes a therapeutic composition associating arginine and silicon used in high-protein low-calorie diets. This composition is orally administrable and aims to improve the effectiveness of a high-protein diet thanks to the lipolytic activity of silicon and to avoid side effects on kidney function with arginine. The patent N
o
EP-A-0.281.435 relates to a therapeutic product consisting in asilanols-aminoacids complex, said product being appropriate to prepare medicines which are regulators and activators of metabolism, growth and multiplication of some cells. The active agent is the silanol, which biological activity is improved by complexation with a natural aminoacid that can be L-arginine.
Lastly, the use of L-arginine as NO
o
precursor was described, but the purpose was protecting the tissues from oxidative stress (Cordeiro P. G., Santamaria E, Hu Q. Y. “Use of a nitric oxide precursor to protect pig myocutaneous flaps from ischemia-reperfusion injury”—Plastic & Reconstructive surgery, vol. 102, (1998) n
o
6, pp. 2040-2048).
The present invention relates to a new cosmetic composition for slimming comprising, in association with any cosmetically acceptable excipient, at least one compound which is L-arginine, an L-arginine analogue or one of their derivatives, or any of their salts, said compound having the following general formula:
where:
R
1
represents a hydrogen atom, an hydroxyl group, an acyl or acyloxy radical, or an aminoacid substituted or not on its free &agr;-amino function, bound by a peptidic bond,
R
2
represents an hydroxyl group, an amine, alkylamine or alcoxy radical, a silyloxy group, or an aminoacid substituted or not on its free &agr;-carboxylic function, bound by a peptidic bond,
and n is equal to 2 or 3
It is to be noted that the radicals R
1
and R
2
Criares Theodore J.
Exsymol S.A.M.
Lydon James C.
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