Title:  Agents and compositions thereof for the hair treatment

United States Patent:  6,232,302

Assignee:  Crinos Industria Farmacobiologica S.p.A. (Villa Guardia, Como, IT)

Filed:  June 16, 1999

Foreign Application Priority Data:  Jun 16, 1998[IT] (MI98A1367)

Compositions containing depolymerized fucane sulphates characterized by the following parameters (percentages by weight on the dry product): Molecular weight: 5,000-30,000 dalton; Sulphur: 5-16%; Fucose: 25-60%; Uronic acids 2-25%; they increase the percentage of growing hair and inhibit the Pytirosporun growth on the skin.

Description of the Invention

The present invention relates to products to be used as trichogen agents to be topically applied on the scalp, to normalize the hair growth cycle, and as antimycotic agents of the skin microflora, therefore able to reduce dandruff.

More specifically it relates to trichogen agents or compositions thereof having an improved efficacy in increasing the hair percentage in the growing phase, and at the same time active as skin antimicrobic agents, lacking of side effects of the prior art antimycotics and having high skin tolerability.

The hair growth cycle is subdivided in three subsequent phases which periodically repeat themselves during ones lifetime: the anagen phase, in which the hair stalk elongation takes place, the catagen phase, wherein the progressive keratinization of the hair bulb takes place and there is no stalk growth, and telogen phase, wherein there is no change of the hair bulb or of the hair stalk.

The anagen phase usually lasts many months or years, and is much longer than both the catagen phase (3 weeks) and the telogen one (3 months). Under normal conditions about 85% of hair is in anagen phase, 1% in catagen phase and 14% in telogen phase (C. E. Orfanos, R. H. Happle "Hair and hair disease" Springer-Verlag 1990). In subjects having androgenic alopecia both the anagen phase and the percentage of the growing hair is reduced.

A trichogen agent is defined according to the present invention as a substance able to increase the hair growing percentage. Therefore a trichogen agent can contribute to normalize the growth cycle, lengthening again the anagen phase. The substances used as trichogen agents must remain in contact with the skin for rather long periods and therefore they must not cause skin tolerability problems.

On the cutaneous surface and on the scalp a microflora is present among the main components of which lipophilic yeasts of Pytirosporum type, which grow in zones rich of lipids, are counted. The oval Pytirosporum is the most diffused yeast on the scalp.

The excessive growth of the oval Pytirosporum causes the dandruff appearance. In some people with increased sebaceous secretion the proliferation of this fungus can cause also the seborrheic dermatitis, charaterized by seborrhea, exfoliation and inflammation.

From the foregoing it is clear that in order to preserve the morphologic and functional integrity of the skin and of the scalp it is important to maintain the host microflora at physiologic levels.

In order to reach this aim, according to the prior art, the skin is treated with preparations containing compounds having antimycotic activity as ketoconazole, lithium succinate, zinc pirythione, selenium sulphide. These compounds can cause undesired effects on the skin and on the scalp. For example ketoconazole causes local inflammation, dermatites; the lithium succinate is contra-indicated in patients affected by psoriasis since it is a potential inflammatory agent, zinc pirythione can cause peripheral neurites and selenium sulphide can cause inflammation of the scalp, of the conjunctiva and of the internal part of the skin folds. Consequently the contact times with the skin of the preparations containing these compounds must be reduced.

From the foregoing it is clear that according to the prior art it is not possible to carry out a single treatment to normalize the hair growth cycle and to prevent or reduce the dandruff.

It is also known that compounds that are to be used for the percutaneous supply must have a low molecular weight in order to be easily absorbed through the skin. It is also known that to obtain the topic absorption of the natural polymers it is necessary to lower the molecular weight thereof, generally high and in the range of various hundreds of Kilodalton, by a depolymerization process.

The European patent application EP 730,867 relates to the use in the skin and hair dermatological and cosmetic treatment, and in the scalp alopecia, of polymers obtained by depolymerization of polyanions of vegetable origin. The depolymerized products have a molecular weight-range between 5,000 and 100,000, and sulphur content in the range 5-20% by weight. Examples showing the trichogen activity of these products are not supplied, neither are described nor reference is made to methods allowing to obtain these compounds. No mention is made to the fact that the compounds reported in said patent application are active agents in inhibiting the Pytirosporum growth. Tests carried out by the Applicant have shown that among the polymers having the specifications of the depolymerized fucans reported in the patent application EP 730,867, obtained according to the processes of the prior art (see the comparative example) no product able to inhibit the Pytirosporum growth and therefore having antidandruff activity, is obtained, and besides the growth activity is meaningless.

The need was felt to use compounds being effective agents in increasing the hair percentage in the growing phase and at the same time skin antimicrobic agents, specifically active in the dandruff reduction and without the side effects of the prior art antimycotics and having high cutaneous tolerability.

It has been unexpectedly and surprisingly found that it is possible to meet altogether said requirements by using a particular class of depolymerized fucane sulphates having specific characteristics, which result effective in increasing the percentage of hair in the growimg phase and which are able to inhibit the Pytirosporum growth, both on the skin and on the scalp and besides they are lacking of side effects.

An object of the present invention are depolymerized fucane sulphates and their use as trichogen agents characterized by the following parameters (the percentages are by weight on the dry product):

Weight average molecular weight: greater than 5,000-30,000 dalton, preferably 5,500-30,000 dalton

Sulphur: 5-16%;

Fucose: 25-60%;

Uronic acids: 2-25%;

Specifically the fucanes as above defined are able to inhibit the oval Pytirosporum growth.

The depolymerized fucanes obtainable from Fucus vesiculosus, Ascophyllum nodosum, Ecklonia kurome, Eisenia bicyclis, Laminaria digitata, Laminaria japonica, Padina pavonia, Pelvetia canaliculata, Sargassum linifolium, Undaria pinnatifda are particularly preferred.

The methods for determining these parameters are described in the European published application No. 849,280 in the name of the Applicant, herein incorporated by reference.

The depolymerized fucane from brown algae having molecular weight 14,000-30,000 dalton to be used in the present invention are obtainable with the process described in the European published application No. 849,280 herein incorporated by reference.

The polymers having molecular weight lower than 14,000 dalton with the following chemical and chemical-phisical characteristics:

Weight average molecular weight: greater than 5,000-14,000 dalton

Sulphur: 5-12.5%

Fucose: 25-43%

Uronic acids: 9-25%

are obtainable with the following process:

a) dispersion in water under stirring of the alga dry and milled powder, or of the vegetable material as such, in water, so as to have a dry concentration of 12.5% w/w, at a temperature in the range 92-100^oC., extracting the vegetable material under these conditions for 16 hours;

b) suspension filtering and filtrate pH correction at a value in the range 2.0-2.5, removal of the precipitate formed by filtering, surnatant pH correction at a value in the range 6.5-7.5;

c) ultrafiltering on membrane having cut-off of 100,000 dalton to reduce the solution volume to 1/4-1/5 of the initial one, subsequent dialysis in the same equipment against 3 volumes of distilled water, optionally followed by a concentration step;

d) solution salting, addition of two volumes of a precipitating solvent, preferably of ethanol or acetone, and recovery of the crude extract;

e) depolymerization at the temperature of 55^oC. of the crude extract in aqueous solution in the presence of an inorganic salt Cu (II) in % weight ratio with the extract in the range 0.12-0.14%, and of 8% hydrogen peroxide in such amount that the ratio between the weight of the crude extract and the ml volume of the 8% hydrogen peroxide is in the range 1/4-1/10, for the necessary time, determined by lab. tests, to reduce the molecular weight in the range greater than 5,000 and 14,000;

f) solution filtering, salting and precipitation of the depolymerized fucanes Cu (II) salts by addition of 2-3 volumes of a precipitating solvent, preferably of ethanol or acetone;

g) precipitate dissolution in water at a concentration between 5 and 7% w/v and treatment with an ionic exchange resin in the Na⁺ form for about ten hours under slow stirring; resin removal and pH correction at a value in the range 6.0-7.0; salting and precipitation of the depolymerized fucanes in the form of their corresponding sodic salts by addition of 2-3 volumes of a precipitating solvent, preferably ethanol or acetone.

The experimental model which has been used in the present patent application to show that the invention depolymerized fucanes have an improved efficacy in increasing the percentage of the growing hair is described in the publication by M. P. Philpott et al. "Human hair growth in vitro" J. Cell. Sci. 1990, 97 463-471, modified by G. E. Westgate "Prolonged maintenance of human hair follicles in vitro in a serum free medium" J. Cell. Sci. 1993, 129 372-379. The Applicant has used in this experiment sound piliferous follicles, separated by strips of human scalp taken from the occipital zone of male subjects during autografting operations. The piliferous follicles have been cultured in suitable culture medium, containing the substances under examination, as specififed in the Examples.

This model reproduces the following main aspects of the normal physiological cycle of the piliferous follicle:

1) The growth rate of the hair stalk or stem (C. S. Harmon et alii, J. Invest. Dermatol. 1994, 103, 318-322).

2) the same anagen/catagen transition: the stalk proximal keratinization and the dermatic papilla condensation at the end of the anagen phase, which are the same morphological changes observed in vivo in the passage from the anagen phase to the catagen one (M. Taylor et alii, J. Invest. Dermatol. 1993, 100 237-239).

3) The inhibition by means of testosterone or of the epidermal growth factor (C. S. Harmon, see above) of the growth of the follicles in culture, with decrease of the amount of growing follicles.

In the prior art it has been verified that the cyclosporine A (M. Taylor, see above), which causes the side effect of the hairs growth in men, in the same model used by the Applicant, has prolonged the period of hair growth of human piliferous follicles. Therefore the model used in the present invention is predictive of the in vivo activity.

The depolymerized fucanes with the above described chemical and chemical-physical characteristics have shown themselves active in increasing in a statistically meaningful way (w<0.01) the percentage of the growing follicles, with rspect to the untreated controls, for the whole duration of the experiment (28 days) at the used concentration.

These compounds are therefore effective agents for topic administration on the scalp, to normalize the duration of the anagen phase in the cases in which it is reduced such as for example in alopecia.

Surprisingly the invention depolymerized compounds have shown themselves effective agents in inhibiting the oval Pytirosporum growth at very low concentrations, lower than 0.1% w/v.

Therefore the use of the invention depolymerized fucans as antimycotic agents is possible.

The acid depolymerization product of the comparative example has on the contrary no antimycotic property on the oval Pytirosporum.

The tolerability of the preparations containing the fucan sulphates of the invention has resulted very good.

The fucans according to the present invention, topically applied in cosmetic formulations prepared according to the prior art, result effective also in maintaining the cutaneous hydration physiological levels. Consequently the topic application on the skin of these susbstances allows to obtain various advantages.

The uses foreseen in the present invention are achieved by using fucane sulphates carried in preparations for topic use at concentrations in the range 0.01-20%. For compositions under the form of lotions and shampoos, that preferably are to be used for the scalp, concentrations of fucane sulphate in the range 0.01-1% are preferably used. In the creams and gel formulations, concentrations from 1 to 20% w/v are preferably used.

The preparations containing the depolymerized fucane sulphates of the present invention are topically applied, locally on the skin or on the scalp, by rubbing to facilitate the absorption thereof or optionally by devices known in the prior art (e.g. patch).

The preparations containing the depolymerized fucane sulphates of the present invetion are prepared according to methods well known to the skilled in the art. See for example in Remington's Pharmaceutical Sciences 15a Ed.

Claim 1 of 7 Claims

What is claimed is:

1. A method of increasing the percentage of hair in the hair growth cycle of the scalp and for inhibiting Pytirosporum growth on the skin and scalp, said method comprising topically applying an effective amount of a depolymerized fucane sulphate to the skin or scalp requiring treatment, said fucane sulphate having the following parameters:

a molecular weight greater than 5,000 and up to 30,000 daltons;

5-16% sulfur;

25-60% fucose; and

2-25% uronic acids.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.