WO2013093947A1

WO2013093947A1 - Cosmetic composition and uses thereof in the treatment of lipodystrophies

Info

Publication number: WO2013093947A1
Application number: PCT/IT2011/000416
Authority: WO
Inventors: Pasquale MOTOLESE
Original assignee: Motolese Pasquale
Priority date: 2011-12-21
Filing date: 2011-12-21
Publication date: 2013-06-27
Also published as: EP2793813A1

Abstract

The present invention relates to a cosmetic composition based on iron ion (Fe²⁺ and/or Fe³⁺) chelating agents and the use thereof for the non-surgical treatment of lipodystrophies and of so-called "cellulite". In particular, the composition of the present invention comprises at least one Fe²⁺ and/or Fe³⁺ ion chelating agent, at least one osmotic diuretic, at least one amino acid and at least one vitamin. Said composition makes it possible to considerably improve the aesthetic appearance of areas of the body, in particular the lower limbs, affected by an accumulation and structural alteration of adipose tissue. In fact, the degree of satisfaction of the subjects who underwent the cosmetic treatment of the present invention is high.

Description

"Cosmetic composition and uses thereof in the treatment of lipodystrophies"

DESCRIPTION

The present invention relates to a cosmetic composition and uses thereof for the non-surgical treatment of lipodystrophies and of so-called "cellulite". In particular, the cosmetic composition of the present invention is used for the non-surgical treatment of accumulations of localized adiposity and the skin imperfections produced by cellulite.

Lipodystrophy is a syndrome characterized by an alteration in some metabolic functions, affecting, in particular, the metabolism of glycides and lipids and microcirculatory function in subcutaneous adipose tissue, and by an alteration in the distribution and three-dimensional structure of body fat. The alteration in the distribution of adipose tissue causes a characteristic change in physical appearance due to an accumulation of adipose tissue in some regions of the body and a reduction in the volume of adipose tissue in other areas of the body.

For example, an accumulation of fat often forms at the base of the nape (a condition known as "buffalo hump") , around the breasts, or around the abdomen (a condition known as "protease paunch") , or the accumulation of fat can manifest itself through the presence of lipomas (small fat nodules) scattered along the body.

The reduction in cutaneous fat, on the other hand, causes a thinning of the limbs (above all the lower limbs) and thus the prominence of subcutaneous veins, a narrowing of the hips and thighs, a narrowing of the face (cheeks) with an increase in wrinkles and a thinning of abdominal skin.

Included among lipodystrophies, in particular among subcutaneous dystrophies, is a condition scientifically defined as oedematous fibrosclerotic panniculopathy and commonly known as "cellulite".

Cellulite is an unsightly condition that is very widespread. It is typical above all of the female population, and is characterized by the onset of alterations in the skin contour, in particular as regards the lower limbs.

An individual's hormonal and genetic traits, sedentariness and incorrect eating habits are undoubtedly important co-factors in the genesis of this condition; however, the nature and the etiopathogenesis of cellulite are still today very little known and a subject of controversy.

To date three etiopathogenetic theories of cellulite are known: (1) a maldistribution and consequent microcirculatory stasis in subcutaneous adipose tissue specifically tied to the female hormonal cycle; (2) a condition of chronic tissue phlogosis; and (3) a last anatomo-architectural hypothesis which identifies, as the determinant factors of this aesthetic alteration, the presence of fibrous septa perpendicular to the skin surface and the oblique orientation of fat lobules (which in males instead have a horizontal orientation) . The alteration in physical appearance associated with lipodystrophic conditions, including cellulite, is often at the basis of the severe awkwardness that affected subjects manifest in social relations.

In fact, in these subjects, the loss, often severe, of physical harmony has heavy psychosomatic repercussions which compromise the relational capacities of the subjects concerned to such a degree as to seriously undermine their social relations and thus their quality of life.

For this reason, a need has always been felt to find solutions for these aesthetically invalidating conditions, even if only to improve them.

Every subject predisposed to or affected by lipodystrophic conditions can autonomously put into practice remedies based on good sense which involve adopting a balanced lifestyle by exercising with a certain degree of regularity and adopting a healthy diet. At the same time, cosmetic products formulated for autonomous use can be utilized, for example creams, ointments or gels to be applied topically; these have the purpose of activating local circulation, but in any case give very scant results.

In order to improve the aesthetic damage provoked by conditions of lipodystrophy, such as the classic "orange peel" associated with cellulite, surgery is usually undertaken.

Some surgical techniques are highly invasive and require up to 3-4 months of recovery before the results can be appreciated. Moreover, they have associated side effects which can be very dangerous if not promptly dealt with by competent personnel in a properly equipped facility.

One of the most widely adopted surgical techniques is liposuction, which consists in aspirating part of subcutaneous fat.

The operation involves making small incisions in the area to be treated and cannulae connected to a suction apparatus are introduced into these incisions. The movement of the cannula provokes the breakdown of cellulite and adipose lumps, which are aspirated and eliminated.

The operation must be performed correctly; otherwise unattractive depressions of the skin may form. Furthermore, at the end of the operation elastic wrapping bandages are applied in the treated area and the final result is seen after around 3 or 4 months, when the oedema has resolved completely.

One variant of liposuction is microliposculpture, which is performed in localized areas (ankles, knees, neck, hips) with very small cannulae connected to a plastic syringe rather than a suction apparatus as in classic liposuction .

Alternately, recourse may be had to liposculpture, which is less invasive compared to liposuction because it involves making very small incisions associated with micro hematomas that resolve rapidly.

A very effective and minimally invasive technique (thus almost devoid of side effects) , associated with rapid recovery times, is mesotherapy, which is based on injecting a set of drugs at a low dosage using slender needles applied to multi injectors.

On example of a non-surgical cosmetic application for the removal of localized fat accumulations is the subject of patent EP1758590, in which a composition comprising sodium deoxycholate in a concentration of between 0.001 and 5%, without phosphatidylcholine, is administered, in particular by subcutaneous injection. As previously mentioned, in the art there exists a constant need to find better or alternative solutions for the cosmetic treatment of lipodystrophic conditions, especially those as widespread as cellulite .

The present invention fits into this context and solves the above-mentioned needs of the art with a cosmetic composition based on iron ion (Fe²⁺ and/or Fe³⁺) chelating agents. The Applicant has surprisingly found that the application of a composition comprising iron ion chelating agents enables excellent results to be achieved in the non-surgical cosmetic treatment of aesthetic lipodystrophies like cellulite. In fact, following the application of the cosmetic composition of the present invention, a considerable improvement is seen in the aesthetic appearance of the areas of the body, in particular the lower limbs, affected by the accumulation of adipose tissue and an alteration in the structure thereof.

The results of the treatment with the composition of the present invention showed a high degree of satisfaction among the subjects who underwent the cosmetic treatment.

In particular, the Applicant has surprisingly found that the application of the cosmetic composition of the present invention in areas of lipodystrophic adipose tissue is capable of removing the iron ions present in the interstices of adipose tissue and, consequently, avoids the severe damage that iron ions are capable of provoking in tissue. The presence of iron ions in the interstices of adipose tissue is likely to be caused by an increase in vascular permeability related to a condition of micro-circulatory stasis, induced by the female hormonal system, which evolves into a veno- lymphatic stasis. Once released from vessels, the iron ions flow together into the interstices of adipose tissue, where they exert their toxic/degenerative action by releasing free radicals which cause peroxidation of the lipids of the cytoplasmic membrane, with consequent tissue acidosis and an evolution toward tissue fibrosis and sclerosis.

Due to the damage caused by iron ions, a chronic inflammatory state arises in adipocytic tissue; it culminates in the degeneration and in some cases necrosis of adipocytes. The physiological repair of this area by the body induces the formation of atrophic fibrotic tissue, which is the cause of the skin depressions clinically observable in subjects affected by cellulite.

Hereunder the Applicant sets forth a more detailed description of the cosmetic composition of the present invention and the cosmetic use thereof for the nonsurgical treatment of lipodystrophies, in particular cellulite .

The cosmetic composition of the invention comprises at least one iron ion chelating agent, at least one osmotic diuretic, at least one amino acid and at least one vitamin.

A first aspect of the cosmetic composition of the present invention regards the iron ion (Fe²⁺ and/or Fe³⁺) chelating agent, which is preferably selected from among: ethylenediaminetetracetic acid (EDTA) , phosphorylated carbohydrates, e.g. phytic acid, cyclodextrins, deferoxamine, kleptose, cycloamilose, dimercaptopropanol, penicillamine, deferoxamine mesylate, dimercaptosuccinic acid, trientine, acetylacetonate, tetraazacyclotetradecane, oxalate, crown ether, carbonate, 2, 2¹ -bipyridine, glycinate, nitrilotriacetate and polyamines selected from among: diethylenediamine, ethylenediamine, triethylenetetramine and/or combinations thereof.

The chelating agents preferred for the purposes of the present invention are EDTA, phytic acido and/or cyclodextrins.

The chelating agent particularly preferred for the purposes of the present invention is EDTA.

The cyclodextrins are preferably selected from among: alpha, beta and gamma cyclodextrins.

The concentration of said chelating agent preferably ranges from 0.01 to 3 %.

In some cases, said iron ion chelating agent can also be used for the purpose of chelating at least one metal ion selected from among: chrome, mercury, copper, lead, zinc, aluminium, manganese, calcium and magnesium.

A second aspect of the cosmetic composition of the present invention regards the osmotic diuretic, which is preferably selected from among: mannitol, urea, glycerol and/or combinations thereof.

The osmotic diuretic particularly preferred for the purpose of the present invention is mannitol. The concentration of said osmotic diuretic preferably ranges from 0.2 to 10%.

A further aspect of the cosmetic composition of the present invention regards the at least one amino acid, which is selected from among D and/or L amino acids; preferably, said at least one amino acid is an L amino acid .

In a preferred embodiment of the invention, the amino acid is selected from among: alanine, phenylalanine, glycine, isoleucine, leucine, methionine, proline, tryptophan, valine, asparagine, cysteine, glutamine, serine, tyrosine, threonine, aspartate, glutamate, arginine, histidine, lysine and/or combinations thereof. The amino acid preferred for the purpose of the present invention is selected from among: isoleucine, methionine, lysine, proline, glycine, serine, leucine, alanine, valine and/or combinations thereof.

More preferably, the amino acid is a combination of at least two or more amino acids selected from among: isoleucine, methionine, lysine, proline, glycine, serine, leucine, alanine and valine.

The amino acid preferred for the purpose of the present invention is methionine.

Preferably, the amino acid lysine used in the present invention is lysine hydrochloride, in particular of the L series.

The amino acid methionine used to produce the composition of the present invention is preferably SH methionine .

The concentration of use of said at least one amino acid ranges from 0.5 to 10.5%. In particular, _ the concentration of methionine ranges from 0.01 to 1%.

The concentration of isoleucine preferably ranges from 0.1 to 1%.

The concentration of lysine preferably ranges from 0.09 to 0.5%.

The concentration of proline preferably ranges from 0.1 to 1.3%.

The concentration of glycine preferably ranges from 0.1 to 1.3%.

The concentration of serine preferably ranges from 0.1 to 1.3%.

The concentration of leucine preferably ranges from 0.08 to 1.24%.

The concentration of the alanine preferably ranges from 0.02 to 1.36%.

The concentration of the valine preferably ranges from 0.06 to 1.18%.

A further aspect of the cosmetic composition of the present invention regards the at least one vitamin, which is preferably selected from among: A group vitamins, preferably retinoids or carotenoids as precursors of vitamin A; B group vitamins; C group vitamins, preferably ascorbic acid; D group vitamins; E group vitamins, preferably tocopherols; F group vitamins, preferably essential fatty acids, for example omega-3 and/or omega-6; G group vitamins, preferably riboflavin and/or vitamin B2; H group vitamins, preferably biotin and/or vitamin B8; I group vitamins, preferably inositol or vitamin B7; J group vitamins, preferably choline; K group vitamins; L group vitamins, preferably anthranilic acid; M group vitamins, preferably folic acid and/or vitamin B9 and/or vitamin Be; N group vitamins, preferably alpha lipoic acid; P group vitamins, preferably bioflavonoids; PP group vitamins, preferably niacin and/or vitamin B3; Q group vitamins, preferably ubichinon and/or coenzyme Q-10; R group vitamins, preferably para-aminobenzoic acid {PABA) and/or vitamin BIO; S group vitamins, preferably pteroylheptaglutamic acid and/or vitamin Bll; T group vitamins, preferably tocotrienols (dietary factor of sesame seeds) ; U group vitamins, preferably methylmethionine and/or S-methyl-L-methionine ; V group vitamins; group vitamins, preferably pantothenic acid and/or vitamin B5; X group vitamins; Y group vitamins, preferably pyridoxine and/or vitamin B6; Z group vitamins, preferably zinc and/or combinations of said vitamins .

The vitamin particularly preferred for the purpose of the present invention is vitamin C or ascorbic acid.

The concentration of said at least one vitamin preferably ranges from 0.05 to 0.15 %.

The concentrations set forth above are to be understood as weight/volume percent concentrations (% w/v) in 100 ml (100 g) of water.

The composition of the present invention is characterized by a pH that ranges between 6 and 8.

Said pH values of the cosmetic composition of the invention are reached by using a buffer, which is preferably selected from among: a bicarbonate buffer, a phosphate buffer, an acetic acid-sodium acetate buffer, an ammonia-ammonium chloride buffer, an ammonium acetate buffer, an ammonium carbonate buffer, a tricine buffer and a HEPES buffer and/or combinations thereof.

The buffer system particularly preferred for the purpose of the present invention is sodium bicarbonate, most preferably at a pH ranging between 6.7 and 7.2.

The cosmetic composition of the present invention is characterized by an osmolarity preferably comprised between 400-600 mOsm/kg, more preferably between 450-550 mOsm/kg .

The cosmetic composition of the present invention can further comprise at least one pharmacologically acceptable excipient, or a compound acceptable for veterinary use or for human pharmaceutical use, which is useful in the preparation of the composition and is generally biologically safe and nontoxic.

The cosmetic composition of the present invention can further comprise: lubricating agents; humidifying agents; emulsifying and/or suspending agents; preservative agents; dispersing agents and molecules capable of facilitating tissue penetration.

A further aspect of the present invention regards the formulation of the cosmetic composition of the invention, which can be an injectable and/or deliverable solution .

The cosmetic composition of the invention can be, alternatively, formulated as tablets, granules or a solution for oral administration.

Alternatively, the cosmetic composition of the present invention can be formulated for topical use as a cream, gel, oil, emulsion or ointment.

The composition can be formulated to release the active ingredients contained therein rapidly or in a delayed and/or controlled manner after administration.

The formulation of the cosmetic composition preferred for the purpose of the present invention is an injectable and/or deliverable solution.

The cosmetic composition is preferably injected subcutaneously and/or intradermally and/or delivered transdermally .

The injection and/or delivery of the cosmetic composition of the present invention are preferably performed using a mesotherapy protocol.

The cosmetic composition of the present invention is used for the treatment of lipodystrophies and/or for non-surgical removal of accumulations of localized adiposity .

In particular, the cosmetic composition of the invention is used for the non-surgical treatment of cellulite.

For this purpose, the application of the present cosmetic composition, preferably as an injectable and/or deliverable solution, preferably for subcutaneous, intradermal (mesotherapy) and/or transdermal administration, can be combined with or associated with further lipodystrophy treatment protocols.

Said treatment protocols are selected from among: administration of (exposure to) external or internal ultrasound, administration of (exposure to) radiofrequencies, and administration of (exposure to) laser and carboxytherapy. In combination with or as an alternative to said treatment protocols it is possible to use: ultrasound, ionophoresis , electrophoresis, radiofrequencies, cryophoresis, occlusive skin techniques and/pr passive and active skin absorption. EXAMPLE

In order to demonstrate the effectiveness of the composition of the present invention, three female subjects were submitted to a mesotherapeutic cosmetic treatment with the composition of the invention.

The injectable formulation of the cosmetic composition of the invention contains the elements indicated in Table 1, in the respective percentage amounts.

TABLE 1

The three subjects are 33, 35 and 40 years old, are in good overall conditions of health and of normal weight. The same exhibit clinical signs of the presence of cellulite. At the start and at the end of the cosmetic treatment, the treated subjects were submitted to a biopsy of subcutaneous tissue in the anteroposterior region of the thigh.

The histological preparations were stabilized in paraffin and submitted to Perls' staining (Prussian blue) for the purpose of identifying the presence of iron and hemosiderin.

The stained histological preparations were observed under an optical microscope and the results demonstrated that at the start of the cosmetic treatment the adipose tissue was made up of cells of varying dimensions (anisopoikilocytosis) and delimited by a broad area of steatonecrosis .

When the same tissue was observed at greater magnification, it was noted that, in an almost preponderant manner, within the steatonecrotic component there was a widespread presence of hemosiderin, which after Perls' staining appeared blue. At the end of the treatment with the cosmetic composition of the invention, the tissues showed a reduced quantity of iron and there was a subjective improvement in the skin' s appearance based on self- evaluation .

The presence of iron ions in the adipose tissue of the women analyzed (affected by cellulite) is most likely ascribable to a condition of arteriolar stasis, which subsequently becomes a veno-lymphatic stasis induced by sex hormones. The vessel stasis provokes an increase in vascular permeability and thus the passage of iron ions into the interstices of adipose tissue, where the iron ions provoke the release of free radicals, which in turn cause peroxidation of the lipid of the cytoplasmatic membrane arid hence tissue acidosis accompanied by cell, degeneration and necrosis.

The consequent physiological tissue repair by the organism leads to the formation of areas of fibrosis and of tissue atrophy, which are at the basis of the skin depressions clinically observed in subjects affected by lipodystrophies such as cellulite.

After the cosmetic treatment according to the present invention, the iron ions are chelated and rendered soluble and then removed from the tissue. This detoxification results in a better tissue function, with a visible improvement in the skin contour.

Claims

1. A cosmetic composition comprising:

at least one on ion (Fe²⁺ and/or Fe³⁺) chelating agent;

• at least one osmotic diuretic;

• at least one amino acid; and

• at least one vitamin;

The cosmetic composition according to claim 1, wherein said chelating agent is selected from among: ethylenediaminetetracetic acid (EDTA) , phosphorylated carbohydrates, preferably phytic acid, cyclodextrins, deferoxamine, kleptose, cycloamilose, dimercaptopropanol, penicillamine, deferoxamine mesylate, dimercaptosuccinic acid, trientine, acetylacetonate, tetraazacyclotetradecane, oxalate, crown ether, carbonate, 2 , 2 ' -bipyridine, glycinate, nitrilotriacetate and polyamines selected from among: diethylenediamine, ethylenediamine, triethylenetetramine and/or combinations thereof. The cosmetic composition according to claim 1 or 2, wherein said chelating agent is used at a concentration that ranges from 0.01 to 3%.

The cosmetic composition according to any one of claims 1-3, wherein said chelating agent is selected from among: ethylenediaminetetracetic acid (EDTA), phytic acid and/or cyclodextrins.

The cosmetic composition according to any one of claims 1-3, wherein said chelating agent is ethylenediaminetetracetic acid (EDTA) . The cosmetic composition according to claim 1, wherein said at least one osmotic diuretic is selected from among: mannitol, urea, glycerol and/or combinations thereof.

The cosmetic composition according to claim 5, wherein the concentration of said at least one osmotic diuretic ranges from 0.2 to 10%.

The composition according to claim 5 or 6, wherein said at least one osmotic diuretic is mannitol.

The cosmetic composition according to claim 1, wherein said at least one amino acid is selected from among: alanine, phenylalanine, glycine, isoleucine, leucine, methionine, proline, tryptophan, valine, asparagine, cysteine, glutamine, serine, tyrosine, threonine, aspartate, glutamate, arginine, histidine, lysine and/or combinations thereof.

The cosmetic composition according to claim 8, wherein said at least one amino acid is selected from among isoleucine, methionine, preferably SH methionine, lysine, preferably lysine hydrochloride, proline, glycine, serine, leucine, alanine, valine and/or combinations thereof.

The cosmetic composition according to any one of claims 8-10, wherein the concentration of said at least one amino acid ranges from 0.5 to 10.5%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said methionine ranges from 0.01 to 1%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said isoleucine. preferably ranges from 0.1 to 1%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said lysine preferably ranges from 0.09 to 0.5%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said proline preferably ranges from 0.1 to 1.3%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said glycine preferably ranges from 0.1 to 1.3%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said serine preferably ranges from 0.1 to 1.3%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said leucine preferably ranges from 0.08 to 1.24%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said alanine preferably ranges from 0.12 to 1.36%.

The cosmetic composition according to any one of claims 8-11, wherein the concentration of said valine preferably ranges from 0.06 to 1.18%.

The cosmetic composition according to claim 1, wherein said at least one vitamin is selected from among :

A group vitamins, preferably retinoids or carotenoids as precursors of vitamin A; B group vitamins; C group vitamins, preferably ascorbic acid; D group vitamins; E group vitamins, preferably tocopherols; F group vitamins, preferably essential fatty acids, for example omega-3 and/or omega-6; G group vitamins, preferably riboflavin and/or vitamin B2; H group vitamins, preferably biotin and/or vitamin B8; I group vitamins, preferably inositol or vitamin B7; J group vitamins, preferably choline; K group vitamins; L group vitamins, preferably anthranilic acid; group vitamins, preferably folic acid and/or vitamin B9 and/or vitamin Be; N group vitamins, preferably alpha lipoic acid; P group vitamins, preferably bioflavonoids; PP group vitamins, preferably niacin and/or vitamin B3; Q group vitamins, preferably ubichinon and/or coenzyme Q-10; R group vitamins, preferably para- aminobenzoic acid {PABA) and/or vitamin BIO; S group vitamins, preferably pteroylheptaglutamic acid and/or vitamin Bll; T group vitamins, preferably tocotrienols (dietary factor of sesame seeds) ; U group vitamins, preferably methylmethionine and/or S-methyl-L-methionine; V group vitamins; W group vitamins, preferably pantothenic acid and/or vitamin B5; X group vitamins; Y group vitamins, preferably pyridoxine and/or vitamin B6; Z group vitamins, preferably zinc and/or combinations of said vitamins.

The cosmetic composition according to claim 21, wherein said at least one vitamin is vitamin C or ascorbic acid.

The cosmetic composition according to claim 21 or 22, wherein the concentration of said at least one vitamin ranges from 0.05 to 0.15%.

The cosmetic composition according to any one of claims I 23 characterized by an osmolarity comprised between 400-600 mOsm/kg, preferably between 450-550 mOsm/kg.

The cosmetic composition according to any one of claims 1-24, characterized by a pH comprised between 6 and 8.

The composition according to claim 25, wherein said pH is obtained using buffer system selected from among: a bicarbonate buffer, a phosphate buffer, an acetic acid-sodium acetate buffer, an ammonia- ammonium chloride buffer, an ammonium acetate buffer, an ammonium carbonate buffer, a tricine buffer and a HEPES buffer and/or combinations thereof; preferably said buffer is sodium bicarbonate .

The cosmetic composition according to any one of claims 1-26 formulated as an injectable and/or deliverable solution.

The cosmetic composition according to claim 27, wherein said injectable and/or deliverable solution is injected and/or delivered transdermally.

The cosmetic composition according to claim 27 or

28, wherein said injectable and/or deliverable solution is injected and/or delivered by mesotherapy.

A use of a cosmetic composition according to any one of claims 1-29 in the non-surgical treatment of lipodystrophies and/or for the non-surgical removal of accumulations of localized adiposity.

The use according to claim 30, wherein said lipodystrophy is cellulite. The use according to claim 30 or 31, wherein said treatment is associated with at least a further treatment selected from among: administration of (exposure to) external or internal ultrasound, administration of (exposure to) radiofrequencies , administration of (exposure to) laser, carboxytherapy and/or combinations thereof.

A cosmetic method for the non-surgical treatment of lipodystrophies, said method comprising the administration of a composition according to any one of claims 1-29.