The invention relates to compositions comprising hydroxyacids, acetyl amino acids and chitosan for dermoepidermal peeling treatment.

Prior art

The conditions known as skin aging and photoaging represent the objective dermatological manifestations of highly complex biochemical phenomena involving the skin cells and the superficial skin tissue structures and, above all, the deep skin tissue structures.

One of the main strategies used to improve signs of aging, such as loss of dermal trophism, loss of volumes, melanic pigmentation and the appearance of fine, deep wrinkles, is to apply chemical peeling preparations. Said preparations, which have been used for decades, consist of aqueous gels or solutions containing high concentrations of acids with exfoliating, dermostimulating and sebostatic activities, supported by substances with a dermoplastic action (retinoids) and a depigmenting action (azelaic acid, kojic acid, phytic acid and ascorbic acid). These preparations, containing alpha-hydroxyacids such as glycolic acid, beta- hydroxyacids such as salicylic acid, beta-keto acids such as pyruvic acid, and halogenated acids such as trichloroacetic acid (TCA), in high percentages by weight, ranging from 25 to 70%, and combinations thereof with phenols such as resorcin, are the main tools used for dermoepidermal chemical peeling.

More recently, dermostimulating peeling treatments, wherein a first preliminary treatment with alpha- and beta-hydroxyacids to induce keratolysis is followed by application of lipogels or pastes containing high concentrations of retinoids and depigmenting substances such as azelaic, kojic, phytic and ascorbic acid, represented a novel and more rational frame of reference for treating skin aging and photoaging syndromes with signs of hyperkeratosis, poor trophism and dermoepidermal plasticity, and melanic pigmentation [1,2]. High concentrations of retinoic acid and retinol palmitate, up to 10% w/w, elicit a significant increase in dermoepidermal tissue regeneration and, at the same time, a great reduction in sebaceous secretion [3,4]. These effects, which are well documented and confirmed by the medical literature and the presence on the market of well-known proprietary anti-acne products, are based on a receptor interaction between the retinoid and specific nuclear receptors which precede hyperexpression of genes. In particular, retinoids have proved to exert a skin-regenerating stimulus action, increasing the synthesis of glycosaminoglycans and dermal connective tissue proteins such as hyaluronic acid, collagen and elastin [5,6].

However, preparations based on acids and retinoids have some major side effects on the skin, due to the extent of their action mechanism: excessive exfoliation, irritation with sometimes marked inflammation and, in the case of longer-term application, symptoms such as frosting (coagulation of the proteins in the superficial and deep dermal regions) and hypertrophic scars [7].

These side effects are often poorly tolerated by patients, due to the skin pain and discomfort which may last for days, and to the necessary avoidance of social and working situations required by said medical practices, in view of the noticeable inflammation and desquamation which makes patients reluctant to be seen in public. In addition to said problems, there are also other difficulties such as increased risk of opportunistic infections such as cold sores or mycosis, caused by a temporary reduction in the local immune defences exerted by said preparations, and adverse events such as reactive hyperpigmentation and burns [7,8], in the event of medical malpractice or drug interactions.

DESCRIPTION OF THE INVENTION

It has now been found that the drawbacks of the prior art can be overcome by a polyaminoglucosan, in particular chitosan, N-acetyl cysteine and/or L- carnitine, with exfoliating hydroxyacids.

The object of the invention is therefore topical compositions intended for chemical dermoepidermal peeling, consisting of gelled aqueous solutions comprising chitosan, glycolic acid, N-acetyl-L-cysteine and/or L-carnitine. Chitosan therefore takes the form of a polycation, due to the presence of acids that salify glucosamine amino groups.

As well as renewing the epidermis, the compositions according to the invention promote mechanical drainage of melanic pigmentation, reduce its synthesis and induce a sebostatic and comedolytic effect, and are not highly invasive for the patient, as they only cause modest exfoliation and few irritative/inflammatory symptoms .

L-Carnitine, preferably in the form of a chloride, and N-acetyl-L-cysteine contribute to the exfoliating, sebostatic/lipolytic and depigmenting activity. Chitosan, a glucosamine polymer obtained by partial chemical deacetylation of the chitin obtained from marine Crustacea, is a film- forming polymer that only becomes water-soluble after protonation of the amino groups of the glucosamine of which it consists. Said protonation, which takes place at a pH less than or equal to 4, makes the chitosan simultaneously water-soluble and able to swell, giving rise to aqueous gels of varying viscosities. Gelling of chitosan in water in the presence of glycolic acid, L-carnitine and/or N-acetylcysteine makes the compositions according to the invention particularly practical for topical application (skin adherence), unlike liquid preparations, which tend to drip onto the patient's skin. At the same time, gelling reduces the relative aggressiveness of the individual acids, which penetrate the skin evenly, thus reducing accumulation, which can give rise to rashes. L-carnitine chloride performs a sebostatic and lipolytic action, associated with its known ability to increase the entry of fatty substrates into the cell mitochondrion. Said activity is particularly useful to increase the beta- oxidative use of the fats in adipose tissue in conditions such as seborrhoea and cellulite.

N-Acetylcysteine acts as a melanic depigmenting agent, by switching melanin synthesis by the melanocyte towards pheomelanin (synthesis of the pheomelanin precursors cisteinyl-DOPA and glutathionyl-DOPA) [9], and as a mitochondrion-protecting and antioxidant agent (NAC is the precursor of glutathione). NAC is also a hyaluronidase and dennal elastase inhibitor [10].

Chitosan, after being absorbed through the skin, undergoes gradual degradation in the dennal tissue in the presence of acids, leading to the release of glucosamine monomers and N-acetylglucosamine, substrates which selectively promote the synthesis of dennal hyaluronic acid and act as melanic depigmenting agents [11,12,13].

Chitosan preferably has a mean molecular weight, detennined by gel penneation (M _v ), ranging from 10,000 to 250,000 Daltons, and a degree of deacetylation ranging from 70 to 95%. Chitosan is present in concentrations ranging from 0.1 to 2% w/w of the finished preparation.

The concentrations by weight of gly colic acid can range from 30 to 70% w/w, more preferably from 40 to 60% w/w. The L-carnitine chloride concentrations can range from 6 to 15% w/w of the finished preparation.

The N-acetyl cysteine concentrations can range from 1 to 10% w/w of the finished preparation. Compositions containing both L-carnitine chloride and N- acetyl-L-cysteine are prefened.

Said compositions can also contain preservatives, for example sorbic acid salts such as potassium sorbate, benzoic acid salts such as sodium benzoate, and chelating agents such as phytic acid and EDTA.

The composition of the invention has surprisingly proved to induce an effective epidermolytic, depigmenting, lipolytic and sebostatic action, without giving rise to any significant exfoliation or imtative/mflammatory effects, and significantly improves patient compliance; on average, the isolation time from social and working situations was over 70% less than with peeling preparations containing the same concentration and type of acids. The composition also exhibited excellent manageability, very versatile application to a wide range of aesthetic skin syndromes such as skin aging, melanic hyperpigmentation, seborrhoea, comedonic acne and cellulite, and a high safety level, giving rise to few adverse effects, which are easily managed by the doctor and patient.

The invention is illustrated in greater detail in the examples below.

EXAMPLE 1

AGING FACE-NECK PEELING GEL (60% GLYCOLIC ACID)

*DD=degree of deacetylation

Preparation method

Prepare Phase A by dissolving K sorbate under stirring in the available water until completely dissolved. Prepare Phase B by sequentially dissolving N- acetylcysteine and L-carnitine HCl in 70% glycolic acid solution, heating gently to 50°C if necessary and stirring with a magnetic stirrer until completely dissolved (check that NAC has dissolved before adding L-carnitine HCl). Combine Phase A drop by drop with Phase B under stirring. Finally, disperse chitosan (Phase C) under stirring, maintaining t=45°C until complete hydration and a translucent dispersion without undissolved aggregates is obtained. Cool gel and check that the pH is 0.5<pH<0.8. EXAMPLE 2

SEBOREHOEA/ACNE PEELING GEL (40% GLYCOLIC ACID)

*DD— degree of deacetylation

Preparation method

Prepare Phase A by dissolving K sorbate under stirring in the available water until completely dissolved. Prepare Phase B by sequentially dissolving N- acetylcysteine and L-caraitine HC1 in the available water; then, when a clear solution without aggregates has been obtained, disperse the 70% glycolic acid solution under stining until a clear solution is obtained. Combine Phase A drop by drop with Phase B under stirring. Finally, disperse chitosan (Phase C) under stirring, maintaining t=45°C until complete hydration and a translucent dispersion without undissolved aggregates is obtained. Cool gel and check that the pH is 0.5<pH<0.8. EXAMPLE 3

CELLULITE AND ADIPOSITY PEELING GEL (60% GLYCOLIC ACID)

*DD= degree of deacetylation

Preparation method

Prepare Phase A by dissolving K sorbate under stirring in the available water until completely dissolved. Prepare Phase B by sequentially dissolving N- acetylcysteine and L-carnitine HCl in 70% glycolic acid solution under stirring until a clear solution is obtained. Combine Phase A drop by drop with Phase B under stirring. Finally, disperse chitosan (Phase C) under stirring, maintaining t=45°C until complete hydration and a translucent dispersion without undissolved aggregates is obtained. Cool gel and check that the pH is 0.5<pH<0.8.

REFERENCES

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2. Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging. 2006;l(4):327-48.

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4. Mukherjee S, Date A, Patravale V, Korting HC, Roeder A, Weindl G. Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clin Interv Aging. 2006;l(4):327-48.

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9. JP Benedetto, JP Ortonne, C Voulot, C Khatchadourian, G Prota and J Thivolet. Role of thiol compounds in mammalian melanin pigmentation: Part I. Reduced and oxidized glutathione. Journal of Investigative Dermatology, Vol 77, 402-405.

10. Sunitha K, Suresh P, Santhosh MS, Hemshekhar M, Thushara RM, Marathe GK, Thirunavukkarasu C, Kemparaju K, Kumar MS, Girish KS. Inhibition of hyaluronidase by N-acetyl cysteine and glutathione: role of thiol group in hyaluronan protection. Int J Biol Macromol. 2013 Apr;55:39-46.

11. Kimball AB, Kaczvinsky JR, Li J, Robinson LR, Marts PJ, Berge CA, Miyamoto K, Bissett DL. Reduction in the appearance of facial hyperpigmentation after use of moisturizers with a combination of topical niacinamide and N-acetyl glucosamine: results of a randomized, double-blind, vehicle-controlled trial. Br J Dermatol. 2010 Feb 1;162(2):435-41.

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13. Pohibinska A, Cwalinski J, Baum E, Breborowicz A. N-Acetylglucosamine modulates function of the skin fibroblasts. Int J Cosmet Sci. 2013 Oct;35(5):472-6.