WO2005079765A1

WO2005079765A1 - Compositions for the treatment of nail and skin disorders

Info

Publication number: WO2005079765A1
Application number: PCT/EP2005/001780
Authority: WO
Inventors: Adolfo Gasparetto
Original assignee: Euroderm Rdc S.P.A.
Priority date: 2004-02-24
Filing date: 2005-02-21
Publication date: 2005-09-01
Also published as: ITMI20040312A1

Abstract

Topical compositions are disclosed for the treatment of skin and nail disorders containing at least one active agent, an acidifier, an agent that increases the absorption of the active substances, at least one volatile solvent and a combination of two acrylates copolymer film formers, characterised in that the acidifying agents are selected from salicylic acid, glycolic acid and ascorbic acid, and the polymeric film forming agent is selected from copolymers of acrylic acid available under the Avalure brands, in particular Avalure AC 315 and Avalure AC 210.

Description

COMPOSITIONS FOR THE TREATMENT OF NAIL AND SKIN DISORDERS

This invention relates to compositions for the treatment of nail and skin disorders, including mycosis, bacterial infections, psoriasis, acne lesions, erythema, dermatitis and dermatosis. The invention also relates to a method for the treatment of normal conditions of the nails, in order to regulate their shape and growth. More particularly, the invention relates to a composition which can vary the degree and duration of adherence to the skin, thereby influencing its penetration. The invention also includes a varnish formulation which is useful to treat skin and nail disorders. BACKGROUND OF THE INVENTION US 6231875 describes compositions for the treatment of nail and skin disorders, in the form of topical compositions comprising a polymeric film former, an antibacterial and antifungal drug and a volatile solvent, which said compositions are acidified with hydrochloric acid. The same patent illustrates in detail the problem of pharmacological treatment of onychomycosis, which sometimes requires the administration of antifungals after removal of the nail. US 5696164 and EP 503988 relate to compositions comprising particular agents which facilitate the penetration of antifungals into the nail, such as cysteine, N-acetylcysteine, caprolactam, dimethyl sulphoxide, glycols and other hydrophilic compounds. US 2003/0091519 discloses compositions comprising sulphur-containing glycine residues and urea as nail penetration enhancers. WO 99/49835 also discloses compositions for the treatment of nail and skin diseases comprising a medicament, a volatile solvent and one acidifϊer: although several organic and inorganic acid are generically cited, a clear preference is given to strong inorganic acids, particularly 37% or 10% HC1. A film former may also be present. However, the need is still felt for a film-forming composition containing a substance which increases penetration and is therefore able to transport a drug into and through the nails, skin and mucous membranes in a therapeutically effective quantity, as demonstrated in earlier publications

(Eur J Pharm Biopharm) 2002 Jan; 53(l):23-7, J Pharm Sci. 1994 Oct;

83(10):1508-1510, J Pharm Pharmacol 9, 1991; 43(9):609-14, Skin Pharmacol

1991; 4(4) :235-245), and adheres to the nail, skin and mucous membranes for a lengthy period (7 to 72 hours). The invention therefore relates to a composition in the form of a varnish, lacquer or the like, which is non-irritant to the skin and mucous membranes and, more particularly, allows a selective adsorption of the medicament through the intercellular route rather than through the two other possible adsorption routes, namely that through cutaneous annexes (sudoriparous and piliferous bulbs) and the intracellular route through keratinocytes. SUMMARY OF THE INVENTION This invention relates to an acidified composition for the treatment of nail disorders such as onychomycosis and psoriatic onychodysplasia. The compositions according to the invention can also be used for the treatment of dermatological disorders such as dermatitis, dermatosis and disorders of the mucous membranes (oral and vaginal). The compositions according to the invention, characterised by the use of a specific class of film-forming agents, enable the time for which the varnish or film adheres to the skin, mucous membranes or nails, and absorption of the active substances, to be modulated. Transdermal delivery of drugs or chemical substances that require low dosages for long periods can be more effective, less costly, and less painful than traditional alternatives such as injection, intravenous infusion, or oral ingestion. The developed system is accurate and reliable delivery of chemical transport through the skin. This can yield vantages regarding the important features and processes that contribute to the retardation or blocking or enhancement of chemical permeation. Hair follicles and sweat glands that penetrate the skin, potentially creating shunts for chemical transport through the skin, developing, in this mode, systems that involve complex, multiphase, heterogeneous structures with transient diffusion and adsorption of chemical species. The block of variable systems or the use of part of this by chemical substances (eg. PVP, transcutol) allows a selective permeation trough the skin with beneficial effects in drugs/substances pharmacokinetic and pharmacodynamic. In particular, the invention comprises a composition containing at least one active agent, an acidifier, an agent able to increase the absorption of the active substances into the tissue (skin and nails), at least one volatile solvent and a combination of two polymeric film formers which, depending on the concentration, adheres to the surface to a directly proportional extent. The compositions according to the invention are preferably in the form of nail varnish, but may also be presented in forms more convenient for application to the skin, such as film-forming sprays and the like. The polymeric film formers consist of a mixture of a first acrylate copolymer having a molecular weight of about 5000, available under the trade-name of Avalure® AC 210 and a second acrylate copolymer having a molecular weight of about 200.000 available under the trade-name of Avalure® AC 315, in the concentration of between 0.5% and 20% of the total weight of the mixture, preferably from 0.5 to 5% weight/volume. The ratio between the low-molecular weight and the high molecular weight acrylate copolymers range from about 5:1 to 2:1, respectively. Preferably, the ratio of Avalure AC 201 /Avalure AC 315 is 3:1. The absorption promoter is preferably selected from among diethylene glycol monoethyl ether (Transcutol®), propylene glycol monolaurate, polyethylene glycol and derivatives thereof, dimethyl sulphoxide, N,N-diethyl-m-toluamide-sorbitan monolaurate, isopropyl myristate, undecylenic acid, linoleic acid and derivatives thereof, triethyl citrate and oxazolidinone or mixtures thereof, Polyvynylpyrrolidone(PVP), in concentrations ranging between 10% and 50% in weight. Diethylene glycol monoethyl ether is particularly preferred. The acidifying agent is selected from among salicylic acid, glycolic acid and ascorbic acid or mixtures thereof, in concentrations ranging between 1% and 10%. Salicylic acid, in concentrations of between 1% and 3%, is particularly preferred. The association of diethylene glycol monoethyl ether or similar substances with one of the acids specified enables the penetration and application time to be modulated as well as performing a synergic action. The volatile solvent comprises ethanol, ethyl acetate, isopropanol, butyl acetate and acetone, preferably ethanol, at a concentration of between 5% and 80%. The active agent can be selected substantially from among all the active constituents having the desired activity for the required therapeutic purposes. In particular, antifungals, antibacterials, antihistamines, antibiotics, retinoids, hormones and growth factors, anti-inflammatories, local anaesthetics, steroids and immunosuppressants can be used. Examples of these drugs include: amphotericin B, miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, butenafine, undecylenic acid, haloprogin, tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifϊne, elubiol, griseofulvin, corticosteroids, calcipotriene, anthralin, minoxidil, retinoids, cysteine, N-acetylcysteine, methionine, glutathione, biotin, finasteride, ethocyn, tea tree oil, mupirocin, bacitracin, neomycin, polymyxin B, levofloxacin, chlortetracycline, oxytetracycline, tetracycline, clindamycin phosphate, gentamicin sulphate, erythromycin, gamma linoleic acid, tretinoin, isotretinoin, acitretin, benzoyl-peroxide, azelaic acid, dapsone, tar, etretin, placenta extracts and growth factors, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium, phenol, quaternary ammonium compounds, urea, triclocarban, triclosan, iodopovidone, zinc peroxide, lidocaine, benzocaine, antihistamines (dexchlorpheniramine, dimetindene, diphenhydramine, isothipendyl, promethazine, loratadine), immunosuppressant agents (e.g. mycophenolic acid, cyclosporin and tacrolimus), immunobiological modifiers (e.g. interleukin and monoclonal antibodies), oestrogens, androgens, etc., possibly in the form of salts or pharmaceutically acceptable derivatives). Their concentration can obviously vary within wide limits which will be determined by experts in the field, according to pharmacological action and potency. Broadly, however, the percentage interval in weight of the total formulation will be between approx. 0.01 % and approx. 10%. The compositions according to the invention are prepared by suspending the polymeric film formers in water, and possibly heating under agitation to 60-80°C. After the addition of a neutralising base to the free carboxy groups, the other constituents, in particular the absorption promoter, the solvent (such as ethanol), the acid, any pH regulators and the active constituent, are added after cooling to obtain an aqueous polymer solution. Spray cans with pumps and dispenser caps are then filled, for example with 30 ~ 32 ml/can. The invention is described in detail in the following examples: EXAMPLE 1

EXAMPLE 2

EXAMPLE 3

EXAMPLE 4

The formulation in Example 4, containing 0.05%) retinoic acid, showedrox. 28% increase in the quantity of retinoic acid retained in the stratum corneum after 50 hours. The experiment was conducted with human skin stratum corneum, maintained with the epidermal side immersed in a flow of saline solution according to the Franz method at the temperature of 39°C, while the skin temperature measured was 32°C. The formulation was applied to the stratum corneum and evaluated by a non-occlusive method. The drug concentration in the cell receptors was evaluated by means of an HPLC assay. The flow, permeability, stability coefficient and diffusion coefficient in the stratum corneum were determined by the cumulative permeability (micrograms/ sq.cm) in relation to the time of application. Molecular diffusion was calculated according to the Flynn and Stewart method (1988). The result demonstrates that this formulation is effective in increasing the local deposit of retinoic acid in the stratum corneum.

Claims

1. Topical compositions which contains at least one active agent, an acidifier, an agent able to increase the absorption of the active substances, at least one volatile solvent and a polymeric film former, characterised in that the acidifying agents are selected from salicylic acid, glycolic acid and ascorbic acid and the polymeric film formers consist of a mixture of a first acrylate copolymer having a molecular weight of about 5000, and a second acrylate copolymer having a molecular weight of about 200.000.

2. Compositions as claimed in claim 1, wherein the acidifier is salicylic acid in concentrations of between 1% and 3%.

3. Compositions as claimed in claim 1 or 2, wherein the polymeric film former is present in concentrations in the concentration of between 0.5% and 20% of the total weight of the mixture, preferably from 0.5 to 5%.

4. Compositions as claimed in any of claims 1 to 3, wherein the absorption promoter is selected from diethylene glycol monoethyl ether, propylene glycol monolaurate, polyethylene glycol and derivatives thereof, dimethyl sulphoxide, N,N-diethyl-m-toluamide-sorbitan monolaurate, isopropyl myristate, undecylenic acid, linoleic acid and derivatives thereof, triethyl citrate, PVP, oxazolidinone or mixtures thereof, in concentrations ranging between 10% and 50% in weight.

5. Compositions as claimed in any of claims 1 to 4, wherein the volatile solvent is selected from among ethanol, ethyl acetate, isopropanol, butyl acetate and acetone.

6. Compositions as claimed in claim 5, wherein the volatile solvent is ethanol in the concentration of between 5% and 80%.

7. Compositions as claimed in any of claims 1 to 6, wherein the active ingredient is selected from among antifungals, antibacterials, antihistamines, antibiotics, retinoids, hormones and growth factors, anti-inflammatories, local anaesthetics, steroids and immunosuppressants.