The present invention relates to use of chitosan, a chit an derivative or a physiologically acceptable salt thereof, for the preparation of a medicament, or a medical device, or a sanitary product, or a cosmetic, in form of a nail lacquer, useful for the topical treatment of inflammatory diseases of the nails, such as psoriasis, lichen planus and atopic dermatitis.
Psoriasis is a genetically predetermined hyperproliferative skin disease, characterized by increased cell proliferation, glycogen accumulation and incomplete differentiation in the cells of the epidermis. Nail involvement in psoriasis is common and has been reported in between 50% and 56% of cases. It is estimated that over a lifetime between 80% and 90% of psoriatic patients will suffer nail localization of psoriasis (de Berker, Baran & Dawber: the nail in dermatological disease. In: Baran & Dawber's: Diseases of the nails and their management. Baran et al Eds, 3rd ed. Blackwell Science, 2001). Overall, 58% of patients with nail psoriasis consider that this condition interferes with their job and 52% describe pain as a symptom. Nail psoriasis is affecting adults and children. In children, nail involvement has been found to range between 7% and 39% according to the different authors. In children with juvenile psoriatic arthritis, 80% of children developed pitting, a nail manifestation of psoriasis.
Severe nail involvement may not imply severe psoriasis of the skin and the type of the nail change is not associated with any particular distribution of the skin lesions. The clinical signs of psoriasis can be correlated with the site of involvement of the epidermal structures of the nail. The main psoriatic features in the nails are, in order of frequency:
1) pitting: pits are punctate depressions, usually small and shallow, that can vary in size, depth and shape. They originate from focal psoriasis of the proximal matrix (the region where the nail is formed). Most pits are superficial, and when extensive they can produce gross abnormalities in colour and texture, and can render the nail fragile. Histologically, pits represent a defect in superficial layers of the nail plate and when the psoriasis becomes more marked, a pit may enlarge and produce a hole in the nail plate.
2) discoloration of the nail: typical pictures are leuconychia (white nail appearance), when the nail matrix is involved, or salmon colour when the nail bed is involved. Psoriasis in the nail bed produces oval, salmon coloured, oily spots of various size.
3) onycholysis: this is a detachment of the nail plate from the nail bed. This occurs mainly when oily spots affect the hyponychium (the part under the nail plate) medially or laterally. Onycholytic nail has a yellowish colour, due to a combination of air and the accumulation of squames under the nail interface.
4) subungual hyperkeratosis: this is a thickening of the tissues under the nail plate. It is manifested as accumulated squames, and is an expression of the alteration of the keratin composition in nail bed psoriasis.
5) nail plate abnormalities: they include serial transverse depression, especially on the thumbs where they mimic washboard nails. Other common, abnormalities are longitudinal ridges of the nail with bumps that resemble drops of melted wax.
6) splinter haemorrhages: they occur in fingernails of 42% of psoriatic patients with nail disease and in 6% of their toenails. The sign reflects the orientation of the capillary vessels in the nail bed and the proliferation and fragility of these capillaries in active psoriasis.
There may be psoriatic scaling of the proximal nail fold with soft tissue swelling or chronic paronychia. The changes observed in the nail plate depend on the location and duration of the disease process. The lesions may reflect transient matrix dysfunction and be limited in extent, such as pits and transverse furrows. Alternatively, they may represent persistent disease and result in sustained nail abnormalities, such as loss or thickening of the nail plate. Besides the aesthetic appearance, the psoriatic nails are fragile and painful, and patients are prevented from their daily life activities.
The treatment of the nail psoriasis includes systemic and/or topical therapies. Systemic therapies include potent corticosteroids, Vitamin D analogues, retinoids or immunosuppressive agents, and are generally avoided due to their potential toxicity, unless the patient presents a very severe, generalized psoriasis.
Topical therapies are mainly for application to the base of the nail. At this site, they may treat psoriasis of the nail fold and penetrate through the underlying matrix to a limited extent. Some of the transverse ridging in the psoriatic nails is associated with inflammation of the proximal nail fold. If this is reduced, the matrix function returns towards normal and nail ridging diminishes. If onycholysis is present, the nail plate must be trimmed back to the point of separation.
Topical products used in psoriasis are the following:    1. corticosteroids: fluocinolone acetonide, triamcinolone acetonide, betamethasone salts, clobetasol propionate, are known in the art. All of them are applied under occlusive medication, and side effects such as distal phalangeal dystrophy have been reported (Deffer & Goette Archives of dermatology, 1987, 123:571-572. Requena of al. Archives of dermatology, 1990, 126:1013-1014).    2. calcipotriol: according to some literature reports (Kokely et al., 1994, J. Dermatol. Treatment, 5:149-150) topical calcipotriol may be useful as treatment of nail psoriasis. The limit of this therapy is represented by need of occlusive medication, which is bothersome for the patients, and risk of severe systemic side effects, due to the impairment of renal function and calcium metabolism, thus this drug is not recommended e.g. in children.    3. cyclosporine: topical cyclosporine was used in a single subject, applying a 10% oily preparation under occlusive medication for several months, with clinical benefit (Tosti A., Dermatologica, 1990, 180:110).    4. retinoids: topical use under occlusive medication of a tazarotene cream gave clinical benefit (Bianchi at al. Br J Dermatol. 2003, 149:207-9).
All topical treatments of nail psoriasis in the art are characterized by the need of occlusive medication, which is bothersome for the patient, impairs their quality of life and may be applied in practice only in the night hours. Thus, there is a strong unsatisfied need for new effective therapeutic agents, simple to use and safe enough to allow chronic use by patients.
Lichen planus is also an inflammatory disease of the skin, with evidence of a genetic susceptibility, probably due to an immune imbalance, often associated with systemic involvement (de Berker, Baran & Dawber: the nail in dermatological disease. In: Baran & Dawber's: Diseases of the nails and their management, Baran et al Eds, 3rd ed. Blackwell Science, 2001).
Lichen planus may involve the nail plate by appearing in the following clinical subtypes:                1) typical lichen planus        2) twenty nail dystrophy        3) idiopathic atrophy of the nails        
When a nail fold disease is present, this indicates that the proximal nail matrix is involved and nail plate changes are likely to occur soon afterwards. The nail gradually reflects the disease process with a longitudinal red line indicating a thinning nail plate, evolving to distal splitting, where it is most fragile. The next stage is complete split. Ulceration, hemorrhagic erosions and scarring may appear. Pitting is also a manifestation of lichen planus of the proximal nail matrix. Lichen planus seldom involves exclusively the nail bed and features of nail bed disease include hyperkeratosis and onycholysis.
The prognosis depends on the degree of matrix involvement and scarring. Complete involvement of nail matrix and nail bed will produce a total loss of the nail plate and permanent atrophy with scarring. Treatment is symptomatic, including oral corticosteroids, retinoids and azathioprine. Severe non-scarring types may be helped by topical treatment with potent corticosteroids.
Of course, nail inflammatory diseases are chronic conditions, that do not respond definitely to a therapeutic treatment. Thus, as for skin, the ideal treatment is lifelong and is put in practice as two or more therapeutic cycles per year for the patient's life.
Chitosan derivatives are amino-polysaccharides, derived from the chitin extracted from the exoskeleton of the crustaceans, known in the art for their use in different preparations for skin. KR20020084672 discloses chitosan as an ingredient of microspheres, useful as a carrier for separation of proteins or peptides; KR20020048534 reports chitosan as an ingredient of a pack composition for skin massage, including paraffin wax as an effective component; JP2005306746 is teaching the use of chitosan to obtain a wrinkle therapeutic agent as an ingredient of gel-like or spongy preparations of botulinus toxin. WO2005055924 reports chitosan derivatives as ingredients of hydrogels useful for cavity-filling wound dressings. JP2004231604 teaches compositions of chitosans having a high deacetylation degree, as an ingredient of a carrier sheet with a porous spongy texture. WO03042251 discloses compositions comprising chitosan in the form of a network of nano-sized fibres. WO02057983 discloses a multi-layered, air gap sheet of chitosan with a regular lamellar structure which retains drugs for a prolonged period of time; JP11060605 teaches an amphiphilic chitosan derivative which can be used as dispersion stabilizer or emulsifier in a drug for application to skin. US2004043963 discloses chitosan conjugated linoleic acid and a chitosan conjugated Vitamin A for the preparation of compositions for treatment of inflammatory skin diseases, including atopic dermatitis, eczema and psoriasis. Moreover, EP1303249 reports the use of water soluble chitosan derivatives as film forming ingredients of nail lacquers, including antimycotic agents for the treatment of nail fungal infections, whereas WO2004/112814 discloses a nail restructuring composition based on one herb extract from the genus Equisetum in combination with hydroxypropylchitosan, which is used as a film forming agent. The use of chitosans as film forming agents is also disclosed in WO2006111426 and in WO2007042682.
WO03051376 discloses the use of chitosan oligomers having a molecular weight of less than 10000 Da for preventing or reducing inflammation or hypersensitivity.
None of the references known in the art reports any activity of chitosans or chitosan amino-polysaccharides in nail inflammatory diseases, chitosans having being used until now as carriers of actives in various diseases or as a film forming agent in mycotic infections.
It has now surprisingly been found that chitosans, chitosan amino-polysaccharides and/or physiologically acceptable salts thereof, are useful for the topical treatment of inflammatory diseases of the nails, such as psoriasis, lichen planus, alopecia areata and atopic dermatitis. Chitosans and chitosan amino-polysaccharides permeate the keratin structures and reach the nail matrix, where the defect of keratinisation occurs during inflammatory diseases, by decreasing inflammation at that level, thus by allowing the growth of a healthy, smooth nail. When chronically applied onto the nail surface, nail lacquers containing chitosan or its derivatives result in a decrease or disappearance of pitting and of desquamation, thus rendering the nail less fragile and reducing pain.
Nail lacquers based on chitosan and/or chitosan derivatives, such as chitosan amino-polysaccharides, are simple to use and safe enough to allow chronic application by patients. Moreover, the nail lacquers may contain other agents active on nail inflammation, thus strengthening their activity and allowing a long lasting adherence to the nail surface, suitable for long lasting release to the nail, avoiding occlusive medications.
USPTO Backgrounds
USPTO Backgrounds