The present invention is in the field of pharmacotherapy. More specifically, it relates to the treatment of diseases and conditions affecting the nails of humans and other mammals.
While many cutaneous disorders affect the skin itself, there also exist diseases and conditions which relate to the skin appendages, in particular to the nails. These are often difficult to treat due to the thick and dense nail plate largely composed of keratin and its poor uptake of therapeutic agents.
Nails are hardenings of the horny zone of the epidermis. They appear as sheet-like appendages covering the skin on the dorsal side of the terminal phalanges of fingers and toes. The horny zone of the nail is composed of hard alpha-keratin and has a distal, exposed part, or body, and a proximal, hidden portion, or root. The root is covered by a distal prolongation of the stratum corneum of the skin. This narrow fold is composed of soft-keratin and is termed the eponychium. Distal to the eponychium is the “half-moon,” or lunula, a part of the horny zone that is opaque to the underlying capillaries.
Deep to the distal or free border of the nail, the horny zone of the fingertip is thickened and is frequently termed the hyponychium. The horny zone of the nail is attached to the underlying nail bed. The matrix, or proximal part of the bed, produces hard-keratin. Further distally, however, the bed may also generate nail substance. Moreover, the most superficial layer of the nail may be produced by the epithelium immediately dorsal to the root and proximal to the eponychium. The growth of the nail is affected by nutrition, hormones, and disease. Nail growth involves considerable protein synthesis, as a result of which nonspecific changes occur in the nails in response to various local and systemic disturbances.
Nails develop in the fetus as epidermal thickenings that undercut the skin to form folds from which the horny substance of the nail grows distally. In adult humans, it takes about 6 months for a fingernail to form, which corresponds to a growth rate of approx. 2-3 mm per month. Toenails tend to grow more slowly than fingernails.
Nails are about two magnitudes thicker than the stratum corneum of the skin. Hard alpha-keratin, the major constituent of the horny zone, is a fibrous structural protein characterised by a high content of cysteine which readily forms thermostable crosslinks via sulphide bridges. The water content of nails is rather low, and typically ranges from about 10 to 30%. Generally speaking, nails are very resistant to the permeation of molecules such as drug substances.
The main function of nails is to protect the sensitive tips of fingers and toes. In addition, fingernails serve in scratching. Toenails are also important for balance.
One of the most common diseases affecting the nail apparatus is fungal infection, also referred to as onychomycosis, a condition affecting about 20% of the adult population in the USA. The incidence is increasing worldwide. In fact, about 30% of all superficial fungal infections affect the nail. Infection may be due to dermatophyte (ringworm, tinea unguium), yeast, or other non-dermatophyte (mould) species. In paronychia, chronic infection of the nail fold is most often caused by Candida species, but bacterial infection with Gram negative species such as Pseudomonas may coexist. Acute paronychia (whitlow) due to staphylococcal infection may also occur, and the presence of these bacterial infections will influence management. Invasion of the nail plate by Candida species may occur in the presence of paronychia, immune deficiency states (including chronic mucocutaneous candidiasis), Raynaud's disease, or endocrine disorders.
Another common condition is nail psoriasis, one of the possible manifestations of psoriasis, which produces a variety of changes in the appearance of finger and toe nails. These changes include discolouring under the nail plate, pitting of the nails, lines going across the nails, thickening of the skin under the nail, and the loosening (onycholysis) and crumbling of the nail.
Most people who have psoriasis of the nails also have skin psoriasis (cutaneous psoriasis). Only 5% of people with psoriasis of the nails do not have skin psoriasis. In people who have skin psoriasis, 10%-55% have psoriasis of the nails (also called psoriatic nail disease). About 10%-20% of people who have skin psoriasis also have psoriatic arthritis, a specific condition in which people have symptoms of both arthritis and psoriasis. Of people with psoriatic arthritis, 53%-86% have affected nails, often with pitting.
Another condition of the nail is onychia, which is an inflammation of the nail folds surrounding tissue of the nail plate with formation of pus and shedding of the nail. One of the causes of onychia is a posttraumatic bacterial infection.
Onycholysis refers to a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the lunula. It may be related to numerous possible causes including infections and allergic reactions.
A number of other nail conditions such as onychodystrophy, onychomadesis, and onychoptosis often represent adverse reactions to drugs, for example antibiotics or anticancer agents.
Interestingly, conditions of the nails are rather often treated systemically, which itself indicates how difficult it is to achieve a therapeutic drug concentration in the nails by local administration. For example, onychomycosis is treated with oral terbinafine 250 mg daily for 3-6 months, or itraconazole 200 mg daily for 3-6 months. Even the rather conventional therapy with oral griseofulvin 10 mg/kg/daily (500 mg twice daily) for 6-18 months is still being recommended today. In particular proximal nail disease or severe nail bed involvement are being considered as indications for systemic rather than local treatment.
Some topical preparations of known antifungal agents for treatment of onychomycosis exist, such as nail lacquers comprising ciclopirox, amorolfine, or butenafine. While there is some evidence of efficacy, it is believed that successful topical antifungal therapy requires treatment over very long periods, such as a year or even more. Some experts recommend the combination of topical and systemic treatment for better efficacy. Without adequate treatment and patient compliance, the infection will not disappear.
Also for nail psoriasis, the most effective treatment options appear to be systemic rather than topical. Recent reports suggest that some injectable biological medicines such as infliximab and etanercept may be highly effective. However, these treatments are associated with substantial risks of adverse effects, and they are very expensive.
Topical treatments in their currently available formulations are considered much less effective. Solutions containing vitamin D derivatives such as calcipotriol may be applied twice daily to the nail folds. Topical high-potency corticosteroid solutions or ointments are another option. Some experts also recommend 5-fluorouracil cream applied to the matrix for 6 months to improve pitting and subungual hyperkeratosis. Antifungal treatment is indicated whenever a secondary fungal infection is present, which is very frequent in cases of nail psoriasis.
There have been various efforts to make topical treatment of nail diseases more successful, mostly focussing on an improved permeation of the drug substance into the nail matrix. Often, co-treatment with urea cream is recommended in order to soften the nail keratin and make it more permeable. While some evidence for an improved antifungal therapy in combination with urea exists, it still appears that systemic therapy with all its risks and adverse effects is considerably more effective.
Other permeation enhancers have been proposed for enhancing trans-nail delivery of antifungal agents, such as in U.S. Pat. No. 6,042,845, U.S. Pat. No. 6,159,977, U.S. Pat. No. 6,224,887 and U.S. Pat. No. 6,391,879. Most of the suggested compounds are however not approved for pharmaceutical products and exhibit unknown health risks.
U.S. Pat. No. 5,326,566 describes a composition of a pharmacological agent in combination with dibutyl adipate, or a mixture of dibutyl adipate and isopropyl myristate, which could enhance the penetration through keratin. However, substantial problems may arise when the penetration enhancers are incompatible with a particular drug substance, leading to drug instability and degradation into potentially harmful degradants.
US 2005/0079210 A1 proposes the use of liposomes the epicutaneous administration of drugs and cosmetically useful agents. However, liposomes are difficult to manufacture cost-effectively and in a reproducible manner.
Other delivery strategies for topical medications require the occlusion of the nail after administration, which is however perceived as inconvenient by many patients.
There clearly remains a need for pharmaceutical formulations and vehicles which allow the effective treatment of nail disorders by topical administration. It is therefore an object of the present invention to provide such improved compositions which overcome one or more disadvantages of known compositions. In particular, it is an object of the invention to provide compositions of topically active drug substances which can effectively penetrate the dense nail plate and which are convenient to use. Further objects of the invention will become clear on the basis of the description of the invention below, including the examples, and of the patent claims.