Brief description of the invention

The present invention relates to the use of a pharmaceutical film forming nail lacquer containing a vitamin D metabolite or a vitamin D derivative, or a vitamin A derivative, or a combin¬ ation of such substances for the treatment of keratinic and/or psoriatic disorders affecting human nails on fingers and toes, the nail bed, the nail matrix, and/or the surrounding tissue.

Background for the invention

It is known that substances belonging to the groups of vitamin D metabolites, vitamin D derivatives and Vitamin A derivatives possess therapeutic activities against keratinic and psoriatic disorders of the human skin. Thus,drug products, suc as oint¬ ments and creams, are available for topical treatment of such skin disorders. However, treatment of the disorcerc. ,nen affect¬ ing nails and/or the tissues under and surrounαiπ -e nails, is difficult. Application of the therapeutic suBstάnce_ :- .πe forms of creams and ointments to nails does not cause __c_rr: :.-. into tissues to a sufficient extent. Such prepar3-:c--, :•.- r____y .ash¬ ed or wiped off the nails, and exposure is cc-.s. _ ^■ -• ^■ - ^* . • -_ch too short. Covering treated nails with paαs cr _a--_ .. - •• ^* .ip cream and ointment to stay in place, but icng ._. ^* - ^• .rr..:-r~ ^* .. ."• such man- ner is usually associated with poor patient .c~-._ _:_-__ .

Systemic treatment with drug of the therapeutic categories mention¬ ed is possible, but associated with considerable risks and side effects which most often may be considered unacceptable. Thus, syst¬ emic treatment with vitamin D metabolites and derivatives at a dose level sufficiently high to be effective for treatment of a skin disorder most likely will cause hypercalcae ia. Consequently, at this point in time, no products for oral administration containing vitamin D metabolites or derivatives have been developed and ap¬ proved for such indications. Systemic treatment with vitamin A derivatives is employed at rare occassions for treatment of severe cases of keratinic disorders and psoriasis. Such treatment is, however, associated with many side effects and also with the risk arising from the fact that

compounds of this group are documented as having teratogenic effects, which means that such treatment inevitably will have to be restricted. Thus, the unfavourable benefit/risk ratio of systemic treatment for disorders affecting nails means that such disorders may be left untreated which is much to the inconven¬ ience of the patients. A topical treatment for keratinic and psoriatic disorders affecting nails and their surroundings is therefore needed.

Detailed description of the invention

Therapeutic substances belonging to the categories of vitamin D metabolites and derivatives and vitamin A derivatives are often lipophilic and exhibit extremely low solubilities in solvents u- sually considered acceptable for long term exposure to the human body. On the other hand, these substances usually show high affin¬ ity to keratin.

The pharmaceutical nail preparation of the present invention com¬ prises a solvent system which is suitable for dissolution of the quantities of the active substances of these groups necessary for penetration at therapeutic levels into and through the nail plate. Such quantities may be several times higher than the concentrations usually employed in topical skin formulations. Among the solvents available for dissolution of lipophilic substances, the solvent system is selected to comprise solvents acceptable for short term exposure by application to the nail plates. As still another aspect the solvent system employed shall also be suitable for dissolution of the polymer resin selected for the preparation. Application of the lacquer preparation according to this invention containing a suitable solvent system and a suitable polymer resin dissolved therein will, after subsequent evaporation of the solvents, leave the active substances indwelling in the polymer in close con¬ tact with the keratinic nail plate.

The polymer resin is chozen among those offered by respectable pharmaceutical suppliers as being of innocuous nature. Furthermore, as a main characteristic of a suitable polymer resin, it shall form a water insoluble stable film layer on the nail surface, from which the active substance(s) can penetrate into the nail plate. It is an

important feature of the invention that the nail plate is given a functional role in the drug administration, namely the function of a drug depot gradually releasing the active substances to the tis¬ sue under the nail and surrounding it. A primary criterium for the choice of the solvent system is its ability to dissolve the active substance(s) and the polymer resin. However, the solvent system shall also be chozen in such a way that the solvents evaporate quickly after application of the lacquer to the nails, preferably within 3-5 minutes leaving on the nails a dry lacquer film being a stable continous self supporting layer of sufficient hardness, durability and flexibility. Various organic solvents may be suitable, in particular methylene chloride or iso¬ propanol, which is an efficient solvent for even the most sparingly soluble substances within the therapeutic categories concerned. Isopropanol is a preferred solvent since the main solvent primarily shall be of inert nature, and because isopropanol is known as being safe for application to human skin. Methylene chloride may be con¬ sidered less acceptable for exposure to skin, but nevertheless use- full in this particular case because of the very small quantities employed . It has the advantage of facilitating penetration into keratinic material, for which reason it may be used at least partly as a solvent in the nail preparation. By using it, it shall also be considered that it may exert other functions beyond that of an inert solvent and a penetration enhancer, sice it nay also act as an eva- poration enhancer at the same time.

The polymer resin preferred for the preparation of this invention, is an acrylic resin which is soluble in lower alcohols including isopropanol, and also in methylene chloride, and therefore, the sol¬ vent or solvent system chozen as being suitable for dissolution of the active substance(s) of the therapeutic categories concerned, is also appropriate as a solvent for the polymer resin. For compatibility with those of the active substances within said categories, being sensitive to acidic hydrolysis, it is important to select a polymer resin which is cationic in its character, since the use of an aqueous alkaline buffer system is not applicable to this non-aqueous organic solvent system.

Polymer substances having such qualities are commercially available the company Rohm Pharma under the trade mark EUDRAGIT". These resins are copolymerisates based on acrylic acid esters and methacrylic

acid esters having an average molecular weight of about 150,000 and which can be characterized by the following partial formula:

CH,

—CH-—-C—CH-—C— 2 i 2 i

in which R.. can be H or CH, and R_ can be lower aliphatic substi- tuents. Various types of these resins are available, and they may be used solely or may be mixed with one another according to the particular requirements. Polymer resins of this category have good swelling capacities and porosity which ensures a high rate of dif¬ fusion and a high rate of permeability for the active substance(s) . Furthermore, the use of such polymer resins also guarantees a high degree of resistance of the resulting lacquer film against washing off and against mechanical damage. This makes it possible for the active substance(s) to remain in close contact with the nail sur¬ face for a long period of time, and consequently the period between two applications can be as long as several days, may be 3-4 days, whereas daily application is still possible, if so desired. Before a new application to the nails, previously applied lacquer film shall be removed by use of a suitable solvent.

In addition to the main solvent, which may be inert, or which may be at least partially constituted by a solvent having other funct¬ ions in the preparation as well, the solvent system may also con¬ tain other solvents, part of which may be an evaporation enhancer selected to have a boiling point lower than the main solvent, and part of which may be an evaporation retarder selected among suit- able solvents having a boiling point higher than the main solvent. In a solvent system composed according to these principles and primarily based on isopropanol as the main solvent, methylene chloride may be a suitable evaporation enhancer, and in this way having a special functional presence in the solvent system.

Another possible evaporation enhancer will be ethyl acetate. As an evaporation retarder, butyl acetate is a suitable choice, al¬ though other miscible and compatible solvents having a boiling point at a similar level maybe chosen. Other examples of evaporat- ion retarders are toluene, butanol, amyl alcohol and amyl acetate. It is possible, if desired, within the scope of the invention to add to the nail lacquer also other functional constituents such as plastisizers, anti-oxidants, UV-absorbants, complex binders, preservatives and penetration enhancers. However it is not man- datory for the preparation if this invention, or for the use ac¬ cording to the invention that such compounds are included. The active substances to be used in the preparation according to the invention are compounds active against keratinic and/or pso¬ riatic disorders and selected from the groups of therapeutically active agents being vitamin D metabolites or vitamin D derivatives or vitamin A derivatives, or a combination of substances from these groups.

As an example of a vitamin D metabolite, calcitriol is most suit¬ able for the purpose. Active substances belonging to the group of vitamin D-derivatives may be selected from those described in the following published documents: a) Calverley, M.: Tetrahedron 43, 4609-4619 (1987), b) Binderup, L. and E. Bramm : Biochemical Pharmacology 37, 8B9-895 (1988), c) International Patent Application Number PCT/DK 66/00081, international filing date 14. July 19B6, d) International Patent Application Number PCT/DK 89/00079, international filing date 7. April 1989, e) Ostrem, V.K. et al: Proc. Natl. Acad. Sci. USA 84, 2610-2614 (1987) f) Abe, J. et al : FEBS Letters 226, 58-62 (1987), more specifically, preferred compounds of this group of vitamin D derivatives comprise calcipotriol (USAN: calcipotriene) which is mentioned in Example 5 of said reference c) and also mentioned by its code name MC 903 in said reference b) or alternatively 24-homo- l_t,25-dihydroxy-vitamin D,mentioned in said reference e) or as still another alternative 20-oxa-21-nor-l«,25-dihydroxy-vitamin D, mentioned in said reference f) .

Vitamin A derivatives may preferably be either tretinoin or iso- tretinoin.

Suitable combinations may be selected to comprise any combination of therapeutically active, and compatible substances of the two ca- tegories being on one hand the vitamin D metabolites and vitamin D derivatives and on the other hand vitamin A derivatives. More spe¬ cifically, a combination of a vitamin A derivative with a vitamin D metabolite or vitamin D derivative may be selected from those described in Australian Patent Application Number 37161/93, appli- cation date 23. April 1993.

It is a feature within the scope of the present invention, that the active compounds may be present as added to the preparation in any form desirable, as base or salt, being anhydrous or as a hydrate, as suitable for the preparation with respect to relevant proper- ties such as stability and solubility. An example of this feature is the hydrate of calcipotriol mentioned in the published patent application GB 93763 filed 15. January 1993.

A preferred embodiment of a composition in accordance with the in¬ vention is a composition containing a vitamin D metabolite or a vitamin D derivative, selected from the substances referred to, in a concentration within the range 0.01-1.0 wt/vol ?., more specifi¬ cally calcipotriol (USAN: calcipotriene) in a concentration of 0.05- 0.5 wt/vol .., or a vitamin A derivative as referred to in ccncentra- tions within the range 0.1-10 wt/vol ?., or a combination of such active substances selected from these two categories in concentrat¬ ions within the ranges mentioned.

In accordance with the preferred embodiment of the invention, the polymer resin to be used in the nail lacquer preparation of this invention may be selected from those provided by Rohm Pharma under their trade mark EUDRAGIT , being water insoluble copolymerizates based on acrylic acid esters and neutral methacrylic acid esters having an average molecular weight of about 150,000 which shall be present in the fluent lacquer preparation in a concentration of about 10-eθ wt/vol, ⁰ ., preferably about 12.5 °ό.

More specifically, the polymer resins will be selected from the EUDRAGIT ^R types designated EUDRAGIT ^R RL-100 and EUDRAGIR ^R RS-100, although types belonging to other groups as for example EUDRAGIT

E-100 may be used as well .

Also in accordance with the preferred embodiment of the invention, the main solvent, which may be isopropanol or methylene chloride, or both employed at the same time, but with a preference for isopro¬ panol in concentrations of 10-73 .L of the fluent lacquer composition more specifically 15-65 ?., and within this preferred embodiment an evaporation enhancer, which may be ethyl acetate and/or methylene chloride, preferably ethyl acetate present in an amount of 5-20 fό in the fluent lacquer composition, preferably 10-20 ?ό. and also within this preferred embodiment an evaporation retarder, which pre- ferably is, although not limited to, butyl acetate in concentrations of 5-80 % of the fluent lacquer composition, preferably 5-65 ?., and especially 5-40 % of the composition. Still in accordance with the preferred embed iπent of the invention, the preferred main solvent and/or the preferred evaporation enhancer may be totally or parti- ally replaced by methylene chloride, which may be present in concen¬ trations within the range of 5-75 °. of the fluent lacquer composi¬ tion depending on the functional role designated for it in the par¬ ticular composition.

The use of a solvent system as described provides proper qualities of the nail lacquer, not only with respect to suitable bioavailabi- lity of sparingly soluble compounds of the groups of therapeutic substances concerned, but it also provides proper qualities of the lacquer with regard to its application by producing a continous and homogenous fluent preparation of suitable viscosity and with good spreadability allowing a thin homogenous layer to be applied to the nail surface on which it will dry within few minutes leaving a con¬ tinous self supporting and well adhering lacquer film on the nail plate. The use of the polymer resins of the preferred type guaran¬ tees resistance to mechanical damage and to washing off of the lacquer coating.. Furtehrmore , the good swelling capacity and po¬ rosity of the copolymerizates employed with this invention pro¬ vides high rates of diffusion and permeability of active substances thereby facilitating their penetration into the nail plate.

EXAMPLE 1.

A preparation in accordance with the invention containing calcipo¬ triol (USAN:calcipotriene) as the active substance and isopropanol

as the main solvent may have the following composition: Calcipotriol (calcipotriene) 0.1 g EUDRAGIT ^R RL-100 12.5 g

Butyl acetate 15.0 g Ethyl acetate 20.0 g

Isopropanol ad 100.0 ml

EXAMPLE 2.

A preparation in accordance with the invention containing calcipo¬ triol (calcipotriene) as the active substance, and a solvent system partly comprising methylene chloride may have the following com¬ position:

Calcipotriol (calcipotriene) 0.1 g EUDRAGIT ^R RL-100 12.5 g

Butyl acetate 20.0 g

Methylene chloride 20.0 g Isopropanol ad 100.0 ml