WO1996014048A1

WO1996014048A1 - Treatment of keratinic and psoriatic disorders with a nail lacquer containing a vitamin d metabolite or derivative and/or a vitamin a derivative

Info

Publication number: WO1996014048A1
Application number: PCT/DK1995/000439
Authority: WO
Inventors: Edel K. Seidenschnur
Original assignee: Seidenschnur Edel K
Priority date: 1994-11-08
Filing date: 1995-11-06
Publication date: 1996-05-17
Also published as: DK128494A

Abstract

Treatment of keratinic or psoriatic disorders prevailing in tissue under or surrounding nails with a pharmaceutical nail lacquer containing a therapeutically active vitamin D metabolite or a vitamin D derivative, or a vitamin A derivative, or a combination of such substances in a water insoluble film forming lacquer composition comprising an acrylic resin being a copolymerisate of acrylic acid esters and methacrylic acid esters, and a solvent system providing suitable characteristics with respect to viscosity, flow and spreading properties, short drying time, and satisfactory hardness, nail adhesion and durability of the dry lacquer film. Application to the nails once or twice a week allows the active substance(s) to penetrate into the keratinic tissue of the nail plate which acts as a depot for delivery of active substance(s) at therapeutically active concentrations to the nail bed, the nail matrix and nail surroundings.

Description

Treatment of keratinic and psoriatic disorders with a nail lacquer containing a vitamin D metabolite or derivative and/or a vitamin A derivative

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 combination 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 ointments and creams, are available for topical treatment of such skin disorders. However, treatment of the disorders. ,then affecting nails and/or the tissues under and surrounding the nails, is difficult. Application of the therapeutic substances in the forms of creams and ointments to nails does not cause into tissues to a sufficient extent. Such preparations easily washed or wiped off the nails, and exposure is such too short. Covering treated nails with pads or cream and ointment to stay in place, but long in such manner is usually associated with poor patient .

Systemic treatment with drug of the therapeutic categories mentioned is possible, but associated with considerable risks and side effects which most often may be considered unacceptable. Thus, systemic 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 hypercalcaemia. Consequently, at this point in time, no products for oral administration containing vitamin D metabolites or derivatives have been developed and approved 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 inconvenience 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 usually considered acceptable for long term exposure to the human body. On the other hand, these substances usually show high affinity to keratin.

The pharmaceutical nail preparation of the present invention comprises 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 contact 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 tissue 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 considered less acceptable for exposure to skin, but nevertheless usefull 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 may also act as an evaporation 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 solvent 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 Röhm Pharma under the trade mark EUDRAGIT^R. 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:

in which R₁ can be H or CH₃ and R₂ can be lower aliphatic substituents. 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 diffusion 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 surface 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 functions in the preparation as well, the solvent system may also contain 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 suitable 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, although other miscible and compatible solvents having a boiling point at a similar level maybe chosen. Other examples of evaporation 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 mandatory for the preparation if this invention, or for the use according 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 psoriatic 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 suitable 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-1α,25-dihydroxy-vitamin D₃mentioned in said reference e) or as still another alternative 20-oxa-21-nor-1α,25-dihydroxy-vitamin D₃ mentioned in said reference f). Vitamin A derivatives may preferably be either tretinoin or isotretinoin.

Suitable combinations may be selected to comprise any combination of therapeutically active, and compatible substances of the two categories being on one hand the vitamin D metabolites and vitamin D derivatives and on the other hand vitamin A derivatives. More specifically, 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, application 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 properties 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 invention 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 specifically calcipotriol (USAN: calcipotriene) in a concentration of 0.05- 0.5 wt/vol %, or a vitamin A derivative as referred to in ccncentrations within the range 0.1-10 wt/vol %, or a combination of such active substances selected from these two categories in concentrations 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^R, 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 10-20 wt/vol%, preferably about 12.5 %.

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 ^R

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 isopropanol in concentrations of 10-73 % 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 % in the fluent lacquer composition, preferably 10-20 %. and also within this preferred embodiment an evaporation retarder, which preferably 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 embediment of the invention, the preferred main solvent and/or the preferred evaporation enhancer may be totally or partially replaced by methylene chloride, which may be present in concentrations within the range of 5-75 % of the fluent lacquer composition depending on the functional role designated for it in the particular composition.

The use of a solvent system as described provides proper qualities of the nail lacquer, not only with respect to suitable bioavailability 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 continous self supporting and well adhering lacquer film on the nail plate. The use of the polymer resins of the preferred type guarantees resistance to mechanical damage and to washing off of the lacquer coating. Furtehrmore , the good swelling capacity and porosity of the copolymerizates employed with this invention provides 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 calcipotriol (USAN:calcipotriene) as the active substance and isopropanol as the main solvent may have the following composition:

EXAMPLE 2. A preparation in accordance with the invention containing calcipotriol (calcipotriene) as the active substance, and a solvent system partly comprising methylene chloride may have the following composition:

Claims

What I claim is:

1. The use in treatment of keratinic and/or psoriatic disorders of nails, nail bed, nail matrix, and nail surroundings of a pharmaceutical film forming nail lacquer containing one or more therapeutically active substance(s) selected from the groups comprising vitamin D metabolites, vitamin D derivatives and vitamin A derivatives.

2. The use according to claim 1 of a pharmaceutical film forming nail lacquer in which the vitamin D metabolite is calcitriol.

3. The use according to claim 1 of a pharmaceutical film forming nail lacquer in which the vitamin D derivative is selected from the compounds described in one of the following documents:

a) Calverley, M.: Tetrahedron 43, 4609-4619 (1987),

b) Binderup, L. and E. Bramm: Biochemical Pharmacology 37, 889-895 (1988),

c) International Patent Application Number PCT/DK 86/ 00081, international filing date 14. July 1986,

d) International Patent Application Number PCT/DK 89/ 00079, international filing date 07. 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),

g) British Patent Application Number 93763, filed 15.Jan.1993, more specifically the preferred compounds are either calcipotriol (calcipotriene as USAN) as mentioned in Example 5 of said reference c), and also mentioned by its laboratory code name MC 903 in said reference b), or alternatively 24-homo-1α,25-dihydroxy vitamin D₃ as mentioned in said reference e), or as still another alternative 20-oxa-21-nor-1α,25-dihydroxy-vitamin D₃ mentioned in said reference f).

4. The use according to claim 1 of a pharmaceutical film forming nail lacquer in which the vitamin A derivative is tretinoin or isotretinoin.

5. The use according to claim 1 of a pharmaceutical film forming nail lacquer in which the therapeutically active substances are a combination of a vitamin D metabolite or vitamin D derivative with a vitamin A derivative being one of those combinations described in Australian Patent Application Number 37161/93, application date 23. April 1993.

6. A pharmaceutical film forming nail lacquer to be used according to claim 1, and containing therapeutically active substance(s) according to claim 1, which after application to the nails and subsequent drying forms a self supporting and water insoluble lacquer film containing an acrylic polymer resin, and composed of a solvent system suitable for the dissolution of the active substance(s) , and also being suitable in its composition to provide suitable characteristics with respect to viscosity, flow and spreading of the fluent preparation, short drying time, and also suitable characteristics of the dry lacquer film with respect to nail aαhesicn, hardness and durability.

7. A pharmaceutical nail lacquer according to claim 6 in which the acrylic polymer resin is a copolymer having a molecular height about 150.000 being cationic in character and based on

amino ethyl methacrylate and neutral methacrylic acid esters, and in which the solvent system comprises a main organic which may be inert or may possess properties suitable for the properties of the lacquer composition, and which depending on the choise of the main solvent may also contain an evaporation enhancer and an evaporation retarder.

8. A pharmaceutical nail lacquer according to claim 7 in which said copolymer is present in the fluent lacquer composition in a quantity constituting 10-20 wt/vol %, preferably about 12.5 wt/vol % of the composition, and in which the main solvent is isopropanol and/or methylene chloride, constituting 10-75 %, more specifically 15-65 ?. of the lacquer composition, and in which the evaporation enhancer is ethyl acetate and/or methylene chloride present in an amount of 5-20%, preferably 10-20 % of the lacquer composition, and in which the evaporation retarder is butyl acetate present in an amount of 10-80 %, preferably 15-70 % of the lacquer composition.

9. A pharmaceutical nail lacquer according to claims 6-8 to be used according to claim 1, and containing a vitamin D metabolite or derivative as described in claims 2-3 in concentrations of 0.01-1.0 wt/vol %, preferably calcipotriol (calcipotriene as USAN) in a concentration of 0.05-0.5 wt/vol %, or containing a vitamin A derivative as described in claim 4 in a concentration of 0.1-10 wt/vol %, or containing a combination of such active substances as described in claim 5 at similar concentration levels.

10. A pharmaceutically film forming nail lacquer according to claims 6-9 which additionally may contain, if desired, one or more component(s) selected among such functional constituents as plastcisers, solubilisers, anti-oxidants, UV-absorbers, complex binders, preservatives and penetration enhancers.