Onychomycosis Treatment Compositions and Methods

Abstract

Compositions and methods are presented that provide substantially improved physical and pharmacological parameters for subungually administrable formulations. Most beneficially, the compositions presented herein have a viscosity and film-forming capacity that retain the liquid formulation in sufficient quantities and that help penetrate the polysaccharide matrix commonly associated with onychomycosis. In especially preferred aspects, the carrier is formulated to have a high concentration of the active pharmaceutically active agent (API), to allow migration of the formulation within the subungual space, and to reduce systemic absorption while promoting diffusion of the API into the nail plate at or above minimum inhibitory concentration into a larger treatment space.

What is claimed is: 
     
         1 . An antifungal liquid pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier comprising a hydrophobic solvent, an optional hydrophilic solvent, an optional polymeric film forming agent, and an antifungal agent;   wherein the antifungal agent is present in the composition in an amount that, upon subungual administration, produces with respect to a fungal pathogen a minimum inhibitory concentration of the antifungal agent in the subungual space and in a treatment space that extends beyond the subungual space; and   wherein the carrier has a composition that, upon subungual administration, preferentially partitions the antifungal agent into a nail plate as compared to a systemic circulation; and   wherein the pharmaceutical composition has a viscosity effective to retain at least 60% of the composition in the subungual space for at least 1 week.   
     
     
         2 . The antifungal composition of  claim 1 , wherein the carrier has a composition such that upon subungual administration, absorption of the antifungal agent into the systemic circulation from the composition is at least 200-fold below absorption into the systemic absorption upon oral administration as measured by mean peak plasma concentration. 
     
     
         3 . The antifungal composition of  claim 1 , wherein the hydrophobic solvent is selected from the group consisting of isostearic acid, benzyl alcohol, diisopropyl adipate, diethyl sebacate, isopropyl myristate, and combinations thereof. 
     
     
         4 . The antifungal composition of  claim 1 , wherein the hydrophobic solvent comprises isopropyl myristate. 
     
     
         5 . The antifungal composition of  claim 4 , wherein the isopropyl myristate present in the composition in an amount of at least 25 wt. % based on a total weight of the composition. 
     
     
         6 . The high-dose antifungal composition of  claim 4 , wherein the hydrophobic solvent further comprises diisopropyl adipate, benzyl alcohol, or a combination thereof. 
     
     
         7 . The antifungal composition of  claim 6 , wherein the carrier comprises the hydrophilic solvent, and wherein the hydrophilic solvent is selected from the group consisting of dimethyl isosorbide, propylene carbonate, D,L-lactic acid, and combinations thereof. 
     
     
         8 . The antifungal composition of  claim 1 , wherein the carrier comprises the hydrophilic solvent, and wherein the hydrophilic solvent is selected from the group consisting of dimethyl isosorbide, propylene carbonate, D,L-lactic acid, and combinations thereof. 
     
     
         9 . The antifungal composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises the polymeric film forming agent. 
     
     
         10 . The antifungal composition of  claim 9  wherein the polymeric film forming agent comprises a substituted cellulose. 
     
     
         11 . The antifungal composition of  claim 9 , wherein the polymeric film forming agent is present in the composition in an amount of at least 2 wt. % based on a total weight of the composition. 
     
     
         12 . The antifungal composition of  claim 1 , wherein the antifungal agent is an allylamine antifungal drug. 
     
     
         13 . The antifungal composition of  claim 1 , wherein the antifungal agent is terbinafine. 
     
     
         14 . The antifungal composition of  claim 1 , wherein the antifungal agent is present in an amount of at least 10 wt %. 
     
     
         15 . The antifungal composition of  claim 1 , wherein composition has a viscosity of between about 500-2,500 cP (mPa*s). 
     
     
         16 . The antifungal composition of  claim 1 , wherein the antifungal agent is stable for at least 3 months when the composition is stored at 25° C. and 60% relative humidity. 
     
     
         17 . A method of treating a subungual space in a mammal, comprising:
 administering an antifungal liquid pharmaceutical composition according to  claim 1  to a subungual space located between the nail plate and the nail bed;   wherein the step of administering is performed using a blunt-tip cannula that is atraumatically inserted into the subungual space; and   wherein between 10 and 200 μL of the liquid pharmaceutical composition are deposited into the subungual space.   
     
     
         18 . The method of  claim 17 , wherein at least 70% of the subungual space are filled with the liquid pharmaceutical composition. 
     
     
         19 . The method of  claim 18 , wherein administration is performed without use of an anesthetic drug. 
     
     
         20 . The method of  claim 17 , wherein administration further includes topical administration in a lateral nail fold.