Patent Publication Number: US-2022211717-A1

Title: Topical treatment of fungal infections of the hair, skin, and nails

Description:
CROSS-REFERENCE 
     Not applicable. 
     FIELD OF THE INVENTION 
     The invention pertains to the field of pharmaceutical science and the safe and effective topical treatment of resistant fungal infections of the, hair, skin and nails. 
     BACKGROUND OF INVENTION 
     Fungal infections of the scalp (tines capitis) and nails (tines unguium/onychomycosis) are resistant to topical and systemic antimycotic therapy. The oral antimycotic drugs can have serious adverse reactions, drug interactions, contraindications and limited effectiveness. 
     Onychomycosis, a common infection in adults, is difficult to treat. All topical antimycotic drugs that have FDA indication for the treatment of onychomycosis have a low cure rate and the newer topical medications are also extremely expensive. 
     Tines capitis, also difficult to treat, usually requires initial systemic treatment with oral antifungal medication. Topical agents are not indicated for initial treatment. 
     Saadeh (U.S. Pat. No. 20170290810) describes pharmaceutical compositions containing three ergosterol biosynthesis inhibitors, one allylamine and two azole (imidazoles and triazoles). All the azoles (imidazoles and triazoles) inhibit the biosynthesis of ergosterol through inhibition of 14alpha-demethylase (FIG. 1). 1  The use of two azoles that block the same enzyme, 14alpha-demethylase, is redundant and unnecessary. 
     The present invention uses two or three different ergosterol biosynthesis inhibitors selected from three different classis, an allylamine, an azole, or a morpholine. Each class of ergosterol biosynthesis inhibitors block the biosysnthesis of ergosterol at different key steps. The allylamines blocks the enzyme squalene epoxidase, the azoles (imidazole and triazoles) blocks the enzyme 14alpha-demethylase and the morpholines blocks two enzymes, delta14-reductase and delta8, delta7 isomerase (FIG. 1). 1    
     There exists a need for a novel approach for treating relatively innocuous fungal infections of the hair, skin and nails which are more effective and safer than present treatments. This patent allows for an effective topical treatment of resistant fungal infections of the skin and nails and avoiding the problems seen with oral antimycotic medications. 
    
    
     DETAILED DESCRIPTION 
     A. Embodiments of the Invention 
     The invention is a pharmaceutical composition for the topical treatment of fungal infections of the hair, skin and nails that are difficult to treat. The invention uses two or three different classes of antimycotic medications selected from 3 classes to treat the infection. The three chemical classes of antifungal agents, an allylamine, an azole, or morpholines, blocks the biosynthesis of ergosterol from squalene at different steps. Erogosterol is an important structural component of the fungal cell membrane. The decrease in total ergosterol content of cell membrane and the buildup of sequalene in the fungus cell results in fungus cell death. The synergistic effect from these combinations make it possible to effectively treat resistant mycotic infection topically. 
     The two or three drug combinations can be ultra-micronized to increase penetration into the skin 
     The concentration the of the antifungal medications are between 0.1 to 20% depending the particular drug used and the dosage form. 
     The dosage is in the form of a cream, gel, lotion, nail lacquer, patch, shampoo, solution, suspension or tincture. 
     The medications can be applied topically to affected area daily to twice daily, as a combination product (mixed together) or applied individually. 
     The duration and frequency of application will depend on the type, severity and location of infection. 
     The following are examples of preparing and instructions for use of invention. 
     Example 1 
       
     
       
         
           
               
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 clotrimazole 
                 0.5 g 
                   
               
               
                   
                   
                 terbinafine 
                 0.5 g 
                   
               
               
                   
                   
                 ethoxy diglycol 
                 qs 
                   
               
               
                   
                   
                 Lipopen Ultra Cream Base 
                 qs 100 g 
               
               
                   
                   
               
            
           
         
       
     
     Method of preparation: Weigh or measure each ingredient. Titrate the powders together. Add sufficient quantity of ethoxy diglycol to form a smooth paste. Geometrically, incorporate the Lipopen Ultra Cream Base to final weight. 
     Method of application: Apply to toenail and skin around nail twice daily. 
     Example 2 
       
     
       
         
           
               
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 itraconazole 
                 0.5 g 
                   
               
               
                   
                   
                 butenafine 
                 0.5 g 
                   
               
               
                   
                   
                 amoroline 
                 0.5 g 
                   
               
               
                   
                   
                 ethoxy diglycol 
                 qs 
                   
               
               
                   
                   
                 Lipopen Ultra Cream Base 
                 qs 100 g 
               
               
                   
                   
               
            
           
         
       
     
     Method of preparation: Weigh or measure each ingredient. Triturate the powders together. Add sufficient quantity of ethoxy diglycol to form a paste. Geometrically, incorporate the Lipopen Ultra Cream Base to final weight. 
     Method of application: Apply morning and evening to affected area on scalp. 
     Example 3 
       
     
       
         
           
               
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                   
                 ketoconazole 
                  2 g 
                   
               
               
                   
                   
                 butenafine 
                 0.5 g  
                   
               
               
                   
                   
                 ethoxy diglycol 
                 qs 
                   
               
               
                   
                   
                 Dr. Bronners Tea Tree Liquid Soap 
               
               
                   
                   
               
            
           
         
       
     
     Method of preparation: Weigh or measure each ingredient. Triturate the powders together. Add sufficient quantity of ethoxy diglycol to form a paste. Geometrically, incorporate the Dr. Bronners Tea Tree Liquid Soap. 
     Method of application: Shampoo scalp, leave on for 10 to 15 minutes then wash off. Use twice weekly as needed. 
     Biosynthesis of Ergosterol 
     Squalene 
     |Squalene epoxidase 
     | Allyamines—Squalene epoxidase Inhibitors 
     | 
     Squalene Epoxide 
     | 
     Lanosterol 
     |14alpha-demethylase 
     |Azoles-14alpha-demthylase inhibitors 
     |(imidazole and triazole) 
     4,4-dimethyldimethylcholestra-8,14,24 trienol 
     |delta14-reductase 
     4,4-dimethylzymosterol Morpholines-delta14-reductase and 
     |delta8, delta7 isomerase 
     |delta8, delta7 isomerase inhibitors 
     | 
     Fecosterol 
     | 
     Episterol 
     | 
     Ergosterol 
     REFERENCES 
     
         
         1. Lemke, T., Williams, A. Roche, V., Zito, S. Foye&#39;s Principles of Medicinal Chemistry sixth edition.