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(12) Patent Application Publication (10) Pub. No.: US 2007/0092547 A1 Birnbaum Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0092547 A1 Birnbaum Et Al US 200700.92547A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0092547 A1 Birnbaum et al. (43) Pub. Date: Apr. 26, 2007 (54) METHOD FOR (22) Filed: Oct. 2, 2006 TREATING/CONTROLLING/KILLING FUNG AND BACTERIA Related U.S. Application Data (76) Inventors: Jay E. Birnbaum, Montville, NJ (US); (60) Provisional application No. 60/729,624, filed on Oct. Thomas Blake, Budd Lake, NJ (US); 24, 2005. Mahmoud Ghannoum, Hudson, OH (US); Steven Vallespir, Princeton, NJ Publication Classification (US); Mark David Antonacci, Randolph, NJ (US); Michael Patrick (51) Int. Cl. Ryan, Mendham, NJ (US) AOIN 25/00 (2006.01) AOIN 65/00 (2006.01) Correspondence Address: (52) U.S. Cl. ......................... 424/405; 424/750: 424/769: SONNENSCHEN NATH & ROSENTHAL LLP 424f778 P.O. BOX O6108O WACKER DRIVE STATION, SEARS TOWER (57) ABSTRACT CHICAGO, IL 60606-1080 (US) This present teaching describes how to treat substrates with novel compositions in order to limit fungi, dermatophytes, (21) Appl. No.: 11/541,822 yeasts, and bacteria thereon. Patent Application Publication Apr. 26, 2007 Sheet 1 of 10 US 2007/0092547 A1 Patent Application Publication Apr. 26, 2007 Sheet 2 of 10 US 2007/0092547 A1 Patent Application Publication Apr. 26, 2007 Sheet 3 of 10 US 2007/0092547 A1 Figure 3 Patent Application Publication Apr. 26, 2007 Sheet 4 of 10 US 2007/0092547 A1 (A) s 1 S. 1 S 1F s 1 N 1F 3 1 9 1 Leather Pretreatment Figure 4 Patent Application Publication Apr. 26, 2007 Sheet 5 of 10 US 2007/0092547 A1 Patent Application Publication Apr. 26, 2007 Sheet 6 of 10 US 2007/0092547 A1 Figure 6 Patent Application Publication Apr. 26, 2007 Sheet 7 of 10 US 2007/0092547 A1 Patent Application Publication Apr. 26, 2007 Sheet 8 of 10 US 2007/0092547 A1 SOJuoo lueuleej-e Jo lueulee Luoppegui-Sod Patent Application Publication Apr. 26, 2007 Sheet 9 of 10 US 2007/0092547 A1 Tsrael SIOguod lueue33 Patent Application Publication Apr. 26, 2007 Sheet 10 of 10 US 2007/0092547 A1 O d' y e . Fig. 10Aa enectorpretreatment21 s of insoles with (A) 0.01%S. e. 3% tea tree oil, or (C) 0.01% tolnaftate +3% tea tree oil on T. rubrun r i. a. Fig. 10B. Effect of post-treatment: of infe nsoles with (A) 0.01% tolnaftate, (B) 3% tea tree oil, or (C) 0.01% tolnaftate + 3% tea tree oil on T. rubrunt growth. US 2007/0092547 A1 Apr. 26, 2007 METHOD FOR particularly useful as it can include several compounds TREATING/CONTROLLING/KILLING FUNG AND which have different activities which can act synergistically. BACTERA A mixture is applied 'simultaneously, namely all com pounds in the mixture are applied at the same time. CROSS-REFERENCE TO RELATED 0010. In a further aspect the invention includes a method APPLICATIONS for treating a substrate with an antifungal compound via a 0001. This application claims priority from U.S. Provi delivery method. sional Application Ser. No. 60/729,624 filed on Oct. 24. 0011. The inventors have also discovered that certain 2005, which is incorporated herein by reference in its antifungal compounds have antibacterial, as well as antifun entirety. gal, activity. The use of these compounds in treatment either INCORPORATION-BY-REFERENCE OF alone or in combination with other antifungal compounds MATERIAL SUBMITTED ON A COMPACT will lead to inhibition of bacterial and fungal growth on a DISC substrate. 0012. In another aspect the current invention includes a 0002) Not Applicable. method of decreasing the LD50 (Lethal Dose 50) of a compound with antifungal properties by combining said FIELD antifungal with a second compound wherein said second 0003. The present teachings relate to methods for treat compound may, or may not be, a naturally occurring anti ing/preventing fungi and bacteria on Substrates. fungal compound, synthetic, semi-synthetic, pro-drug, salt, etc. INTRODUCTION 0013 These and other features, aspects and advantages of 0004 Fungi are responsible for a broad range of diseases the present teachings will become better understood with of the epidermis of people and animals, including compan reference to a following description, examples and appended ion animals and pets. claims. 0005 The current invention involves a method, and com positions for the prevention and reduction of fungal diseases DRAWINGS in man and animals, including companion animals and pets 0014 FIG. 1. Pre-treatment assay: (A) Active agents by treating a substrate with at least one antifungal com showed a clearance Zone (arrow) around the biopsy disc, pound. Such treatment may lead to decontamination of the while (B) inactive agents showed fungal growth around the substrate. disc. Post treatment assay: (C) Discs treated with active agents showed no fungal growth. (D) Inactive agents SUMMARY showed fungal growth on discs. 0006 The present teachings include methods for treating 0.015 FIG. 2. (A) CVS Double Air Foam Insole, (B) Odor a Substrate that, directly or indirectly, contacts an epidermis eater insoles, (C) CVS Odor Stop Insoles, (D) Dr Scholls including: a) treating the Substrate with a first antifungal or Air Pillow Insoles. (E) Control. Dr. Scholls insoles did not antibacterial compound, and/or b) treating the Substrate with inhibit fungal growth. a second antifungal or antibacterial compound, and/or treat ing the Substrate with a third antifungal or antibacterial 0016 FIG. 3. Effect of 30% isopropanol on Trichophyton compound. mentagrophytes growth on (A) leather and (B) Dr. Scholls insole. Isopropanol did not inhibit fungal growth. 0007 Provided herein are newly discovered properties of compounds which include antibacterial, antifungal, and 0017 FIG. 4. Effect of pretreatment of insoles (A) or sporicidal properties. Also novel are the combinations of leather (B) biopsy discs with different agents on growth of compounds which lead to unexpected results in the treat dermatophytes. Zone diameter indicates Zone of clearance. ment and pre-treatment of Substrates against common fungi, dermatophytes, spores, and bacteria. The inventors show for 0018 FIG. 5. Effect of pretreatment of insoles with (A) the first time that combining naturally occurring fungicides 1% terbinafine. (B) 1% tolnaftate, or (C) 1% tea tree oil with known fungicides leads to unexpectedly good results 0.019 FIG. 6. Effect of acetone on the activity of tolnaf and they also show that uses of naturally occurring com tate against dermatophyte growth. (A) Growth of T. menta pounds (including fungicidal compounds), and for the first grophytes on insole disc pretreated with (A) acetone or (B) time, expands their utility against bacteria. 4% tolnaftate (w/v., prepared in acetone). (C) Activity of 4% tolnaftate (dissolved in acetone) on already established 0008 Provided herein are also compounds which exhibit contamination of T. mentagrophytes. (no fungal regrowth both antifungal and antibacterial properties. Such a com pound, or mixture, is particularly useful as it creates a was observed). treatment, or pre-treatment, that gives both fungal disinfec 0020 FIG. 7. Effect of post-infection treatment of insole tant and deodorant qualities to Substrates (including but not (A) or leather (B) biopsy discs with different agents on limited to shoes). dermatophyte growth. Zone diameter indicates Zone of 0009. In a further aspect of the method the antifungal growth. Treatment with 30% isopropanol served as vehicle compound(s) are applied in a single application (e.g. as a control. mixture) or in separate applications that are done serially, 0021 FIG. 8. Scanning electron microscopy (SEM) simultaneously, and some mixture thereof. A mixture is analyses of insoles infected with T. mentagrophytes. Mag US 2007/0092547 A1 Apr. 26, 2007 nification x2000 for all panels. Bar represents 20 uM for kill/inhibit the growth of fungal spores, for example, panels A through F, while it represents 10 uM for the any Substance that possesses a sporistatic (inhibitory) post-infected treated discs (Panels G-I). or sporicidal (killing) activity. See definition of Spori 0022 FIG. 9. Scanning electron microscopy (SEM) cidal compound below. analyses of leather biopsies infected with T. mentagrophytes. 0.031) Throughout this document the term ANTIFUN Magnification x2000; bar-20 lum. GAL COMPOUND will be an all encompassing term referring to any Substance (synthetic, semisynthetic, 0023 FIG. 10. FIG. 10A. Effect of pretreatment of salt, pro-drug, natural, etc.) with antifungal activity, insoles with (A) 0.01% tolnaftate. (B) 3% tea tree oil, or (C) including, inhibitory, killing, static, cidal, sporistatic or 0.01% tolnaftate +3% tea tree oil on T. rubrum growth on sporicidal activity. These compounds can in turn be shoe insoles. FIG. 10B. Effect of post-treatment of infected mixed with, for example, other antifungal compounds, insoles with (A) 0.01% tolnaftate. (B) 3% tea tree oil, or (C) detergents, and/or inactive ingredients to create formu 0.01% tolnaftate +3% tea tree oil on T. rubrum growth. lations. DETAILED DESCRIPTION 0032) SPORE: A spore is a fungus in its dormant, pro Abbreviations and Definitions tected State. It has a small, usually single-celled reproductive body that is highly resistant to desiccation and heat and is 0024 BOTANICAL: Abotanical is a compound isolated capable of growing into a new organism, produced espe from a plant. Botanical antifungal compounds can be iso cially by certain bacteria, fungi, algae, and non-flowering lated from, for example, Ocimum basilicum (Basil), Cinna plants. momum aromaticum var. Cassia (Cinnamon), Cedrus libani (Cedar of Lebanon), any Cedrus spp., Chamaemelum nobile 0033 SPORICIDAL COMPOUND: a substance that (Chamomile), Cymbopogon nardus (Citronella), Syzygium either inhibits the growth of, increase the susceptibility of aromaticum (Clove & clove bud), Cuminum cyminum and/or destroys fungal spores. These can be synthetic or (Cumin), Foeniculum vulgare (Fennel), Melaleuca altenfo naturally occurring. Activating spores allows fungicides that lia (Tea Tree), Mentha x piperita (Peppermint), Mentha only kill or inactivate actively growing fungi to kill those spicata (Spearmint), Curcuna longa (Tumeric), Cymbo spores activated.
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