Method and compositions for the treatment of onychomycosis
Patent Information
- Authority / Receiving Office
- CA · CA
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2025-01-29
- Publication Date
- 2025-08-07
AI Technical Summary
Current treatments for onychomycosis, a fungal infection of the nail, are limited and there has not been a new FDA-approved therapy since 2014, with existing therapies facing challenges in efficacy and penetration through nail material.
Development of compositions containing trichostatin A (TSA) for topical application, formulated with solvents like dimethyl sulfoxide and ethanol, and optionally including an antioxidant, to effectively penetrate and inhibit fungal growth in nails.
TSA compositions demonstrate potent antifungal activity against various fungal strains, including pan-resistant Candida auris, with improved penetration and stability, outperforming existing treatments in inhibiting fungal growth in nail samples.
Abstract
Description
[0001] Method and Compositions for the Treatment of Onychomycosis
[0002] Cross-Reference to Related Applications
[0003] This application claims the benefit of co-pending US Provisional Patent Application No. 63 / 626,942, filed 30 January 2024, which is incorporated herein as though fully set forth.
[0004] Background
[0005] Onychomycosis, or tinea unguium, is a fungal infection of the nail. Onychomycosis can result in discoloration of the nail, onycholysis (nail separation from the nail bed), and nail plate thickening. Onychomycosis accounts for one half of all nail disease with a US prevalence of 14%. In addition to cosmetic issues, onychomycosis infection may indirectly decrease peripheral circulation, thereby worsening conditions such as venous stasis and diabetic foot ulcers.
[0006] VTR-297, trichostatin A (TSA), is a small molecule histone deacetylase (HDAC) inhibitor with activity against dermatophytes and fungi, originally isolated from the yeast species Streptomyces hygroscopicus as an antifungal antibiotic, first described in 1976. Current therapies for onychomycosis include topical agents JUBLIA® (efinaconzole), KERYDIN® (tavaborole), and PENLAC® (ciclopirox). There have not been any new onychomycosis treatments approved by the FDA since 2014.
[0007] Summary
[0008] In one embodiment, the invention provides a method of treating a patient having onychomycosis, the method comprising: applying to a surface of a toenail of the patient an effective amount of a composition comprising trichostatin A (TSA), wherein the effective amount is an amount effective to reduce at least one symptom of onychomycosis in the patient.
[0009] In another embodiment, the invention provides, in a method of treating a patient with trichostatin A (TSA), the improvement comprising: selecting as said patient an individual suffering from onychomycosis; and applying to a surface of a toenail of the patient an effective amount of TSA.
[0010] In still another embodiment, the invention provides a composition comprising: trichostatin A (TSA) at a concentration between 0.1% and 5%; and at least one vehicle selected from a group consisting of: dimethyl sulfoxide, ethyl acetate, and ethanol.
[0011] Brief Description of the Drawings
[0012] FIG. 1 shows stability data for a TSA formulation at various temperatures over a four- week period.
[0013] FIGS. 2-7 show stability data for TSA Formulations 1-6 at various temperatures over a six-month period.
[0014] Detailed Description
[0015] Applicant has, in conducting several in vitro and in vivo studies, developed compositions containing TSA useful in the treatment of onychomycosis.
[0016] Minimum inhibitory concentration (MIC) studies show that TSA exhibits potent in vitro efficacy against T. rubrum, M. canis, and E. floccosum. Further MIC studies show that TSA exhibits potent in vitro antifungal activity against various strains of Candida auris, including pan-resistant strains. As compared to other antifungals, TSA is effective against C. auris at lower concentrations than fluconazole.
[0017] Table 1 — TSA solubility
[0018] TSA has high solubility in DMSO alone as well as in binary and ternary DMSO, dehydrated alcohol (ethanol), and PEG 400 or ethyl acetate mixtures. Interestingly, TSA solubility in a binary solvent mixture of 30% ethyl acetate and 70% dehydrated alcohol is higher than that in solvents individually. Due to good TSA solubility and the IIG (FDA’s inactive ingredients guide) limit of DMSO in topical formulations (45.5%), 1, 5 and 7.5% TSA formulations containing DMSO (40%) and dehydrated alcohol (60%) are possible candidates for development.
[0019] Solubility of the active ingredient, however, is not the only or even principal characteristic to be considered in the development of a formulation for topical application, as would be useful in the treatment of onychomycosis. The ability of an active ingredient within a composition to penetrate nail material directly affects the effectiveness of that active ingredient in treating onychomicosis. Table 2 below shows the makeup of various test compositions having varying TSA concentrations and varying vehicles.
[0020] Table 2 - Compositions containing TSA
[0021] The compositions above are applied to cadaver nails and assessed for their abilities to inhibit four strains of T. rubrum. Results show the ability of TSA in the above compositions to penetrate human nail and significantly inhibit fungal growth. In vehicles of ethyl acetate / ethanol or DMSO / ethanol, the compositions exhibit comparable zones of inhibition across similar concentrations. All compositions in Table 1 exhibit greater zones of inhibition than 8% PENLAC®.
[0022] The stability of a 7.5% TSA formulation in 40% DMSO / 60% dehydrated alcohol at various temperatures over the course of four weeks is shown in FIG. 1. As can be seen, total impurities increase over the four-week period at 25°C and 2-8°C, but not at -20°C. TSA is known to be susceptible to oxidation. Therefore, additional formulations including an antioxidant excipient are contemplated. Table 3 below shows the compositions of four formulations, two (formulations 1 and 3) including butylated hydroxytoluene (BHT) as the antioxidant excipient.
[0023] Table 3 — TSA formulations
[0024] Stability results for Formulations 1-4 are shown in FIGS. 2-5 following six months’ storage at temperatures of -20°C, 2-8°C, 25°C, and 40°C. As can be seen, Formulations 1 and 3, containing BHT, exhibit lower total impurities at both 25°C and 40°C as compared to Formulations 2 and 4, which do not contain BHT. In addition, Formulations 1 and 2, which contain ethyl acetate, show precipitation when stored at -20°C and 2-8°C, possibly due to the effect of temperature on solubility.
[0025] Two additional formulations — Formulations 5 and 6 — are shown in Table 4 below. In these formulations, TSA is reduced to 2.5% and 3% w / v, respectively.
[0026] Table 4 — TSA formulations
[0027] Stability results for Formulations 5 and 6 are shown in FIGS. 6 and 7. As can be seen, Formulation 5, which does not include PEG 400, exhibits lower total impurities at 40°C, as compared to Formulation 6, which does include PEG 400. TSA formulations, including, for example, Formulation 5 above, may be applied transungally and / or subungally in the treatment of onychomycosis. Table 5 below shows dosing levels at various TSA concentrations. Table 5 — TSA dosing levels
[0028] Typically, a user will apply two drops (each of approximately 14 ± 1 pL) of the TSA formulation to the top surface of the nail of each great toe, two drops under and along the tip of the nail of each great toe, and one drop to the top surface of each other toe, for a total of 16 drops across 10 toes, per application. The viscosity of the TSA formulation is such that it will typically spread easily across toenail surfaces but may be spread with the dropper used for application, if needed.
[0029] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless expressly states otherwise or the context clearly indicates otherwise. It will be further understood that the terms “comprises” and / or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. “Optional” or “optionally” means that the subsequently described element, event, or circumstance may or may not occur, and that the description includes instances where the element, event, or circumstance occurs or is present and instances where it does not occur or is not present.
[0030] The corresponding structures, materials, acts, and equivalents of all means or step plus function elements in the claims are intended to include any structure, material, or act for performing a function in combination with other claimed elements as specifically claimed. The description of the present disclosure is presented for purposes of illustration and description but is not intended to be exhaustive or limited to the disclosure in the form disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the disclosure. Any embodiments chosen and described herein appear to best explain the principles of the disclosure and their practical application, and to enable others of ordinary skill in the art to understand the disclosure for various embodiments with various modifications as are suited to the particular use contemplated.
Claims
ClaimsWhat is claimed is:
1. A method of treating a patient having onychomycosis, the method comprising: applying to a surface of a toenail of the patient an effective amount of a composition comprising trichostatin A (TSA), wherein the effective amount is an amount effective to reduce at least one symptom of onychomycosis in the patient.
2. The method of claim 1, wherein the at least one symptom of onychomycosis is selected from a group consisting of: nail discoloration, onycholysis, nail plate thickening, and decreased peripheral circulation.
3. The method of claim 1, wherein the composition includes TSA at a concentration between 0.1% and 5%.
4. The method of claim 3, wherein the composition includes TSA at a concentration of 0.1%.
5. The method of claim 3, wherein the composition includes TSA at a concentration of 1%6. The method of claim 3, wherein the composition includes TSA at a ocncentration of 2%.
7. The method of claim 3, wherein the composition includes TSA at a concentration of 2.5%.
8. The method of claim 3, wherein the composition includes TSA at a concentration of 3%.
9. The method of claim 3, wherein the composition includes TSA at a concentration of 5%.
10. The method of claim 3, wherein the composition further includes at least one vehicle selected from a group consisting of: dimethyl sulfoxide, ethyl acetate, and ethanol.
11. The method of claim 10, wherein the composition further includes at least one excipient selected from a group consisting of: polyethylene glycol, butylated hydroxytoluene, and eudragit.
12. The method of claim 1, wherein the composition comprises:2.5% w / v TSA;30% v / v ethyl acetate;0.2% w / v butylated hydroxytoluene; and quantum satis to 100% v / v dehydrated alcohol.
13. The method of claim 1, wherein the effective amount is an amount effective to inhibit growth of one or more microbial species selected from a group consisting of: T. rubrum, M. cams, E. floccosum, and C. auris.
14. The method of claim 1, wherein applying to the surface of the toenail includes applying two drops to a top surface of a nail of a great toe, each drop comprising approximately 14 ± 1 pL of the composition.
15. The method of claim 1, wherein applying to the surface of the toenail includes applying two drops under and along a tip of a nail of a great toe, each drop comprising approximately 14 ± 1 pL of the composition.
16. The method of claim 1, wherein applying to the surface of the toenail includes applying one drop to a top surface of a nail of a toe other than a great toe, each drop comprising approximately 14 ± 1 pL of the composition.
17. In a method of treating a patient with trichostatin A (TSA), the improvement comprising: selecting as said patient an individual suffering from onychomycosis; and applying to a surface of a toenail of the patient an effective amount of TSA.
18. The improvement of claim 17, wherein the individual is also suffering from or at risk for at least one condition or disease selected from a group consisting of: chronic venous insufficiency (CVI), venous stasis dermatitis, diabetic foot ulcers, and diabetes.
19. The improvement of claim 17, wherein the composition includes TSA at a concentration between 0.1% and 5%.
20. The improvement of claim 19, wherein the composition includes TSA at a concentration of 0.1%.
21. The improvement of claim 19, wherein the composition includes TSA at a concentration of 1%22. The improvement of claim 19, wherein the composition includes TSA at a concentration of 2%.
23. The improvement of claim 19, wherein the composition includes TSA at a concentration of 2.5%.
24. The improvement of claim 19, wherein the composition includes TSA at a concentration of 3%.
25. The improvement of claim 19, wherein the composition includes TSA at a concentration of 5%.
26. The improvement of claim 17, wherein the composition further includes at least one vehicle selected from a group consisting of: dimethyl sulfoxide, ethyl acetate, and ethanol.T1. The improvement of claim 26, wherein the composition further includes at least one excipient selected from a group consisting of: polyethylene glycol, butylated hydroxytoluene, and eudragit.
28. The improvement of claim 17, wherein the composition comprises:2.5% w / v TSA;30% v / v ethyl acetate;0.2% w / v butylated hydroxytoluene; and quantum satis to 100% v / v dehydrated alcohol.
29. The method of claim 17, wherein the effective amount is an amount effective to inhibit growth of one or more microbial species selected from a group consisting of: T. rubrum, M. cams, E. floccosum, and C. auris.
30. The method of claim 17, wherein applying to the surface of the toenail includes applying two drops to a top surface of a nail of a great toe, each drop comprising approximately 14 ± 1 pL of the composition.
31. The method of claim 17, wherein applying to the surface of the toenail includes applying two drops under and along a tip of a nail of a great toe, each drop comprising approximately 14 ± 1 pL of the composition.
32. The method of claim 17, wherein applying to the surface of the toenail includes applying one drop to a top surface of a nail of a toe other than a great toe, each drop comprising approximately 14 ± 1 pL of the composition.
33. A composition comprising: trichostatin A (TSA) at a concentration between 0.1% and 5%; and at least one vehicle selected from a group consisting of: dimethyl sulfoxide, ethyl acetate, and ethanol.
34. The composition of claim 33, wherein the concentration of TSA is 0.1%.
35. The composition of claim 33, wherein the concentration of TSA is 1%.
36. The composition of claim 33, wherein the concentration of TSA is 2%.
37. The composition of claim 33, wherein the concentration of TSA is 2.5%.
38. The composition of claim 27 wherein the concentration of TSA is 3%.
39. The composition of claim 33, wherein the concentration of TSA is 5%.
40. The composition of claim 33, further comprising: at least one excipient selected from a group consisting of: polyethylene glycol, butylated hydroxytoluene, and eudragit.
41. The composition of claim 33, comprising:2.5% w / v TSA;30% v / v ethyl acetate;0.2% w / v butylated hydroxytoluene; and quantum satis to 100% v / v dehydrated alcohol.