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WO2022197927A1 - Méthodes et compositions pour le traitement d'infections topiques résistantes aux médicaments - Google Patents

Méthodes et compositions pour le traitement d'infections topiques résistantes aux médicaments Download PDF

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Publication number
WO2022197927A1
WO2022197927A1 PCT/US2022/020756 US2022020756W WO2022197927A1 WO 2022197927 A1 WO2022197927 A1 WO 2022197927A1 US 2022020756 W US2022020756 W US 2022020756W WO 2022197927 A1 WO2022197927 A1 WO 2022197927A1
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Prior art keywords
composition according
iodine
nail
ethyl pyruvate
infection
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Melvin Reichman
George C. Prendergast
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Lankenau Institute for Medical Research
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Lankenau Institute for Medical Research
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Priority to US18/550,919 priority Critical patent/US20240156795A1/en
Publication of WO2022197927A1 publication Critical patent/WO2022197927A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Definitions

  • onychomycosis continues to be a common and intractable problem in adults.
  • Topical treatments have very poor efficacy [1] while oral agents have significant risk of hepatotoxicity [2]
  • Disease recurrences are frequent and can become the source of more widespread disease [3]
  • onychomycosis represents an important risk factor for the development of diabetic foot syndrome and foot ulcers leading to amputations [4]
  • toenail infection can develop other complications, including systemic infection in high-risk patients
  • the commonly held explanation for the poor efficacy of topical toenail fungus treatments is that they are unable to diffuse past the nail barrier to penetrate deep into the nail matrix.
  • Onychomycosis is a common fungal infection of the nail seen clinically most frequently in toenails. Onychomycosis in the toenail is seen frequently in the podiatry clinic where it presents not only a difficult physical problem but also an emotional concern to patients and their caregivers. The prevalence of this condition is 6-8% in the general adult population, but far higher among diabetics, athletes, the elderly, and patients undergoing chemotherapy.
  • Onychomycosis occurs in 10% of the general population, 20% of persons older than 60 years, and 50% of those older than 70 years, compared to 0.7% in patients younger than 19 years of age [6] Further, men are up to three times more likely to have onychomycosis than women, though the reasons for this gender difference are not clear [5] Changing demographic characteristics such as the relative aging of the population, the increasing prevalence of diabetes and peripheral vascular disease, extensive use of broad- spectrum antibiotics, and more widespread iatrogenic immunosuppression are likely to increase the prevalence for onychomycosis [7] Regardless of the drug prescribed by the clinician, long treatment durations may extend to a full year.
  • Hepatotoxicity is a particular concern in elderly patients or with co-occurring disorders such as diabetes, hypertension, and cancer, where polypharmacy will contraindicate oral antifungals. Due to the high potential for persistence of some pathogens within the nail unit after visible clearance of infection, relapse and re-infection are common and can occur in many patients
  • FIG. 1 shows ciclopirox enhances HTF levels in B6 cells.
  • Cells derived from B6 HIF- luciferase reporter mice were assayed ex vivo to detect the stabilization of HIFl protein. Values are means of duplicate determinations ⁇ SD.
  • FIG. 2 shows ciclopirox inhibits IDOl.
  • IDOl activity in U937 cells was assessed by spectrophotometric measurement of kynurenine formation in the medium at least 24 hours post-induction with IFN-g. Values are means of duplicate determinations ⁇ SD.
  • FIG. 3 shows a study design overview.
  • FIG. 4 shows treatment of a skin Staphylococcus infection on a patient’s foot. Upper panel- pre-treatment; Lower panel- post-treatment.
  • the provided compositions and methods for inhibiting, treating, and/or preventing topical infections, particularly drug resistant topical infections are provided.
  • the topical infection is onychomycosis.
  • the topical infection is onychomycosis.
  • the composition comprises a) at least one antimicrobial agent; b) at least one immune enhancer or wound healing agent; and c) a carrier.
  • the composition may further comprise: a) at least one immunomodulatory agent such as an IDO/TDO inhibitor or agent that enhances regenerative healing, such as a HIF1 activator, including an agent with both these activities [bifunctional]; b) at least one broad-spectrum antiseptic.
  • the composition may further comprise at least one penetrant, and/or keratolytic agent, such as ethyl pyruvate, DMSO, salicylate or urea, etc.
  • the composition may further comprise at least one wound healing agent such as a HIF-1/2 a activator.
  • the composition comprises iodine or chlorhexidine, and ethyl pyruvate.
  • the composition comprises ciclopirox, iodine or chlorhexidine, and ethyl pyruvate.
  • the components are together in a single composition or contained separately as individual units or compositions.
  • the methods provided comprise applying the composition(s) topically, e.g., to the skin or nail of a subject.
  • the human nail plate includes three layers: the dorsal and intermediate layers of the nail and the ventral layer comprising the nail bed.
  • the dorsal layer is a few cell layers thick and consists of hard keratin. This layer is the main barrier to diffusion of therapeutics into and through the nail plate.
  • the intermediate layer is also rich in keratin but behaves somewhat differently than the dorsal layer with regard to diffusion.
  • the ventral layer consists of a soft hyponychium where fungal infections take hold beneath the nail plate. Achieving an effective drug concentration in the ventral layer is important for effective treatment of onychomycosis.
  • MMB malmicrobiome
  • each of the components of the MMB should be addressed for an effective cure. Accordingly, to attack the MMB effectively, 1) the pathogenic driving components of the infection should be attacked; and also 2) simultaneously the local immune tolerance in the infected niche microenvironment should be relieved.
  • the immunosuppression may be two-pronged including ‘extrinsic’ features from the pathogen (e.g., drug resistance) as well as ‘intrinsic’ features from the host (e.g., due to aging, diabetes, chemotherapy, or other disorders that blunt immune competency in clearing pathogens).
  • compositions and methods for treating, inhibiting, and/or preventing topical infections, particularly drug resistant topical infections in a subject are provided.
  • the topical infection is onychomycosis.
  • the infection is on or in the skin.
  • the drug resistant topical infection is onychomycosis present in a toenail.
  • the infection is a diabetic foot ulcers, bedsores, sepsis, or an opportunistic infection.
  • the subject is an athlete, elderly individual, diabetic patient, or a subject undergoing chemotherapy for treating cancer, autoimmune disease, organ transplantation or a subject otherwise immune tolerant or suppressed.
  • the compositions provided herein comprise a) at least one antimicrobial (including antifungals or pan-antiseptics) and b) at least one immunomodulatory agent.
  • the composition is for treating onychomycosis.
  • the compositions provided herein comprise a) an antiseptic and b) an immunomodulatory agent.
  • the composition comprises at least two antifungals that each have distinct mechanisms of action to exploit drug synergy in clearing a MMB infection.
  • the composition may also comprise a pharmaceutically and/or cosmetically acceptable carrier or solvent to improve penetration through the nail bed for the pharmacological agents.
  • a broad-spectrum antimicrobial agent e.g., a pan-disinfectant or pan-antiseptic
  • the composition may comprise at least one pan-antiseptic (broadly effective against at least fungi) and at least one immunomodulatory agent to boost the subject’s immune response for helping clear the pathogen.
  • the compositions may further comprise at least one wound-healing agent.
  • a single agent might serve two functions, for example, a single agent can have both anti-microbial and immune stimulation activities.
  • the compositions may also comprise at least one penetrating agent (penetrant), which also might have another function, including immune enhancement.
  • compositions provided herein may also comprise cosmetic agents such as coloring agents and fragrances that are pharmacologically inert. While compositions provided herein are described as a single composition comprising all of the components, also provided are multiple compositions wherein each composition comprises one or more components (but less than the entirety of the components). The multiple compositions may be mixed prior to use or may be applied sequentially or simultaneously to the nail for treatment.
  • antifungal refers to a substance that inhibits fungal growth and/or replication (i.e., fungistatic) and/or kills fungi (i.e., fungicidal).
  • antifungals include, without limitation: polyene antifungals (e.g., nystatin, amphotericin B, pimaricin, hamycin, natamycin); azole antifungals such as: imidazoles (e.g., clotrimazole, miconazole, ketoconazole, econazole, tioconazole, oxiconazole, sertaconazole, sulconazole, luliconazole, butoconazole); triazoles (e.g., itraconazole, fluconazole, voriconazole, fosfluconazole, efmaconazole, terconazole, hexaconazole, isavuconazole, albaconazole
  • - b-glucan synthase inhibitors e.g., echinocandins, anidulafungin, caspofungin, micafungin;
  • the antifungal is selected from the group consisting of itraconazole, terbinafme, ciclopirox, and fluconazole.
  • Antiseptics are antimicrobial substances that are applied to living tissue/skin to reduce the possibility of infection, sepsis, or putrefaction. Antiseptics are generally distinguished from antibiotics by the latter's ability to be transported through the lymphatic system to destroy bacteria within the body, and from disinfectants, which destroy microorganisms found on non-living objects. Some antiseptics are true germicides, capable of destroying microbes (bactericidal), while others are bacteriostatic and only prevent or inhibit their growth. By continued exposure to antibiotics, bacteria may evolve to the point where they are no longer harmed by these compounds. Bacteria can also develop a resistance to certain antiseptics, but the effect is generally less pronounced.
  • Common antiseptics include but are not limited to: alcohols; chlorhexidine (gluconate); hydrogen peroxide; iodine (including tinctures and polymeric formulations (e.g., povidone-iodine); octenidine dihydrochloride; polyhexanide; and hypochlorite sodium.
  • penetrant refers to agents or compounds capable of penetrating the outer layers of the nail and/or agents or compounds capable of enhancing the permeability of the nail. Chemical penetration through the nail relies upon water solubility and molecular size. Penetrants have been studied to increase diffusion of effective chemicals into/through the human nail plate, including but not limited to agents such as DMSO. Examples of penetrants that also have keratolytic actions include, without limitation, ibuprofen, salicylic acid, benzoic acid, methyl pyruvate, urea, and ethyl pyruvate, among others.
  • antimicrobial refers to a substance that kills or inhibits the growth of microbes such as bacteria, mycobacteria, parasites, fungi, yeast, viruses, or other microscopic organisms.
  • antimicrobial agents e.g., a pan-disinfectants
  • iodine e.g., polymer iodine, tincture of iodine, etc.
  • chlorhexidine e.g., hypochlorite, acetic acid, and hydrogen peroxide.
  • immunomodulatory agent refers to an agent that induces an immunomodulatory effect or alteration (i.e., immunostimulation) as measured, for example, by a variety of immunoassays well known in the art.
  • the immunomodulatory agent is an immunostimulant.
  • immunomodulatory agents include, without limitation: indoleamine dioxygenase (IDO) inhibitors, and immune checkpoint inhibitors including but not limited to PD-1 and CTLA4 antibodies.
  • IDO inhibitor refers to an agent capable of inhibiting the activity of indoleamine 2,3-dioxygenase (IDO), particularly IDOl, and thereby reversing IDO-mediated immunosuppression.
  • IDO inhibitor may be a competitive (reversibly inhibits IDO enzyme activity at the catalytic site), noncompetitive (reversibly inhibits IDO enzyme activity at a non-catalytic site), or irreversible (irreversibly destroys IDO enzyme activity, for example, by forming a covalent bond with the enzyme) IDO inhibitor.
  • An IDO inhibitor may be an inhibitor of the IDO immune pathway.
  • IDO inhibitors include, without limitation: D- tryptophan, D-tryptophan analogs (e.g., indoximod, 1-methyl-DL-tryptophan, 1-methyl-D- tryptophan, P-(3-benzofuranyl)-DL-alanine, beta-(3-benzo[b]thienyl)-DL-alanine, 6-nitro-L- tryptophan, methylthiohydantoin-DL-tryptophan), ethyl pyruvate, beta-carbolines (e.g., norharmane), rosmarinic acid, Cox-2 inhibitors (e.g., celecoxib), pyridoxal isonicotinoyl hydrazone, pyrrolidine dithiocarbamate, necrostatin-1, ebselen, brassinin analogs, exfoliazone, chandrananimycin A, indole 3-carbinol, 3,3'-diindolylme
  • IDO inhibitors are also provided, for example, Qian et al. (RSC Adv. (2016) 6:7575-7581) and U.S. Patents 7,705,022; 7,714,139; 8,008,281; 8,389,568; 9,174,942; 8,722,720; 8,748,469; and 9,260,434.
  • the foregoing references are incorporated by reference herein, particularly with regard to the IDO inhibitors provided therein.
  • the IDO inhibitor is D-tryptophan, 1 -methyl -tryptophan, or methylthiohydantoin-tryptophan., or agents that chelate iron, an obligatory cofactor for IDO and other mono-and deoxygenating enzymes (for example, proline hydroxylation domain enzymes, or PHDs).
  • the “IDO inhibitor” refers to an agent that blocks or inhibits the expression, induction, activity, and/or signaling of one or more of IDOl, ID02, or TDO, including, without limitation, the following compounds or a pro-drug, salt, and/or any therapeutically effective formulation of: Indoximod (1-methyl-D-tryptophan, 1MT, NLG-8189)
  • 1 -methyl -L-tryptophan a racemic mixture of 1-methyl-D-tryptophan and 1 -methyl -L-tryptophan Epacadostat (ESiCB024360; Incyte; Wilmington, DE; described in Liu et al. (2010) Blood 115(17):3520-3530; Koblish et al. (2010) Mol. Cancer Ther., 9(2):489-498)) Navoximod (NLG-919, GDC-0919, RG6078; NewLink Genetics/Genentech), Indoximod prodrug NLG802
  • AMG-1 (Amgen), as described in Smith JR et al, Novel indoleamine 2,3- dioxygenase-1 inhibitors from a multistep in silico screen, Bioorganic & Medicinal Chemistry, 20(3): 1354-1363 1 February 2012, incorporated by reference herein; methylthiohydantoin-DL-tryptophan (MTH-Trp), b-(3- P)-DL-alanine,
  • NSC401366 beta-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[l,2-b]pyran-5,6-dione, Flick et al. (2013) Int. J. Tryp. Res. 6:35-45) (ARQ 761; ArQule, now owned by Merck);
  • IDOl indoleamine 2,3-dioxygenase 1
  • MedChemComm indoleamine 2,3-dioxygenase 1
  • tryptophan derivatives inhibitors with an imidazole, 1,2, 3 -triazole or tetrazole scaffold, inhibitors with quinone or iminoquinone, N-hydroxyamidines.
  • Patent 7,705,022 e.g., compounds of Formula I
  • U.S. Patent 8,008,281 e.g., phenyl- TH-DL-trp (3-(N-phenyl-thiohydantoin)-indole), propenyl-TH-DL-trp (3-(N-allyl- thiohydantoin)-indole), and methyl -TH-DL-trp (3- (N-methyl-thiohydantoin)-indole)
  • U.S. Patent 7,714,139 e.g., compounds of Formula I or II
  • 20140066625 e.g., fused imidazole derivatives; compounds of Formula I or II
  • U.S. Patent Application Publication No. 20130177590 e.g., N-hydroxyamidinoheterocycles; compounds of Formulas I-III
  • U.S. Patent Application Publication No. 20140023663 e.g., 1,2,5-oxadiazoles; compounds of Formula I
  • U.S. Patent Application Publication No. 20080146624 e.g., amidines; compounds of Formulas I or II
  • U.S. Patent Application Publication No. 20080119491 e.g., amidinoheterocycles; compounds of Formulas I-IV
  • the IDOl inhibitor is a prodrug (see, e.g., U.S. Patent Application Publication No. 20170022157 and U.S. Provisional Application No. 62/555,726). All references are incorporated by reference herein, particularly for the IDOl inhibitors provided therein.
  • the IDOl inhibitor is ethyl pyruvate (Muller, et al. (2010) Cancer Res. 70:1845-1853) orgleevec (imatinib, Balachandran et al. (2011) Nat. Med.
  • the IDOl inhibitor e.g., inhibitor of downstream signaling pathway
  • the IDOl inhibitor is 1 -methyl -tryptophan, particularly 1-methyl-D-tryptophan (indoximod, NLG-8189; 1-methyl-D-tryptophan; NewLink Genetics), including salts and prodrugs (U.S. Patent Application Publication No. 20170022157) or a racemic mix comprising the same.
  • immune checkpoint inhibitors are used in place of the above immunomodulatory agents or in combination with the above immunomodulatory agents.
  • immune checkpoint inhibitors include, without limitation: PD-1 inhibitors (e.g., antibodies, particularly monoclonal antibodies, immunologically specific for PD-1 such as pembrolizumab (Keytruda®) and nivolumab (Opdivo®)); PD-L1 inhibitors (e.g., antibodies, particularly monoclonal antibodies, immunologically specific for PD-L1 such as atezolizumab (Tecentriq®)); and CTLA-4 inhibitors (e.g., antibodies, particularly monoclonal antibodies, immunologically specific for CTLA-4 such as ipilimumab (Yervoy®)).
  • PD-1 inhibitors e.g., antibodies, particularly monoclonal antibodies, immunologically specific for PD-1 such as pembrolizumab (Keytruda®) and nivolumab (Opdivo®)
  • wound healing agent refers to any substance that facilitates the wound healing process.
  • wound-healing agents include agents that can orient the tissue environment from scarring to regenerative healing by increasing levels of EOF (e.g., a HIF- 1/2 a activator, a master regulator of tissue regeneration.
  • Ciclopirox olamine (Loprox®) is an activator of HIF-a.
  • ciclopirox olamine is also approved for use by the FDA as a topical anti-fungal agent.
  • the antifungal efficacy of ciclopirox may stem from its metal chelating activity (e.g., iron) given that the actual mechanism of its action has not been proven definitively.
  • HIF activators include, without limitation: deferoxamine (e.g., desferoxamine mesylate, desferal), deferoxamine, 3,4-dihydroxybenzoic acid, 1,4- dihydrophenonthrolin-4-one-3-Carboxylic acid (1,4-DPCA) nitric-oxide donor drugs, plant alkaloids (e.g., vinblastine, colchicine), certain phytochemical flavanoids (e.g., quercetin), and oils from tea and other natural -product extracts, as well as known PHD inhibitor now (in 2018) in clinical trials for end-stage kidney failure that act as EPO secretagogues. Some of them work by substrate competition or metal chelation, or both, to inhibit PHD or other enzymes that regulate HIF-a levels in a particular embodiment, the wound healing agent is ciclopirox.
  • deferoxamine e.g., desferoxamine mesylate, desferal
  • deferoxamine 3,4-dihydroxybenz
  • an antimicrobial (e.g., pan-antiseptic) component of the instant compositions may be between about 0.05 % (w/v) to about 20.0 %, about 0.1 % to about 10 %, about 0.1 % to about 7.5 %, about 0.1 % to about 5.0 %, or about 0.5 % to about 5.0 %.
  • ethyl pyruvate is present in the compositions from about 1% (w/v) to about 50%, about 5% to about 40%, about 10% to about 30%, about 10% to about 20%, about 15% to about 20%, or about 15% to about 25%.
  • urea is present in the compositions from about 1% to about 40%, about 5% to about 40%, about 10% to about 30%, or about 15% to about 25%.
  • the antifungal is ciclopirox olamine (0.8% - 8.0%) and the antimicrobial is a pan-disinfectant, particularly iodine or chlorhexidine.
  • the composition may further comprise an immunomodulatory agent, particularly an IDO inhibitor such as D- tryptophan, 1 -methyl-tryptophan, or methylthiohydantoin-tryptophan.
  • ciclopirox is a divalent cation chelator, including iron, and that iron is a co-factor for both HIF-PHD and IDO enzymes
  • ciclopirox can play a poly-pharmacological role by promoting wound healing (HIF-a activator) and immune function (IDO inhibitor), in addition to its designated anti- fungal action, per se.
  • the composition may further comprise an active penetrant, including ethyl pyruvate or salicic acid having ketatolytic activity, or a passive penetrant like DMSO (which does not have keratolytic activity in the absence of KOH). In cases where the nail is debrided, alcohols may also serve as passive penetrating solvents.
  • the composition may further comprise an immunomodulatory agent, particularly an IDO inhibitor such as D-tryptophan, 1-methyl-D-tryptophan, or methylthiohydantoin-DL- tryptophan.
  • the composition may further comprise a wound healing agent, particularly an HIFl/2a activator such as ciclopirox.
  • Each component of the composition may be present, for example, from about 0.1% (w/v) to about 10%, particularly about 0.5% to about 5% or about 1% to about 5% .
  • the carrier of the composition may be, for example, an aqueous nail lacquer.
  • the composition comprises ciclopirox, with or without iodine, chloroxyenol, or chlorhexidine, and ethyl pyruvate in a carrier.
  • the composition further comprises an immunomodulatory agent, particularly an IDO pathway inhibitor such as D-tryptophan, 1 -methyl-tryptophan or methylthiohydantoin-tryptophan.
  • Each of ciclopirox and a pan-antiseptic may be present in the composition, for example, from about 0.1% (w/v) to about 10%, about 0.1% (w/v) to about 1%, about 0.5% to about 5%, or about 1% to about 5%.
  • ciclopirox is present in the composition from about 1% (w/v) to about 10%, about 1% to about 5%, about 2% to about 10%, about 5% to about 10%, or about 2% to about 8%.
  • ciclopirox is present in the composition at about 0.5% (w/v), about 0.8%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.
  • ethyl pyruvate is present in the composition from about 1% (w/v) to about 50%, about 5% to about 40%, about 10% to about 30%, or about 15% to about 25%.
  • ethyl pyruvate is present in the composition at about 1% (w/v), about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, or about 50%.
  • the carrier of the composition may be, for example, an aqueous nail lacquer or DMSO, among others.
  • the composition contains from about 0.8 to about 8% (w/v) ciclopirox olamine, from about 1% to about 3% (w/v) iodine, from about 1% to about 3% (w/v) chloroxyenol or chlorhexidine, and from about 20% to about 50%
  • the composition contains from about 0.8 to about 8% (w/v) ciclopirox olamine, from about 1% to about 3% (w/v) iodine, and from about 20% to about 50% (w/v) ethyl pyruvate. In certain embodiments, the composition contains about 8% (w/v) ciclopirox olamine, about 1% (w/v) iodine, and about 20% (w/v) ethyl pyruvate. In certain embodiments, the composition contains about 8% (w/v) ciclopirox olamine, and about 20% (w/v) ethyl pyruvate.
  • the composition comprises iodine and ethyl pyruvate in a carrier.
  • Iodine may be present in the composition, for example, from about 0.1% (w/v) to about 10%, particularly about 0.5% to about 5% or about 1% to about 5%.
  • iodine is present at about 0.1% (w/v).
  • iodine is present at about 1% (w/v).
  • ethyl pyruvate may be present in the composition from about 1% (w/v) to about 50%, about 5% to about 40%, about 10% to about 30%, about 15% to about 25%, or about 15% to about 20%.
  • ethyl pyruvate is present at about 15% (w/v). In certain embodiments, ethyl pyruvate is present at about 17% (w/v). In certain embodiments, iodine is present from about 0.1% (w/v) to about 1% and ethyl pyruvate is present at about 17% (w/v). In certain embodiments, iodine is present from about 0.1% (w/v) to about 1% and ethyl pyruvate is present at about 15% (w/v).
  • the carrier of the composition may be, for example, an aqueous nail lacquer or DMSO, among others.
  • the compositions provided herein are used to inhibit, treat, and/or prevent onychomycosis.
  • the composition may be applied directly to the nail or may be applied by an applicator such as a brush, wipe, swab, or roller.
  • the compositions may be made into a wide variety of product types such as, without limitation, liquids, lotions, powders, creams, salves, gels, milky lotions, sticks, sprays (e.g., pump spray), aerosols, ointments, pastes, mousses, and other equivalent forms.
  • the compositions are liquids.
  • the compositions provided herein comprise the components described and at least one carrier.
  • the carrier may be a pharmaceutically acceptable carrier and/or a cosmetically acceptable carrier.
  • the carrier should be capable of being commingled with the components of the instant intention in a manner such that there is no interaction which would substantially reduce the efficacy of the active components of the composition (e.g., for treating onychomycosis).
  • a “carrier” refers to, for example, a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an active agent is administered.
  • Carriers may also include stabilizers, penetration enhancers, chelating agents (e.g., EDTA, EDTA derivatives (e.g., disodium EDTA and dipotassium EDTA), iniferine, lactoferrin, and citric acid), and excipients.
  • Carriers can be or comprise sterile liquids, such as water (may be deionized), alcohol (e.g., ethanol, isopropanol), oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like), and other organic compounds or coploymers.
  • emulsions e.g., microemulsions and nanoemulsions
  • gels e.g., an aqueous, alcohol, alcohol/water, or oil (e.g., mineral oil) gel using at least one suitable gelling agent (e.g., natural gums, acrylic acid and acrylate polymers and copolymers, cellulose derivatives (e.g., hydroxymethyl cellulose and hydroxypropyl cellulose), and hydrogenated butyl ene/ethylene/styrene and hydrogenated ethyl ene/propylene/styrene copolymers), solids (e.g., a wax-based stick, soap bar composition, or powder (e.g., bases such as talc, lactose, starch, and the like), and liposomes (e.g.,
  • the carrier is a nail lacquer.
  • a “nail lacquer” also known as a nail varnish or nail polish refers to a composition which forms a coat or film on the nail.
  • a nail lacquer comprises a film-forming, organic polymer in a volatile organic solvent.
  • a common nail lacquer comprises nitrocellulose in butyl acetate or ethyl acetate.
  • the methods comprise administering the composition(s) provided herein to the nail of a subject, particularly a human.
  • the nail may be treated, either debrided or not, multiple times a day (e.g., two times or more) or may be administered daily or less frequently.
  • the composition(s) is administered three times a day, twice a day, daily, once every two days, or less frequently.
  • the treatment of onychomycosis may be monitored using visual inspection and the composition may be administered as desired or as needed. Treatment may continue for as long as needed (e.g., for at least one month or for at least several months).
  • Toxicity and therapeutic efficacy of the particular compositions described herein can be determined by standard pharmaceutical procedures such as, without limitation, in vitro, in cell cultures, ex vivo, or on experimental animals. The data obtained from these studies can be used in formulating a range of dosage for use in human. The dosage may vary depending upon form of administration. Dosage amount and interval may be adjusted individually to levels of the active ingredient which are sufficient to, for example, treat onychomycosis.
  • kits are provided.
  • the kit comprises the composition(s) and, optionally, an applicator for applying the composition(s) to the nail.
  • the composition(s) is present within a contained (e.g., vial) along with the applicator (e.g., brush).
  • the applicator may be affixed to the inside of the cap/lid of the vial.
  • the components may be present within one or more compositions.
  • the kits may comprise multiple containers for the compositions. At least one of the containers may contain an applicator or the applicator may be provided separately.
  • the container is squeezable and allows for the discharge of its contents through an application tip.
  • onychomycosis refers to a fungal infection of the nail plate, matrix, and/or nail bed, also known as Tinea unguium.
  • fungi which are known to cause onychomycosis include, without limitation: dermatophytes (e.g.,
  • Trichophyton rubrum T. interdigitale, Epidermophyton floccosum, T. violaceum, Microsporum gypseum, T. tonsurans, T. soudanense, T. verrucosum); Candida, (e.g., Candida albicans); and nondermatophyte molds (e.g., Aspergillus species, Scopulariosis brevicaulis, Fusarium species, and Scytalidium).
  • Candida e.g., Candida albicans
  • nondermatophyte molds e.g., Aspergillus species, Scopulariosis brevicaulis, Fusarium species, and Scytalidium.
  • drug-resistant skin infection refers to any topical infection that does not respond to an existing standard of care antibiotic or antifungal treatment.
  • a “therapeutically effective amount” of a compound or a pharmaceutical composition refers to an amount effective to prevent, inhibit, treat, or lessen the symptoms of a particular disorder or disease.
  • the treatment of onychomycosis herein may refer to curing, treating, inhibiting, relieving, and/or preventing onychomycosis, the symptom of it, or the predisposition towards it.
  • “pharmaceutically acceptable” indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • cosmetically acceptable refers to entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to an animal, particularly a human, particularly to the skin or nail.
  • a “cosmetically acceptable” carrier refers to a carrier that can be used without undue toxicity, irritation, allergic response, and the like.
  • the cosmetically acceptable carrier should be capable of being commingled with the components of the instant intention in a manner such that there is no interaction which would substantially reduce the efficacy of the active components of the composition (e.g., for treating onychomycosis).
  • a “carrier” refers to, for example, a diluent, adjuvant, excipient, auxiliary agent or vehicle with which an active agent is administered.
  • Pharmaceutically acceptable carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described, for example, in “Remington's Pharmaceutical Sciences” by E.W. Martin. A carrier might in some cases also have pharmacological of biological activity, for example, DMSO.
  • an “antibody” or “antibody molecule” is any immunoglobulin, including antibodies and fragments thereof, that binds to a specific antigen. As used herein, antibody or antibody molecule contemplates intact immunoglobulin molecules, immunologically active portions of an immunoglobulin molecule, and fusions of immunologically active portions of an immunoglobulin molecule.
  • immunologically specific refers to proteins/polypeptides, particularly antibodies, that bind to one or more epitopes of a protein or compound of interest, but which do not substantially recognize and bind other molecules in a sample containing a mixed population of antigenic biological molecules.
  • the term “prevent” refers to the prophylactic treatment of a subject who is at risk of developing a condition resulting in a decrease in the probability that the subject will develop the condition.
  • treat refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the condition, etc.
  • anti a type of target organism (e.g., antimicrobial, antiviral, antifungal, antibacterial, antiparasitic) refers to having any deleterious effects upon those organisms or their ability to cause symptoms in a host or patient. Examples include, but are not limited to, inhibiting or preventing infection, inhibiting or preventing growth or reproduction, killing of the organism or cells, and/or inhibiting any metabolic activity of the target organism.
  • antimicrobial refers to any substance or compound that when contacted with a living cell, organism, virus, or other entity capable of replication, results in a reduction of growth, viability, or pathogenicity of that entity.
  • kits generally refers to a collection of elements that together are suitable for a defined use.
  • a “kit” refers to a collection of containers containing the necessary compositions to carry out the method provided, typically in an arrangement both convenient to the user and which ensures the chemical stability of the compositions.
  • the kit may comprise a delivery system having one or more containers (such as tubes or vials).
  • containers such as tubes or vials.
  • such delivery systems include systems (e.g., enclosures (e.g., boxes)) that allow for the storage, transport, or delivery of compositions provided herein and/or supporting materials (e.g., instruction material) from one location to another.
  • an “instructional material” includes a publication, a recording, a diagram, or any other medium (including electronic) of expression which can be used to communicate the usefulness of the compositions provided herein for performing a method as provided herein.
  • the instructional material of the kit can be shipped or provided with the kit (e.g., affixed to a container) or can be shipped or provided separately from the kit with the intention that the instructional material and kit be used cooperatively by the recipient.
  • Penlac® (ciclopirox olamine) is an approved antifungal topical for fungal nail treatment.
  • Penlac® (ciclopirox olamine) is an approved synthetic hydroxypyrimidine antifungal agent thought to inhibit catalase and peroxidase enzymes in fungi as part of its mechanism of action. It is indicated to treat tinea pedis (athlete’s foot) and tinea corporis (ringworm) (El-Gohary (2014) The Cochrane database of systematic reviews 8:CD009992).
  • Ciclopirox olamine is used in nail lacquers for topical treatment of onychomycosis, albeit with poor cure rates. Typically, it is used at a 8.0% concentration for the topical treatment of nail fungus.
  • Iodine is a simple, yet highly effective, broad-spectrum antimicrobial agent used widely as a topical antiseptic in medicine. Iodine is not only efficacious against diverse bacteria and protists, including fungi and fungi spores, but unlike other anti-microbial agents it is not susceptible to drug resistance.
  • aqueous iodine is also used commonly on skin and nails (tincture of iodine).
  • aqueous iodine may be relatively more effective in microbe killing at concentrations of ⁇ 1% (e.g., 0.1-1%), which is lower than used traditionally in clinical medicine (-10% for PVP-I).
  • Chloroxyenol or chlorhexidine is a broad-spectrum antimicrobial chemical used to control bacteria, algae, fungi and virus. Either is used widely in antiseptics, antibacterial soaps, and wound-cleansing applications. Neither is significantly toxic to humans but at high concentrations can be a mild skin irritant in some individuals. Either is used widely in topical antiseptic products at l%-4% concentration. There is no medical literature on their use to treat onychomycosis.
  • EP Ethyl pyruvate
  • GASS safe substance
  • EP is a safe excipient compound that is known to improve skin penetration of various skin care products and cosmetics, although not for nail care products.
  • EP is known to have keratinolysing properties and nails are also composed of keratins like skin.
  • EP does not react with molecular iodine under physiological conditions (Bell et al. (1967) Proc. Royal Soc. London, Math. Phys. Sci., 298:178-183).
  • EP is useful as a formulant to iodine to improve its antiseptic activities in the nail bed, based on the established ability of EP to improve drug penetration where keratin-based structures are the chief barrier to penetration.
  • EP also has immunostimulatory properties, based on its ability to block the immunosuppressive enzyme indoleamine 2,3 -di oxygenase (IDO) (Muller et al. (2010) Cancer Res., 70:1845-1853). Thus, EP also helps relieve local immune tolerance of infections, including MMB infections.
  • IDO immunosuppressive enzyme indoleamine 2,3 -di oxygenase
  • EP also helps relieve local immune tolerance of infections, including MMB infections.
  • 1% iodine or 3% chlorhexidine and 20% EP is formulated with or without 8.0% ciclopirox olamine in an aqueous solution to treat topical skin infections, or in a standard nail lacquer formulation to treat nail infections, to generate the medicinal cocktail termed EPIC (Ethyl -pyruvate + Penlac + Iodine or Chlorhexidine).
  • RAIDS reflexive anti -infective drug synergy
  • ciclopirox is a weak antifungal drug. Our data also suggests that ciclopirox has more potent activities on two signaling pathways that mediate innate immunity: namely, indoleamine di oxygenase- 1 (IDOl) and hypoxia inducing factor- 1 (HIFl). i. Ciclopirox Enhances HIFl Levels
  • IDO is an iron-dependent enzyme, and we demonstrated that ciclopirox can also act as an IDO enzyme inhibitor.
  • ciclopirox inhibited IDO in a cellular assay with an IC50 of ⁇ 2 mM (FIG. 2). This is finding is not previously reported in the literature. The details of the assay protocol are published elsewhere [27]
  • Onychomycosis is a Polymicrobial Infection
  • Up to 50 patients are enrolled to help ensure that 20 patients in each treatment cohort complete the trial.
  • the treatment duration is up to 48 weeks from the time of first treatment in the podiatrist’s office to the last office visit.
  • Dynamic randomization proceeds as patients are enrolled to avoid demographic or medical bias in the treatment arms.
  • the treatments limbs are double-blinded to investigators and patients, until after all data analyses are completed.
  • the inclusion of patients aged 50-70 years is intentionally narrow to avoid variability of response due to age in this relatively small pilot trial. Diagnosis of onychomycosis is confirmed before beginning a treatment regimen.
  • the primary endpoint of the study is complete clinical and mycological cure, assessed at week 52 (4-weeks after completion of therapy). Complete clinical cure is defined as 0% visible involvement of the target toenail. Mycological cure is a negative KOH test.
  • the primary efficacy endpoint is evaluated by treatment group, and within subgroups based on sex, ethnicity and median percent affected toenail area ( ⁇ 40% and >40%).
  • Clinical cure rates in the three treatment groups are measured as follows: the outline of the nail in photos is separated into eight segments, each representing 12.5% of the nail. If > 50% of the segment has an area of infection, the entire segment is counted as area of involved nail.
  • the clinician performs assessments visually at each visit and document the findings to monitor response to treatment. Photographic editing software (Photoshop CS3, Adobe Systems, Inc., San Jose, CA) is used to calculate the ratio of affected nail area to total nail area (in pixel units) for each photograph taken during the course of the study.
  • the ingredients of the EPIC formulation are: ⁇ ) ethyl pyruvate (EP at 20%); II) 1% iodine (PVP-I; III) 8% ciclopirox; all mixed in the same base as Penlac, which serves as the standard-of-care Control cohort.
  • Ethyl pyruvate is a safe food ingredient. Inclusion of ethyl pyruvate can normalize the suppressed immune microenvironment at the root of the active infections, acting synergistically with ciclopirox [27,32,33]
  • Iodine (povidone) at 1% is a very safe and effective pan-antimicrobial agent. It is very efficacious against diverse gram-positive and gram-negative bacteria and protists, including fungi and fungal spores; but unlike other anti-microbial agents, it is not susceptible to drug resistance. The antimicrobial action of iodine is rapid, even at concentrations less than 1% [34]
  • Penlac ® is an FDA-approved antifungal topical treatment for onychomycosis.
  • hypoxia-induced factor (HIF) pathway a master mediator of wound healing
  • IDO hypoxia-induced factor
  • a portion of the nail sample from each patient used for the KOH test and its associated tissue debris is sent to PathoGenius Inc, a CRO in Lubbock, Texas, for DNA analysis of pathogens.
  • the microbial DNA is extracted from the specimen, and then sequenced using next generation platforms to specifically identify fungal and bacterial pathogens.
  • a detailed, statistical report of all pathogens is provided shortly (1-2 weeks) after the samples are received.
  • the approach determines the relative sequence abundance of pathogens in the infected nail sample. This process is accomplished using comparative DNA sequencing analysis, which is widely considered superior to culture analysis for microbial identification.
  • Sequence data are generated by advanced platforms; including Ion Torrent PGM, Ion Proton, and Illumina, and are compared against a sequence database that is curated with updated microbial sequences as they are published.
  • This approach enables the research team to determine the causative pathogens that represent the disease bioburden of the patient.
  • the data can be used to better understand the outcomes from the clinical study of the EPIC versus ciclopirox formulations (FIG. 3).
  • Example 3 Jubliac
  • Jubliac is formulation which is a combination of efmaconazole (Jublia®) and ciclopirox (Penlac®).
  • the combination has two different mechanisms of antifungal activity. More importantly, the iron-chelating activity of ciclopirox serves to upregulate HIF-a, which promotes wound healing and also inhibit IDO, an effect which enhances immune-aided clearance of the infection.
  • a passive penetrant like DMSO or an active penetrant like EP can be included, among other carriers, including in a nail lacquer.
  • CicloHex is the combination of ciclopirox for its iron-chelation activity (enhances HIF-a and inhibits IDO -in addition to its antifungal activity) and a pan-antiseptic like chlorhexidine to also quench fungal species.
  • Ciclo-EP is the combination of ciclopirox and ethyl pyruvate
  • EPI Ethyl pyruvate + iodine
  • iodine-only skin infections or nail infections (onychomycosis).
  • the study is a two-arm design with patients that are randomized to receive nail lacquer formulations that include iodine, a broad-spectrum antimicrobial, with or without ethyl pyruvate, an approved nail penetrant that has been shown to have immunomodulatory properties.
  • the period of treatment is 3 months after recruitment to the study, with follow-up at clinical office visits that are part of standard of care with documentation at 1, 3 and 6 months after the start of treatment.
  • the human nail plate includes three layers, the dorsal and intermediate layers of the nail and the ventral layer comprising the nail bed.
  • the dorsal layer is a few cell layers thick and consists of hard keratin. This layer is the main barrier to diffusion of therapeutics into and through the nail plate.
  • the intermediate layer is also rich in keratin but behaves somewhat differently than the dorsal layer with regard to diffusion.
  • the ventral layer consists of a soft hyponychial where infections take hold beneath the nail plate. Achieving an effective drug concentration in the ventral layer is a key goal of new anti-infective formulations. Chemical penetration through the nail relies upon water solubility and molecular size (Merlin and Lippold, 1997).
  • Penetration enhancers have been studied to increase diffusion of effective chemicals into/through the human nail plate, but agents such as DMSO and isopropyl alcohol that are effective in penetrating skin are either ineffective or impede penetration in the nail. Accordingly, the formulation created for testing in this study includes ethyl pyruvate (EP), a safe approved compound with nail penetrant activity that has been shown to be immunomodulatory.
  • EP ethyl pyruvate
  • Iodine is a broad-spectrum antimicrobial agent that kills bacteria, fungi and protists. Notably, unlike other antimicrobial agents, iodine is not susceptible to drug resistance. Low concentrations ( ⁇ 1%) are as potent as higher concentrations used historically in medicine (e.g. -10% in PVP-I [Betadine®]). For example, low concentration tincture of iodine is available OTC as ‘white iodine’ and can be used as a home remedy for topical infections.
  • Ethyl pyruvate is widely used as a pharmaceutical excipient (formulant) to improve skin penetration of various skin care products and cosmetics. It is defined by the FDA as a generally regarded as safe substance (GRASS). In considering its co-formulation with iodine, studies have shown that EP does not react with molecular iodine under physiological conditions (Bell and Ridgewell, 1967). Notably, it was discovered that EP can stimulate immunity by blocking expression of indoleamine 2,3-dioxygenase (IDO) (Muller et ak, 2010), an immunosuppressive enzyme elevated in certain chronic skin infections (e.g. warts (Xie et ak, 2017)). Thus, EP can improve the antiseptic properties of iodine by two mechanisms, one through improving nail bed penetration and another by relieving immune tolerance to MMB infections such as onychomycosis.
  • IDO indoleamine 2,3-dioxygenase
  • the primary endpoints of the study are to determine the nail infection status after treatment at 1, 3 and 6 -month visits, documenting the final status or absence of infection in all patients.
  • GMP formulations EPI Formulations
  • EP is a stable and metabolizable derivative of pyruvate that has been studied in animals and humans where no evidence of significant toxicities have been reported (Fink, 2007; Kao and Fink, 2010).
  • EP has been delivered by i.v. infusion of >50% solutions where toxicity issues as part of an IND application were addressed in support of a Phase Eli trial in cardiac surgery (http://clinicaltrials.gov/ct2/show/NCT00107666). No significant toxicities were reported in this study which also failed to reveal any therapeutic benefit (Bennett-Guerrero et ak, 2009).
  • OTC formulations available as “tincture of iodine” are low-concentration preparations 0.1-1% iodine, sometimes known informally as “colorless” or “white” iodine. Tincture of iodine has been used for nail treatment as a home remedy. While over the years some studies have suggested that the topical use of iodine may involve limited safety risks, more methodical hospital-based studies do not corroborate these suggestions and instead find iodine to be very safe as well as effective (Vermeulen et ak, 2010). Given the long history of experience with iodine as topical antiseptics, the risk-benefit ratio from their use is argued to be extremely low.
  • Aim 1 Record the clinical status of the nail infection of patients at the start of the study and at each follow up visit (i.e. diagnosis, extent of infection visible, number of nails infected)
  • Aim 2 Record the standard-of-care treatment provided to the patient at the first study visit, if any. At the same visit where informed consent is obtained, or within two weeks of consent, all patients who participate in the study receive clinical standard of care for nail infections that may include topical debridement or removal of part of the nail. These treatments are variably employed at the discretion of the clinical investigators. Diagnosis, location, size and number of infections are recorded along with the type of care provided per clinical standards.
  • Aim 3 Randomize patients to the EPI or I-only arms of the trial, providing treatment at the first study visit. At the end of the first visit, patients are randomized into two cohorts constituting the EPI or I-only groups. Patients are provided with a vial containing each formulation. Each vial is labeled ‘For Nail Treatment’ with the one-sentence instruction ‘Apply the treatment to fingernails twice a day for three months’. These instructions are confirmed verbally by the study coordinator before the patient leaves the first study visit.
  • Aim 4 Receive nail photographs taken bimonthly by patients on their mobile phone and emailed to the clinical coordinator. Every two weeks, patients take mobile phone photographs of the back of the hand close enough to show the status of their fingernails, and then email the photos to the clinical coordinator. These instructions are confirmed verbally before the patient leaves the study visit.
  • Aim 5 Record the clinical status of the nail infection(s) on the patient, if any, indirectly from photos every two weeks and directly at follow-up visits at the end of months 1, 3 and 6 (study endpoint). Patients are examined one month after the first study visit to assess the outcome of their first treatment month. Nail status and care, if provided, are recorded at the time of care during this second study visit. The same exam is performed at months 3 and 6. A biostatistician serves as a consultant for comparative interpretation of the clinical observations. Study Timeline
  • Phase 1 Finalize protocol (months 0-3).
  • Phase 2 Recruit subjects (months 4-15).
  • Phase 3 Perform subject follow-up (months 16-19).
  • Phase 5 Conduct data analysis and prepare communications (months 20-24).
  • Example 6 Treatment of a skin infection
  • EPI and EPIC formulations are suitable for topical treatment of skin infections.
  • a patient having a skin Staphylococcus infection on the foot was treated with an EPI formulation.
  • Treatment was administered topically daily for one week.
  • the patient received no other treatment for the infection.
  • FIG. 4 shows clinicopathology photos taken before (top) and after (bottom) treatment.

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Abstract

L'invention concerne des compositions et des méthodes pour le traitement d'infections topiques telles que l'onychomycose.
PCT/US2022/020756 2020-11-24 2022-03-17 Méthodes et compositions pour le traitement d'infections topiques résistantes aux médicaments Ceased WO2022197927A1 (fr)

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Citations (4)

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US20060160830A1 (en) * 2004-12-17 2006-07-20 Anadys Pharmaceuticals, Inc. 3,5-Disubsitituted and 3,5,7-trisubstituted-3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds and prodrugs thereof
US20060166932A1 (en) * 2002-11-06 2006-07-27 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
WO2020055716A1 (fr) * 2018-09-14 2020-03-19 3M Innovative Properties Company Compositions antimicrobiennes comprenant de la chlorhexidine
US20200163915A1 (en) * 2011-12-13 2020-05-28 Io Therapeutics, Inc. Treatment of diseases by concurrently eliciting remyelination effects and immunomodulatory effects using selective rxr agonists

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Publication number Priority date Publication date Assignee Title
US20060166932A1 (en) * 2002-11-06 2006-07-27 Celgene Corporation Methods for the treatment and management of myeloproliferative diseases using 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
US20060160830A1 (en) * 2004-12-17 2006-07-20 Anadys Pharmaceuticals, Inc. 3,5-Disubsitituted and 3,5,7-trisubstituted-3H-oxazolo and 3H-thiazolo[4,5-d]pyrimidin-2-one compounds and prodrugs thereof
US20200163915A1 (en) * 2011-12-13 2020-05-28 Io Therapeutics, Inc. Treatment of diseases by concurrently eliciting remyelination effects and immunomodulatory effects using selective rxr agonists
WO2020055716A1 (fr) * 2018-09-14 2020-03-19 3M Innovative Properties Company Compositions antimicrobiennes comprenant de la chlorhexidine

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