Compositions and methods for treating cutaneous fungal infections

Abstract

A composition comprising an antifungal drug and a drying agent can be used to treat fungal infections of the skin, such as athletes foot, jock itch, ringworm, and intertrigo. The drying agent enhances antifungal activity. The composition may be formulated as an anhydrous stick for application to affected areas of the skin.

Description

COMPOSITIONS AND METHODS FOR TREATING CUTANEOUS FUNGAL INFECTIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 693,793 filed September 12, 2024, and U.S. Provisional Patent Application Serial No. 63 / 783,779, filed April 4, 2025, the content of each of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The technology relates to compositions and methods for treatment and prevention of cutaneous fungal infections such as including tinea pedis, tinea corporis, tinea cruris, intertrigo and tina versicolor and perspiration conditions and related disorders.BACKGROUND

[0003] Eccrine glands are secretory glands in humans that are in higher density on the soles of the feet and the forehead, followed by the palms and the cheeks. Eccrine gland sweating is the primary means for thermoregulation of the human body. Sweat glands in the dermis and epidermis are distributed over the entire surface of the body except for the margins of the limbs, sex organs, and ear drums. Sweat glands are innervated by the sympathetic nervous system. When the body's internal temperature exceeds the hypothalamic set point, activation of a sympathetic reflex causes an increase in sweat output. In non-occluded areas of the body, evaporation of the sweat leads to a decrease in body temperature. However, for areas of the body such as the feet, that are captive within occlusive athletic footwear, the lack of evaporation results in a hot, moist environment that can be maintained for hours. Thus, athletic footwear creates the perfect environment for the symptomatic fungal infection tinea pedis, more commonly known as athlete’s foot. It has been previously reported that combining an antifungal drug with an antiperspirant drug leads to synergism that provides an accelerated therapeutic effect in the treatment of tinea pedis (see, e.g., USPN 10,251,822 and USPN 11,554,108, each of which are incorporated herein by reference).

[0004] Aluminum antiperspirants are topically applied and limit eccrine sweat production due to the Al(III) and ZAG salts containing Zr(IV) ions penetrating into the duct and forming an occlusive plug of polycationic Aluminum ions with polyanionic salts such as the amino acids, peptides, and proteins from sweat or even the ductal wall. These antiperspirants are very effective at reducing sweat.

[0005] The Al(III) salt, aluminum chloride, was first used in antiperspirants in 1903. However, the highly acidic pH of AlCh was irritating to the skin and damaging to clothing. Less acidic salts such as aluminum chlorohydrate (ACH), were better tolerated and eventually more effective salts were designed by blending ACH with zirconyl chloride or zirconyl hydroxychloride in the presence of glycine. The zirconium salts blended in the presence of glycine were specifically developed for anhydrous formulations. Table 1 lists aluminum drug actives that have been found efficacious in reducing perspiration and sweating according to the U.S. Food and Drug Administration (FDA) Over-the-Counter (OTC) Monograph M019: Antiperspirant Drug Products for Over-the- Counter Human Use. When used below the concentrations shown in Table 1, these drug actives are regarded as safe for formulation in an antiperspirant product.Table 1.Aluminum chloride up to 15 percentAluminum chlorohydrate up to 25 percentAluminum chlorohydrex polyethylene glycol up to 25 percentAluminum chlorohydrex propylene glycol up to 25 percentAluminum dichlorohydrate up to 25 percentAluminum dichlorohydrex polyethylene glycol up to 25 percentAluminum dichlorohydrex propylene glycol up to 25 percentAluminum sesquichlorohydrate up to 25 percentAluminum sesquichlorohydrex polyethylene glycol up to 25 percentAluminum sesquichlorohydrex propylene glycol up to 25 percentAluminum zirconium octachlorohydrate up to 20 percentAluminum zirconium octachlorohydrex gly up to 20 percentAluminum zirconium pentachlorohydrate up to 20 percentAluminum zirconium pentachlorohydrex gly up to 20 percentAluminum zirconium tetrachlorohydrate up to 20 percentAluminum zirconium tetrachlorohydrex gly up to 20 percentAluminum zirconium trichlorohydrate up to 20 percent Aluminum zirconium trichlorohydrex gly up to 20 percent

[0006] Aluminum antiperspirants have shown synergism when combined with an antifungal to accelerate therapeutic effect in the treatment of tinea pedis. However, continued concern about aluminum neurotoxicity and links to Alzheimer’s and breast cancer often dampen enthusiasm for the use of Al(III) antiperspirants. Antiperspirants can be introduced into the body through intentional absorption of the active into the eccrine sweat gland and / or incidental inhalation of the active. Accidental inhalation of antiperspirant sprays is thought to introduce more aluminum into the body than can be absorbed into the blood from the polycationic aluminum ion plug located in the duct of the eccrine gland. For these reasons, the FDA expects that combining an antifungal drug with any antiperspirant in Monograph M019 will pose a substantial safety risk and will not permit sales of a combination product without extensive safety testing.

[0007] Alternative treatments for physiological reduction of perspiration and sweating include local injections of botulinum toxin and systemic use of anti-cholinergic drugs. Botulinum toxin injections reduce sweating because of their anti-cholinergic effects at the neuromuscular junction and in the postganglionic sympathetic cholinergic nerves in the sweat glands, but these injections are painful, expensive and must be repeated every three months. Systemic anti-cholinergic drugs are effective at reducing sweating, but the dosages required to reduce sweating also result in adverse side effects including dryness of the mouth, constipation, blurred vision, lack of appetite, nausea, somnolence and the feeling of raised temperature. Accordingly, neither botulinum toxin nor systemic anti-cholinergic drugs are suitable sweat reducing drugs to combine with a topical antifungal to accelerate healing of superficial fungal infections caused by dermatophytes (tinea pedis, tinea cruris, tinea capitis, etc.) or Candida such as intertrigo.

[0008] Several publications describe a reduction of sweating using actives that do not block the sweat glands or pores. WO 02 / 011690 (Unilever, incorporated herein by reference) describes an antiperspirancy method whereby calcium channels with the secretory coil cells of the eccrine glands are blocked, thereby controlling sweat production at its source. US Pat. No. 8,618,160 B2 (Rose U, incorporated herein by reference) discloses wipes containing glycopyrrolate, a muscarinic anticholinergic, as a treatment for hyperhidrosis. Certain anticholinergic drugs have also been used to treat hyperhidrosis, with varying degrees of success. These drugs include Ditropan® (oxybutynin), Probanthine® (propantheline bromide) and Cogentin® (benzotropine). US 2008 / 0207737 (Zinger, incorporated herein by reference) describes a topical composition for antiperspirant benefit comprising varying levels of oxybutynin. However, the risk of side effects when using these drugs overwhelms the benefit of combination therapy to treat superficial skin infections.

[0009] Powders such as talc, corn starch and sodium bicarbonate have been used for decades as topical drying agents, especially as baby powders. Another use of these drying agents is as foot powders which may include an antifungal. Some of these foot powders also contain zinc oxide which is used as a bulking agent and to give a more brilliant white appearance to the foot powder. The major consumer complaint concerning foot powders is that they are messy, both personally and to the immediate environment. The major health concern about accidental inhalation of powder products in general and talc in particular, is the dangers of prolonged exposure. As of August 2024, more than 61,000 lawsuits have been filed against Johnson & Johnson alleging that its talcum powder products cause ovarian cancer and other health issues.

[0010] Current topical antifungal therapies are delivered in a wide variety of vehicles, each with its own strengths and weaknesses. Creams, such as Lotrimin AF® (clotrimazole), Lamisil AT® (terbinafine), and Tinactin® (tolnaftate), are the most widely used because they spread easily, though patients often find them greasy and prone to rubbing off in shoes and socks. Ointments, including Mycolog-II® (nystatin-triamcinolone) and Nizoral Ointment® (ketoconazole, non-U. S.), provide good occlusion and penetration, but their heavy, sticky texture limits cosmetic acceptabilityfor routine foot care. Lotions and solutions, like Exelderm® (sulconazole), Loprox® (ciclopirox), and Lamisil Solution® (terbinafine), are light and easy to apply over larger or hairy surfaces, but their watery consistency results in rapid loss from the skin.

[0011] Powders, such as Zeasorb AF® (miconazole), Tinactin Powder Spray® (tolnaftate), and Desenex® (miconazole), help absorb moisture but scatter easily and fail to maintain meaningful contact with the stratum corneum. In addition, powders aerosolize and may be inadvertently inhaled, raising further tolerability concerns. Sprays, like Lotrimin Spray Powder® and Lamisil Spray®, offer quick application between the toes and in hard-to-reach areas, though they leave only a thin layer that is easily wiped away with sweat. Gels, including Lamisil Gel® (terbinafine, non-U. S.) and various clotrimazole gel generics, feel cool and pleasant on application, but dry rapidly and lack persistence. Foam formulations, such as Lamisil Once® (terbinafine hydrogel film-forming solution, Europe), are cosmetically elegant, but dissipate quickly and struggle to provide sustained contact under moist conditions.

[0012] Antifungal wipes are also commercially available, though they remain a niche format compared with creams or sprays. Products such as Tinactin Antifungal Wipes® (tolnaftate) and veterinary-adapted wipes containing ketoconazole or chlorhexidine illustrate the category, often marketed for gym, travel, or pet care use. However, wipes require a sealed moisture package, bring the active drug into direct contact with the user’ s hands, and must be disposed of after each use, reducing convenience and hygiene. Furthermore, most are alcohol-based, which can be irritating to macerated or broken skin, limiting their tolerability in patients with active tinea pedis or intertrigo.

[0013] Patches and film-forming systems, exemplified by Lamisil Once® and ciclopirox nail lacquers, can offer longer contact but often adhere poorly on sweaty, mobile skin surfaces like the feet. Finally, stick or bar formats — while not yet widely adopted in antifungal products — are well established in deodorants and antiperspirants and represent an emerging opportunity to combine antifungal activity with moisture control in a portable, non-messy delivery system.SUMMARY OF THE INVENTION

[0014] The compositions, dosage forms, and methods described herein recognize an unmet need for treatments of cutaneous fungal diseases that:• exploit the synergistic effect of combining an antifungal drug with a drying agent without exposing patients to unnecessary risks associated with the antiperspirants, sweat blocking drugs, sprays and powders described above• are effective regardless of the form or variant of the disease (fungal, yeast, and / or bacterial)• can be formulated as a non-aqueous dosage form (mechanical, physical) that conveniently and effectively delivers actives & drying agents to the skin while minimizing systemic exposure• allow for convenient administration and delivery to all parts of the body integument including tough to reach surface areas• can be delivered via a practical device and formulation that induces surface activation while reducing transfer to clothing, socks, or other apparel

[0015] Compositions and methods of the invention provide treatments for excessive sweating and fungal conditions of the skin. Sweating can be reduced by applying drying agents in an anhydrous dosage form. Drying agents also enhance the activity of antifungal drugs. In some embodiments, the drying agent is a non-drug drying agent, meaning that it is not an antiperspirant which enters sweat glands and forms a plug to prevent sweating. An antifungal drug may be combined with a drying agent in an anhydrous dosage form. The drying agent may comprise one or more of aluminum (III) hydroxide [A1(OH)3], magnesium sulfate [MgSOi], magnesium (II) aluminum (III) silicate [MgAlSiOJ, and / or magnesium (II) hydroxide [Mg(OH)2]. The drying agent may also comprise Zinc Oxide [ZnO]. An antifungal drug may be formulated with a non-drug drying agent in an anhydrous dosage form. In some embodiments, the anhydrous dosage form is a waxy stick. The optimization of solids with a waxy emollient for glide, structural support for stability, and absorbent compounds for moisture control in a semi-solid or solid composition yields an unexpected dual benefit: a measurable reduction in perspiration and also fungal clearance. Multiple non-drug drying agents can be combined with an antifungal which, surprisingly, achieves synergistic results and greater mycological cure rates and clinical effectiveness than either the antifungal or non-drug drying agent(s) used alone. In one example, non-drug drying agents such as Mg Al Silicate, MgOHi, MgSC>4 and AIOH are incorporated together with tolnaftate in a stick formulation for the treatment of superficial fungal infections.

[0016] As discussed above, antiperspirants in Monograph M019 are thought to pose a substantial safety risk and the FDA does not permit sales of a combination product involving those antiperspirants without extensive safety testing. Accordingly, reduction of perspiration and sweat on the surface of the skin should use drying agents that cannot be introduced into the body. Furthermore, to achieve synergy between a drying agent and an antifungal to accelerate therapeutic effect in superficial fungal infections, the drying agent is preferably not a drug, does not cross the stratum corneum and cannot be accidentally inhaled.

[0017] One embodiment of the invention is a composition comprising an antifungal drug and a non-drug drying agent. The antifungal drug can be a squalene epoxidase inhibitor. The squalene epoxidase inhibitor can be tolnaftate or terbinafine. The tolnaftate concentration can be about 1%. The terbinafine concentration can be about 1 %. The antifungal drug can be an azole. The azole can bemiconazole nitrate or clotrimazole. The miconazole nitrate concentration can be about 2%. The clotrimazole concentration can be about 1%. The non-drug drying agent can comprise ZnO particles. The ZnO particles concentration can be about 15%. The ZnO particles can have a surface area of 3-5 m2 / g, 8-10.5 m2 / g, or 25-35 m2 / g. The non-drug drying agent can comprise a salt selected from the group consisting of A1(OH)3, MgAISiO i, Mg(OH)2, and MgSO4. The non-drug drying agent can comprise two or more or three or more salts selected from Al(OH)s, MgAISiO i, MglOHh, and MgSO4. The non-drug drying agent can comprise Al(OHh, MgAlSiO4, MglOH b, and MgSO4. The Al(OH)s concentration can be 5% or less, about 5%, about 3%, or about 1%. The MgAlSiO4 concentration can be 3% or less, about 3%, about 1.8%, or about 0.6%. The MglOHh concentration can be 4% or less, about 4%, about 2.4%, or about 0.8%. The MgSO4 concentration can be 7% or less, about 7%, about 4.2%, or about 1.4%. The non-drug drying agent can comprise CaCb or SiCh. The CaCb concentration can be 5% or less. The SiO2 concentration can be 7% or less. The composition can further comprising a supplemental drying agent. The supplemental drying agent can be selected from magnesium oxide, magnesium carbonate, and magnesium chloride, starch, corn, tapioca, baking soda, talc, arrowroot powder, silica, magnesium carbonate, cyclomethicone, caprylic triglyceride, and clay.

[0018] Another embodiment of the invention is an anhydrous dosage form comprising any composition described in the preceding paragraph. The anhydrous dosage form can further comprise cyclopentasiloxane, stearyl alcohol, PPG-17, hydrogenated castor oil, C12-15 alkyl benzoate, oleic acid, behenyl alcohol, and / or pentadecalatone. The anhydrous dosage form can further comprise cyclopentasiloxane, C12-C15 alkyl benzoate, stearyl alcohol, behenyl behenate, tocopheryl acetate, fragrance, and / or arrowroot starch. The anhydrous dosage form can further comprise about 36% cyclopentasiloxane, about 20% C12-C15 alkyl benzoate, about 10% stearyl alcohol, about 11% behenyl behenate, about 1 % tocopheryl acetate, and arrowroot starch. The anhydrous dosage form can further comprise 1% tolnaftate. The anhydrous dosage form can comprise 1% tolnaftate, 5% A1(OH)3, 3% MgAlSiCX, 4% Mg(OH)2, and 7% MgSC The anhydrous dosage form can be an anhydrous stick. The anhydrous dosage form can comprise an anhydrous suppository base, aerosol oleaginous spray, hydrophobic ointment, oil-in-oil emulsion, non-aqueous paste, non-aqueous microemulsion / nanoemulsion, or a non-aqueous gel.

[0019] The composition or anhydrous dosage form can be effective in topically treating a fungal infection. The composition or anhydrous dosage form can be antibiotic-free.

[0020] Another embodiment of the invention is anhydrous dosage form comprising two or more non-drug drying agents selected from the group consisting of A1(OH)3, MgAISiO i, Mg(OHh, MgSO4, CaCT and SiO2. The anhydrous dosage form can comprise three or four non-drug drying agents. Non-drug drying agents can be selected from the group consisting of A1(OH)3, MgAlSiO4, MglOH , and MgSO4. The anhydrous dosage form can further comprise cyclopentasiloxane, stearyl alcohol, PPG-17, hydrogenated castor oil, C12-15 alkyl benzoate, oleic acid, behenyl alcohol, and / orpentadecalatone. The anhydrous dosage form can further comprise cyclopentasiloxane, C12-C15 alkyl benzoate, stearyl alcohol, behenyl behenate, tocopheryl acetate, fragrance, and / or arrowroot starch. The anhydrous dosage form can further comprise about 36% cyclopentasiloxane, about 20% C12-C15 alkyl benzoate, about 10% stearyl alcohol, about 11% behenyl behenate, about 1% tocopheryl acetate, and arrowroot starch. The anhydrous dosage form can further comprise about 5% A KOH) ,, about 3% MgAlSiO4, about 4% Mg(OH)2, and about 7% MgSO4or about 3% A1(OH)3, about 1.8% MgAlSiO4, about 2.4% Mg(OH)2, and about 4.2% MgSO4. The anhydrous dosage form can effective in topically treating hyperhidrosis, such as plantar hyperhidrosis or palmar hyperhidrosis. In a preferred embodiment, the anhydrous dosage form is an anhydrous stick. In other embodiments, the anhydrous dosage form comprises an anhydrous suppository base, aerosol oleaginous spray, hydrophobic ointment, oil-in-oil emulsion, non-aqueous paste, non-aqueous microemulsion / nanoemulsion, or a non-aqueous gel.

[0021] Another embodiment of the invention is a method of treating a subject with a condition associated with a fungal infection of the skin comprising topically administering a composition or anhydrous dosage form described above to an infected skin of the subject. The fungal infection of the skin cam be a dermatophytic infection. The subject can have tinea pedis. The subject can have intertrigo. The subject can have tinea corporis, tinea cruris, or tinea versicolor. The anhydrous stick can be administered twice per day for 10 days. The anhydrous stick can be administered for at least 14 days, for at least 28 days, or for about 30 days.

[0022] Another embodiment of the invention is a method of treating a subject with hyperhidrosis comprising topically administering any of the anhydrous dosage forms described above. The hyperhidrosis can be plantar hyperhidrosis or palmar hyperhidrosis.

[0023] Another embodiment of the invention is a kit comprising two anhydrous sticks comprising any composition described above.

[0024] Another embodiment of the invention is a composition or anhydrous dosage form for use in treating a subject with a condition associated with a fungal infection of the skin. The fungal infection of the skin may be a dermatophytic infection. The subject may have tinea pedis. The subject may have intertrigo. The subject may have tinea corporis, tinea cruris, or tinea versicolor. The anhydrous dosage form may be a stick. The composition or anhydrous dosage form may be administered twice per day for 10 days. The composition or anhydrous dosage form may be administered for at least 14 days, for at least 28 days, or for about 30 days. The composition or anhydrous dosage form may be administered twice per day for 10 days. The composition or anhydrous dosage form may be administered for at least 14 days, for at least 28 days, or for about 30 days.BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The advantages of the invention described above, together with further advantages, may be better understood by referring to the following description taken in conjunction with the accompanying drawings. The drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention.

[0026] FIG. 1 shows an example of an elliptical container according to certain embodiments.

[0027] FIG. 2 shows an example of an elliptical container with a protective cover in place according to certain embodiments.

[0028] FIG. 3A shows a perspective view of an example of a lenticular container according to certain embodiments.

[0029] FIG. 3B shows a top view of a lenticular container according to certain embodiments.

[0030] FIG. 4A shows a perspective view of an example of a fusiform container according to certain embodiments.

[0031] FIG. 4B shows a top view of a fusiform container according to certain embodiments.DETAILED DESCRIPTION OF THE INVENTION

[0032] Application of an anhydrous stick formulation comprising tolnaftate in combination with four non-drug drying agents (Al(OH)s, MgAlSiO4, MglOHE, and MgSO i) cured tinea pedis (athlete’s foot) in at least 90% of patients in four weeks (see Table 7). The non-drug drying agents create a hostile environment for fungal growth that appears to potentiate the activity of antifungal drugs. Sticks comprising all non-drug drying agents that were tested could substantially reduce the amount of sweat collected from feet in a one-hour gravimetric assay, regardless of whether they were tested individually or in combinations of two, three, or four drying agents while certain combinations were found to exhibit sweat reduction comparable to or greater than antiperspirant drugs (see Tables 8-9). These results suggest that sticks comprising combinations of non-drug drying agents may be useful for treating excess sweating due to palmar or plantar hyperhidrosis (sweaty hands or feet), anxiety, close toed shoes, hard work, exercise, high temperature and / or humidity, and that any non- drug drying agent can potentiate the activity of anti-fungal drugs. Tinea pedis can also be cured by treating feet with miconazole nitrate, terbinafine, or clotrimazole in combination with drying agents, suggesting that non-drug drying agents can potentiate the activity of any anti-fungal drug. Stick formulations comprising a drying agent in combination with tolnaftate, miconazole nitrate, terbinafine, or clotrimazole were also effective for treating intertrigo. Likewise, a stick comprising miconazole nitrate and a drying agent was effective for treating tinea versicolor (skin discoloration).

[0033] Tinea pedis is caused primarily by dermatophytic fungi such as Trichophyton rubrum, Trichophyton interdigitale and Epidermophyton floccosum whereas Candida species are the primarycause of intertrigo and Malassezia are the primary cause of tinea versicolor. Thus, combinations of an antifungal drug and a drying agent, preferably in a stick formulation, may be useful for treating any fungal or yeast infection of the skin. Additional supporting evidence comes from successful treatments of tinea corporis (ringworm) with a stick comprising tolnaftate and a drying agent, and tinea cruris (jock itch) and with a stick comprising miconazole nitrate and a drying agent.Definitions

[0034] The term “drug” means a substance which has a physiological effect when ingested or otherwise introduced into the body. FDA Monograph 0198 lists topically applied antiperspirant drugs that reduce sweat and perspiration. Introduction into the body occurs through the intentional absorption of the active into the eccrine sweat gland and the incidental inhalation of the active. Accidental inhalation of antiperspirant sprays is thought to introduce more aluminum into the body than can absorbed into the blood from the polycationic Aluminum ion plug located in the duct of the eccrine gland. For these reasons, reduction of perspiration and sweat on the surface of the skin should use drying agents that cannot be introduced into the body.

[0035] The term “antifungal drug” means all chemical compounds and pharmacologic agents used to treat a fungal infection (mycoses) or disease.

[0036] The term “non-drug” refers to an ingredient considered inactive by the FDA at the levels used in the proposed composition. The FDA maintains a database of inactive ingredients (IID) contained in FDA approved drug products. Key information for each excipient is the identification of that ingredient (Unique Ingredient Identifier or UNIT), route of administration (topical, oral, etc), maximum potency per unit dose and / or maximum daily exposure. The FDA emphasizes that inactive ingredients can also be considered active ingredients under certain circumstances. Take for example aluminum hydroxide, when administered as an oral tablet in a dose of 600 mg it functions as an antacid used for the symptomatic relief of heartburn, acid indigestion, and sour stomach. When administered topically not more than 5 w / w% or as an oral tablet containing not more than 50 mg, aluminum hydroxide is defined by the FDA as an inactive ingredient. Likewise, magnesium hydroxide is a laxative when orally dosed at 5-10 grams, an antacid when orally dosed above 750 mg to 1.5 grams and an inactive ingredient when orally dosed at 750 mg / day or less. A third example of an FDA listed inactive ingredient is magnesium aluminum silicate when dosed topically up to 3 w / w% or dosed orally up to 60 mg / day. Magnesium aluminum silicate is not known to be an active treatment for any condition regardless of route of administration. Thus, any topical product containing an antifungal active and aluminum hydroxide, magnesium aluminum silicate and / or magnesium hydroxide individually or in combination below their IID thresholds would contain a single active ingredient.

[0037] The term “drying agent” means a hygroscopic substance that is used to induce or sustain a state of dryness (desiccation) in its vicinity.

[0038] The term “non-drug drying agent” means a drying agent that is generally regarded as safe (GRAS) by the FDA when applied topically, is applied topically at concentrations below the minimum potency per unit dose to be considered an active ingredient by the FDA, or is listed as an inactive ingredient in the FDA Inactive Ingredient Database when topically applied at concentration below the maximum potency per unit dose.

[0039] The term “anhydrous dosage form” means that 1) no water is added during manufacture, 2) the continuous phase of the finished product contains hydrophobic excipients such as silicones, waxes and oils and 3) hygroscopic excipients are stored in moisture barrier packaging prior to manufacture of the finished product. Anhydrous dosage form does not mean that water is undetectable in the finished product at the time of release or over the shelf-life of the dosage form.

[0040] The term “stick” means a solid composed of active and inert ingredient(s) in a long, slender cylindrical shape and a circular, oval or fusiform cross-section.

[0041] The terms “fungal infection of the skin” and “cutaneous infection” mean that one or more of the several hundred fungi that can cause human disease has invaded the outermost skin layer. Fungi that can decompose the keratin (the structural protein of skin, hair and nails) are called dermatophytes and primarily fall within the three genus of molds Trichophyton, Microsporum and Epidermophyton. The primary genus of yeast that causes human disease in skin folds are Candida species. The Malasseia genus of yeast which require skin oils (sebum) to grow, causes dandruff, skin inflammation and skin discoloration. Fungal infection is also called mycosis.

[0042] The terms “treating” and “treatment” mean methods applied to a human or animal body to cure, prevent, or alleviate disease or other medical conditions. A condition associated with a fungal infection of the skin can be treated by killing fungi, inhibiting fungal growth, and / or reducing symptoms associated with the condition.

[0043] The term “kit” means a combination of multiple components or elements sold together as a package.Antifungal drugs

[0044] Various classes of antifungal drugs are known in the art. Azole (imidazole and triazole) antifungals such as imidazole, itraconazole, butoconazole, fluconazole, metronidazole, miltefosine, oxiconazole, thiabendazole, clotrimazole, miconazole nitrate, ketoconazole, econazole, sertaconaole, terconazole, tioconazole, voriconazole and efinaconazole target sterol 14a-demethylase. Allylamine antifungals such as terbinafine, naftifine and butenafine hydrochloride inhibit squalene epoxidase. Tolnaftate (thiocarbamate tolnaftate) is an antifungal drug that was classified by the FDA as safe and effective for topical use in over-the-counter products in 1965. Other topical antifungalsinclude the echinocandins caspofungin, anidulafungin, or micafungin, the halogenated phenolic ether haloprogin, the tetraene macrolide nystatin, griseofulvin and ciclopirox olamine. In some embodiments, the antifungal drug is selected from butenafine HC1, terbinafine HC1, tolnaftate, miconazole nitrate, clotrimazole, naftifine and efinaconazole. All of these antifungals are useful for treating cutaneous fungal infections. Natural products with antifungal activity such as tea tree oil may be substituted for an antifungal drug, but are not with the scope of the term “antifungal drug”.Zinc Oxide

[0045] In certain embodiments, ZnO may be used as the non-drug drying agent in compositions of the invention. ZnO presents a safer alternative to aluminum cations in antiperspirants, particularly for consumers concerned about potential health risks associated with aluminum-based products. Unlike aluminum compounds, which work by temporarily blocking sweat glands — a process that can lead to skin irritation and has raised concerns, albeit unproven, about long-term health effects — ZnO offers a gentler approach. It effectively controls odor through its natural antibacterial properties without disrupting the body's natural perspiration process. Additionally, ZnO is generally recognized as safe (GRAS) and is less likely to cause allergic reactions or irritation, making it a preferable choice for those with sensitive skin. Its use aligns with the growing demand for "clean" and "natural" personal care products, offering peace of mind to health-conscious consumers.

[0046] Nanosized ZnO in antiperspirants enhances the antibacterial effects and improves the formulation's ability to control odor and moisture. However, ZnO does not work by blocking sweat ducts as aluminum compounds do. Instead, the benefits of ZnO are more focused on surface-level interactions, such as reducing bacterial growth and offering better skin adherence and coverage due to the smaller particle size of the ZnO being used. Safety considerations, particularly regarding skin penetration also favor ZnO over Al compounds since current evidence suggests that nanosized ZnO is generally safe for topical use.

[0047] Specific surface area and pore size distribution are fundamental parameters of many solids including ZnO particles. Micronized ZnO surface area generally correlates to average particle size in nanometers (nm). For example, 10-25 square meters / gm corresponds to an average particle size of about 100 nm. These properties can he investigated using the BET method, a gas adsorption technique named after the developers Stephen Brunauer, Paul Emmett and Edward Teller. In nature, all surfaces adsorb water or other vapors to satisfy surface energy. After ZnO particles are prepared for gas adsorption, the surface energy inherent on each ZnO particle can be determined by adsorbing probe gas molecules. The volume of gas adsorbed on a surface is recorded and plotted versus pressure. From these raw data, several modelling methods can be used to generate reproducible values of the surface area of the particles. The smaller the particle, the greater the surface area. Likewise, a particle containing pores will have a larger surface area than the same size / shaped particle that has asmooth surface. The BET method does not require the particles to be the same size or shape and does not assume that the particles are perfect spheres. In essence, the BET method permits the calculation of a “theoretical monolayer” of gas molecules. By experimentally determining the number of moles of gas comprising that monolayer and knowing the cross-sectional area of a single gas molecule permits the determination of surface area. Carefully recording the mass of the sample permits the reporting of “specific surface area” typically in meters squared per gram. For ZnO, the raw material is mined with the finished material having completed various purification and particle sizing process steps. Specification sheets for a particular grade of ZnO contain a surface area measurement. For example, Grillo UV8+ ZnO has a surface area specification range between 8 and 10.5 m2 / gram which indicates a larger particle size than Grillo UV ProTech ZnO nanoparticles which has a surface area specification range between 25 and 35 m2 / gram.

[0048] In addition to safety and toxicity benefits, ZnO has a favorable price point as compared with many other non-drug drying agent additives, described below. ZnO is referred to herein as a non-drug drying agent and in the context of the technology is considered to be an excipient (i.e., an “inactive” ingredient) in a pharmacological sense

[0049] Additional inactive additives can be used to facilitate the drying function of the ZnO. Magnesium and other compounds can be used for this purpose. Examples of suitable magnesium compounds include magnesium hydroxide, magnesium oxide, magnesium carbonate, and magnesium chloride, in concentrations generally between 1 and 10% by weight. Magnesium hydroxide can be particularly efficacious.

[0050] Examples of other additive drying agents that can be used with the ZnO include starch, corn, tapioca, baking soda, talc, arrowroot powder, magnesium hydroxide, magnesium oxide, silica, magnesium carbonate, magnesium sulfate, caprylic triglyceride and clay. Further, the technology can also be used with other metallic cations having synergistic water absorption, distribution and related drying effects.

[0051] In some embodiments, multiple non-drug drying agents may be combined in a single composition, and at lower concentrations relative to the aforementioned ZnO composition. For example, aluminum (III) hydroxide, magnesium (II) aluminum (III) silicate and magnesium (II) hydroxide may all be used in combination at concentrations of about 5% or less each in a composition with tolnaftate or another antifungal (e.g., at a 1% concentration). In various embodiments, compositions can include an antifungal such as tolnaftate along with one or more non-drug drying agents such as ZnO, aluminum (III) hydroxide, magnesium (II) aluminum (III) silicate and magnesium (II) hydroxide. In some embodiments, tolnaftate may be included as an antifungal agent in a composition with AZTG as the drying agent. As discussed, compositions having tolnaftate at a concentration of around 1% along with ZnO at a concentration of around 15% show a synergistic effect, exhibiting increased efficacy in treating fungal infections over either the antifungal or non-drug drying agent alone.Non-drug drying agents

[0052] Other drying agents can be used, either alone or in combination with ZnO. Examples include Mg(OH)2, MgCO s, KAIGSO i.h' I2H2O, CaCOs and Zr+derivatives. Examples of other drying agents used in healthcare products that can be used with the technology include starch, corn, tapioca, baking soda, talc, arrowroot powder, magnesium oxide, silica, cyclomethicone, caprylic triglyceride and clay.

[0053] In some embodiments, non-drug drying agents can include aluminum (III) hydroxide, magnesium (II) aluminum (III) silicate and magnesium (II) hydroxide, alone or in various combinations. In certain embodiments, all three may be combined, in various concentrations, with an antifungal agent such as tolnaftate. Surprisingly, as shown in Table 7, such combinations can provide a significant boost to antifungal efficacy when compared to ZnO and tolnaftate compounds which already exhibited improved antifungal efficacy over ZnO without an antifungal.

[0054] Additionally, tannins, found in some natural astringents such as witch hazel, can temporarily shrink and constrict sweat glands, reducing the flow of sweat. While they don’t block the pores with a plug, they reduce the amount of sweat released. Such compounds can be used as a substitute or additive with the ZnO technology described in this document.

[0055] In some embodiments, non-drug drying agents can include aluminum (III) hydroxide, magnesium (II) sulfate, magnesium (II) hydroxide and magnesium (H) aluminum (III) silicate, alone or in various combinations. In certain embodiments, all three of the four non-drug drying agents may be combined, in various concentrations, with an antifungal agent such as tolnaftate, miconazole nitrate, terbinafine or clotrimazole. In certain embodiments, all four may be combined, in various concentrations, with an antifungal agent such as tolnaftate miconazole nitrate, terbinafine or clotrimazole.Anhydrous dosage forms

[0056] The dosage form used to apply the non-drug drying agent should be anhydrous. Water should not be added to the finished dosage form during manufacture and excipients should be stored to avoid exposure to moisture in high humidity environments. Well known and commonly used anhydrous dosage forms include suppository bases, aerosol oleaginous sprays, hydrophobic ointments, oil-in-oil emulsions, non-aqueous pastes, non-aqueous microcmulsions / nanocmulsions, and non-aqueous gels. Use of an anhydrous dosage form avoids quenching the drying agent before it is applied to the skin.

[0057] An anhydrous stick is useful as a dosage form to combine an antifungal active with a non-drug drying agent. Preferably the drying agents in the stick product are suspended rather than being completely dissolved in the anhydrous stick formulation. However, some ingredients can be soluble in the anhydrous stick formulation due to properties of the other components. Hence, the anti-fungal agent may be soluble in one or more of the excipients or even in the excipient composition as a whole. However, zinc oxide, for example, is not soluble in any component; it exists as a particulate and, hence, renders the finished stick product as a suspension in the chemical sense.

[0058] The dosage form (i.e., mechanical and physical characteristics) is chosen to effectively deliver actives and excipients (such as drying agents). Stick form is preferred over solutions, pastes and ointments, and can be presented as a “wax” in a “soft solid” or “semi-solid” format. Additionally, a smaller 3D geometry can be used, e.g., to provide access between the toes of a patient. Proper dosage form facilitates use of an effective carrier of actives and drying agents, avoiding problems such as accidental inhalation.

[0059] A wax-like product in a roll-up container offers several notable benefits. The wax's solid consistency ensures a smooth and controlled application, minimizing mess and allowing for precise coverage where it's needed. Unlike traditional cream antifungals or gel antiperspirants, the wax formulation typically adheres well to the skin, providing long-lasting protection without the risk of drips or smudges. This makes it an ideal choice for users who value convenience and a clean application process. Indeed, a semi-solid product has benefits of minimal transference and product delivery, as compared with other forms such as creams, powders or sprays.

[0060] Moreover, wax deodorants and anti-perspirants often feature a higher concentration of active ingredients, which can enhance their effectiveness. The waxy base acts as a carrier that helps these ingredients stay in place and be gradually released throughout the day. This can lead to more effective fungal and sweat control and potentially longer-lasting results compared to other products. Additionally, the solid nature of wax can help reduce waste, as it is less likely to be over-applied and more easily managed to ensure every bit is used efficiently.

[0061] Configuration of the stick formulation is important in providing efficiency and efficacy in treatment of fungal diseases. The stick can be a semi-solid. This allows the formulation to stay together (retain cohesiveness) in both a package or dispenser, as well as after being applied to the skin of the foot. A stick format also permits even spreading of the formulation onto the skin, utilizing friction and heat of the skin itself. These properties permit a smooth and consistent flow of formulation from the stick onto the skin.

[0062] Stick geometry is important to permit sufficient treatment of areas between the toes and improves overall convenience, effective delivery of higher mass of materials, and treatment adherence. Skin folds, creases, and larger surface areas can all be treated with a simple one or two swipes of a stick. A preferred geometry of the stick is oval in a cross-sectional shape. Preferred dimensions of a stick for treating tinea pedis are center of the oval approximately 8 - 16 mm with the edges tapering down. The edges can be sharp or slightly rounded (e.g., having a radius of curvature of 1 - 5 mm). The tapering geometry of the ends can go between the toes without having to use fingers. This is a safer application since there is no auto-inoculating of the socks in the patient’s shoes or the environment, thereby decreasing the risk of spreading. The stick can also go on dry without any waterin the formulation, so it really does go on dry and the wax acts as a barrier which protects in case there’s fissuring and maceration.

[0063] The stick and its associated container can be round, cylindrical, elliptical, lenticular or fusiform depending on the area to be treated. The feet are best treated with a smaller elliptical or round container to fit between toes, whereas for body folds a larger elliptical or round container may provide more effective coverage. The size and outer dimensions of commonly used containers for stick formulations are presented in Table 2. Containers can be filled from the bottom or top.

[0064] In some embodiments, the stick dosage form fits between the toes of a foot. In some embodiments, the smallest dimension of the stick (excluding its container) is at least 4, 5, 6, 7, 8, 9, 10, 11, or 12 mm, no more than 4, 5, 6, 7, 8, 9, 10, 11, or 12 mm, 4-12 mm, 6-12 mm, or 6-10 mm. In other embodiments, a larger stick us used to conditions affecting larger areas of the skin. In some embodiments, the smallest dimension of the stick is at least 10, 12, 14, 16, 18 or 20 mm or no more than 10, 12, 14, 16, 18 or 20 mm. In some embodiments, the mass of the stick (excluding its container) is about 0.1, 0.15, 0.2 or 0.25 mm. In some embodiments, the container for the stick is elliptical, lenticular, or fusiform, wherein the fusiform container has sharper ends with a smaller radius than the lenticular container and the lenticular container has sharper ends than the elliptical container. FIG. 1 shows an example of an elliptical container according to certain embodiments. FIG. 2 shows an example of an elliptical container with a protective cover in place. The elliptical container may contain about 0.5 oz. The elliptical container may have a maximum internal length of about 33 mm, a maximum internal width of about 14 mm, and / or a maximum internal depth of about 50 mm.

[0065] FIG. 3A shows a perspective view of an example of a lenticular container according to certain embodiments. FIG. 3B shows a top view of a lenticular container according to certain embodiments. The lenticular container may contain about 1 oz. The lenticular container may have a maximum internal length of about 54 mm, a maximum internal width of about 15 mm, and / or a maximum internal depth of about 75 mm.

[0066] FIG. 4A shows a perspective view of an example of a fusiform container according to certain embodiments. FIG. 4B shows a top view of a fusiform container according to certain embodiments. The fusiform container may contain about 1 oz. The fusiform container may have a maximum internal length of about 55 mm, a maximum internal width of about 14 mm, and / or a maximum internal depth of about 92 mm.Table 2. Specification of commonly used sticks - outer dimensions of the containerMeasuring Sweat

[0067] Sweat discharge can be measured by collecting sweat or its water vapor. Taylor and Machado-Moreira, Regional variations in transepidermal water loss, eccrine sweat gland density, sweat secretion rates and electrolyte composition in resting and exercising humans, Extreme Physiology & Medicine 2013, 2-4 (https: / / extremephysiolmed.biomedcentral.eom / counter / pdf / 10.1 186 / 2046-7648-2-4. pdf). Discharged sweat is collected on an adsorbent material and quantified by weighing the material before and after collection. Water vapor from discharged sweat is quantified using a probe containing sensors that measure relative humidity and temperature which tightly held against the skin and used to determine transepidermal water loss (TEWL), the evaporation rate from the skin’s surface.

[0068] Other qualitative tests can be used to characterize drying effectiveness, such as wettability of the skin surface. These include viscosity, spreadability, the mass of formulation deposited on skin per specific conditions (rubbing speed, force, etc.) and feel (comfort), i.e. feel vs particle size, concentration of particles in formulation, etc.Features of the Invention

[0069] Other physical properties can also be used to characterize the technology, such as the final formulation or material, which may not apply directly to drying. For example, in addition to sweat reduction, other qualitative and quantitative tests can be used to characterize drying effectiveness. Examples include wettability of the skin surface using contact angle via the sessile drop method, trace water content via the Karl-Fischer method, and HPLC analysis using a swab technique.

[0070] Also, in addition to drying effectiveness, efficacy can also be defined by measurement of the following properties. Note that efficacy can be described by both (1) synergistic effect of the drying agent or ZnO with the anti-fungal agent but also (2) efficient application of the formulation onto the foot.• Ease of spreading 1: Formulation viscosity is an important parameter that dictates flow of the formulation onto a surface. An optimal viscosity exists that allows complete coverage of the anatomical features of the foot. This includes gross and fine features. This is a quantitative technique.• Ease of Spreading 2: Spreading of the formulation onto the skin surface is also defined by the attraction between the skin surface and components in the formulation. Wettability of the formulation onto the skin is important to ensure a smooth, consistent coverage of the entire skin surface. A quantitative technique exists for this testing.• Deposition: Viscosity and ease of spreading have effects on the mass of formulation deposited onto the skin surface. Other important factors include force and speed.• Feel: “Feel” is a subjective or qualitative test. Since treatment of foot conditions necessitates compliance by the user, a feel that encourages use can be beneficial. Feel can be influenced by the specific formulation which includes particle size and concentration.EXAMPLESExample 1. Stick applicators for delivering antifungal drugs and drying agents to the feet and sites of other cutaneous infections

[0071] When antifungal drugs and non-drug drying agents were formulated as a cream, the cream could not wick into tight spaces due to surface tension of this emulsion dosage form. Even if dry particles of ZnO were added to a cream formulation, the 5-60% water in the cream product overwhelmed any capability of ZnO to assist with drying the skin. Additionally, when creams (or powders or sprays) contact the feet they are often shed immediately (or soon thereafter), which createsa potential for shedding fungus into the environment. In contrast, a stick formulation advantageously corrals the fungus.

[0072] To produce a stick, hydrophobic excipients that are either waxes or oils at room temperature are combined and heated (>65°C) until completely melted. With stirring, these excipients will combine to form a single-phase molten liquid. The antifungal drug is dissolved in the molten liquid excipients. The last step is to add the drying agents and any other solid components to be suspended in the non-aqueous dosage form to the molten excipients with vigorous mixing. At higher temperatures (>65°C), mixing must be maintained to assure that the solids remain suspended in the finished product. Once temperatures are reduced (nearer 60°C), the molten hydrophobic excipients will be sufficiently viscous to maintain the solids suspended without the need for mixing. The molten stick suspension is then poured into the appropriate mold, often the primary container closure system for the anhydrous stick dosage form and then forced cooled by passing through a cooling tunnel at a validated rate to form a stick product.Example 2. Stick formulations for treating tinea pedis

[0073] A first set of stick compositions was designed to test the efficacy of an anti-fungal drug (tolnaftate) in combination with non-drug drying agents. Most of these comprise Zinc Oxide (ZnO) particles of defined sizes as the non-drug drying agent. In contrast, Formulations 12-13 include a combination of four non-drug drying agents: aluminum hydroxide, magnesium aluminum silicate, magnesium hydroxide, and magnesium sulfate. Tables 3-6 define the percentages of each ingredient, by weight, in Formulations 1-14.Table 3. Formulations 1-4 comprise an antiperspirant (AZTG) or a non-drug drying agent (ZnO).* Formulation 1 is BAN® unsccntcd stick.Table 4. Formulations 5-7 comprise ZnO particles with different surface areas.Table 5. Formulations 8-10 comprise ZnO particles with different surface areas in combination with various supplemental drying agents.* Starch, corn, tapioca, baking soda, talc, arrowroot powder, silica, magnesium carbonate, cyclomethicone, caprylic triglyceride, and / or clay.Table 6. Formulations 11-14 comprise Zinc Oxide, an antiperspirant (AZTG) or non-drug drying agents including aluminum hydroxide, magnesium aluminum silicate, magnesium hydroxide, and magnesium sulfate.

[0074] Water hydroscopically adsorbs onto the Zinc Oxide (ZnO) particles analogous to the effect of Al compounds. Zinc Oxide when formulated as a stick can reduce perspiration in a similar amount as an aluminum antiperspirant drug formulated as a stick, as determined using TEWL measurements.

[0075] Patients having active athlete's foot (tinea pedis) infections, confirmed by KOH testing of lesion scrapings, were given various topical treatment compositions including Formulations 11, 12, and 14. Patients were instructed to treat the infected area with the provided formulation twice a day for 4 weeks and lesion scrapings were taken and tested via KOH at 2 and 4 weeks to determine the state of infection. Exemplary results in Table 7 show the percentage of patients tested at 2 weeks and 4 weeks that exhibited no remaining infection by KOH testing, which is considered to represent a mycological cure of tinea pedis.Table 7. Drying agents enhance the antifungal effects of tolnaftate against tinea pedis as determined by KOH testing

[0076] When combined with the antifungal tolnaftate, the formulation having about 5% or less each of aluminum (III) hydroxide, magnesium (II) aluminum (III) silicate and magnesium (II) hydroxide shows large and surprising improvements in antifungal activity at both 2 weeks and 4 weeks when compared to compounds using about 15% ZnO or Aluminum Zirconium Tetrachlorohydrex Gly (AZTG) as a drying agent.Example 3. Clinical studies demonstrating safety and efficacy

[0077] Aclinical study was performed to assess the safety, tolerability, and efficacy of 1% tolnaftate delivered in a stick-based topical formulation containing cyclopentasiloxane, C12-15 alkyl benzoate, behenyl behenate, stearyl alcohol, magnesium sulfate, aluminum hydroxide, magnesium hydroxide, magnesium aluminum silicate, maranta arundinacea root extract, tocopheryl acetate, tolnaftate, magnesium citrate nonahydrate, citrus aurantium dulcis peel oil. Participants (22) were trained on proper application to the affected area, soles, and interdigital spaces of both feet and instructed to apply the investigational product twice daily (morning and evening) for four weeks. To ensure compliance and application of a therapeutic dose, patient applicator sticks were weighed prior to dispensing and at each follow-up visit to determine the mass of product applied. Additionally, participants self-reported how many treatments they had missed since the last visit.

[0078] Assessments were performed at baseline (Week 0), midpoint (Week 2), and end of treatment (Week 4). The primary endpoint of mycological cure, as determined by KOH tests, incorporates the important outcome of successful treatment for tinea pedis: elimination of the fungal infection. Secondary endpoints — including erythema, maceration, perspiration, pruritus, and scaling — were assessed using a six-point scale (1 = none, 2 = mild, 3 = mild / moderate, 4 = moderate, 5 = moderate / severe, 6 = severe) similar to that of Kircik and Onumah, J Drugs Dermatol 13, 162-165 (2014). Tertiary endpoints included a modified Athlete’s Foot Severity Scale (AFSS) and patient ratings of tolerability and convenience. The modified AFSS, adapted from Cohen et al. (Mycoses 45,97-100, 2002), is a composite score ranging from 0 to 3: 0 = no tinea pedis, 1 = mild, 2 = moderate, and 3 - severe tinea pedis7. AFSS scores represent a synthesis of secondary endpoints and are based solely on observable physical symptoms, independent of KOH test results. Tolerability and convenience were assessed using a six-point scale (1 = none, 2 = very low, 3 = low, 4 = moderate, 5 = high, 6 = very high). This scale was adapted from validated dermatological instruments designed to evaluate treatment experience in conditions such as psoriasis. The study participants were primarily white (95%) and male (68%) with a mean age of 62. No deaths, serious, or significant adverse events were observed. One patient in each cohort did not comply with a request for a four-week follow-up visit.

[0079] Among the 20 patients who completed the 4- week study, 38% were KOH negative at two weeks and 90% were KOH negative at four weeks. These results compare favorably with the 45% - 65% response rates at four weeks observed in previous studies. Adam JE et al. Can Med Assoc, J 1965;93: 1004-5; Fuerst JF, et al Cutis 1980;25:544-6, 549; Smith EB, et al, South Med J 1974;67:776-8; Shellow et al. J Int Med Res. 1982; 10(1) :28-31. Symptomatic improvements at four weeks included reductions in athlete’s foot severity scale (AFSS) (52%), perspiration (42%), pruritus (itching, or the feeling of wanting to scratch your skin) (42%), maceration (softening and breaking down of skin that occurs when exposed to moisture for too long) (19%), scaling (the loss of the outer layer of the skin in large, scale-like flakes) (15%), and erythema (redness of the skin or mucous membranes) (12%). Patient satisfaction was also high, with self-assessed tolerability rated at 5.5 out of 6 (5.5 / 6) and convenience rated at 5.2 / 6 at the 4-week timepoint. High patent satisfaction should increase compliance. Excellent compliance was verified by weighing the remaining stick products, which revealed use of 19.5 g of the stick at 2 weeks and 32.9 g at four weeks, which was only slightly below the expected use of 21 grams at 2 weeks and 36.4 grams at four weeks.

[0080] A second clinical study is in progress to investigate the efficacy of a large batch of the stick-based topical formulation in a larger cohort of patients with more diverse demographics. Preliminary results for the first 12 patients show 92% achieved a mycological cure (KOH negative) at four weeks, with even higher symptomatic improvements including reduced AFSS (96%), maceration (58%), erythema (54%), scaling (66%), pruritic (49%), perspiration (58%), as well as high patient- reported tolerability (5.7 / 6) and convenience (5.5 / 6).Example 4. Sweat reduction by non-drug drying agents

[0081] Given the remarkable therapeutic effects observed with a combination of tolnaftate and four non-drug drying agents, Al(OH)j, MgAISiO i, Mg(OH)z, and MgSO i. it was next determined whether the drying agents can reduce sweating individually or in combinations of two, three or four agents.

[0082] Non-drug drying agents were tested at the highest concentration disclosed in the FDA Inactive Ingredient Database (100%), which is 5% Al(OH)j, 3% MgAISiO i. 4% Mg(OH)i, and 7% MgSO4, and at two lower concentrations (60% and 20%) and at concentrations equal to 60% and 20% of the highest (maximum) concentration. The agents were incorporated into sticks with a vehicle comprising constant amounts of cyclopentasiloxane (36%), C12-C15 alkyl benzoate (20%), stearyl alcohol (10%), behenyl behenate (11%), tocopheryl acetate (1%) and fragrance (0.1%) and varying levels of arrowroot starch (2.9% - 21.9%). These sticks did not have an antifungal drug.

[0083] A gravimetric method was used to quantify the amount of sweat reduction for each combination of drying agents. The drying agents were formulated into test sticks. Healthy volunteers were instructed to liberally apply a test stick to the sole of a randomly assigned foot. The other foot acted as the control. While keeping their sock off, participants then put a pre-weighed plastic bootie with three 4x4 gauze pads onto each foot. After one hour, the booties were removed, and the gauze was used to wipe residual perspiration from the foot. The amount of perspiration collected was measured by weighing the booties and gauze pads before and after the test. The waxy excipients applied to the foot also transferred to the gauze pads, so the amount of wax applied (determined by weighing the stick before and after application) was subtracted from the weight of perspiration collected from the foot with the test formulation. Results are presented in Table 8.Table 8. Non-drug drying agents reduce sweating when applied individually or in combination.

[0084] The negative control stick containing vehicle alone with no drying agents reduced sweating by 3%, establishing normal variation of the assay. Accordingly, perspiration reduction values of 4% down to negative values are considered insignificant and are reported as NR indicating No Reduction.

[0085] All four drying agents reduced sweating by more than 10% when used individually, in pairs, in triples, and all together. The highest reduction in sweating, 64%, was seen with a combination of all four drying agents at 60% of their maximum concentrations in the IID.

[0086] Two other potential drying agents in the IID, calcium chloride (CaC12) and silicon dioxide (SiO2), also reduced sweating by greater than 10% in a gravimetric test, as shown in Table 9. Interestingly, several non-drug drying agents and combinations had greater sweat reduction activity than Ban® antiperspirant, which contains 19% AZTG.Table 9. Sweat reduction by additional non-drug drying agents and an anti-perspirant.* in combination with Al(OH)s, MgAISiO i, Mg(OH)2, and MgSOi** Ban™ roll-on

[0087] These results indicate that a stick comprising any combination of the drying agents of Tables 8-9 should be useful for treating conditions characterized by excessive sweating. Furthermore, a stick comprising a combination of drying agents (without an antifungal agent) may be useful for treating a condition related to a fungal infection of the skin by generating an environment which is less conducive to fungal growth, thereby facilitating natural resolution of the fungal infection.Example 5. Treating fungal infections of the skin with antifungal drugs and drying agents

[0088] Additional clinical studies were performed using sticks comprising an antifungal drug selected from tolnaftate, terbinafine, miconazole nitrate, or clotrimazole in one of the stick formulations defined in Table 10.Table 10. Base stick formulations with non-drug drying agents for clinical trials.

[0089] Tinea pedis was cured by applying a pharmaceutical stick formulation comprising tolnaftate and four non-drug drying agents, as previously shown in Table 7. Tinea pedis could also be cured by applying sticks comprising other antifungal drugs in combination with non-drug drying agents.• Miconazole: A 60- year-old male was treated for tinea pedis with a pharmaceutical stick comprising 2% miconazole nitrate in Formulation 18.• Terbinafine: A 76-year-old female, 71-year-old male, and a 54-year-old female were treated for tinea pedis with pharmaceutical sticks containing 1 % terbinafine in Formulations 16, 15, and 17, respectively.• Clotrimazole: A 53-year-old male was treated for tinea pedis with a pharmaceutical stick containing 1 % clotrimazole in Formulation 15.

[0090] After 14 days of treatment, the physician global assessment of disease had significantly improved in all Tinea pedis patients.

[0091] Pharmaceutical stick formulations containing various antifungal drugs in combination with non-drug drying agents could also cure intertrigo.• Tolnaftate: a 68-ycar-old male, a 70-ycar-old female, and a 73-ycar-old female were treated for intertrigo with pharmaceutical sticks containing 1 % tolnaftate in Formulations 15, 16, and 16, respectively.• Miconazole: An 81-year-old male and an 82-year-old female were treated for intertrigo with pharmaceutical sticks containing 2% miconazole nitrate in Formulations 18 and 20, respectively.• Terbinafine: A 72-year-old female and a 78-year-old female were treated for intertrigo with pharmaceutical sticks containing 1% terbinafine nitrate in Formulations 15 and 17, respectively.• Clotrimazole: A 79-year-old female, a 75-year-old female, and 75-year-old male were treated for intertrigo with pharmaceutical sticks containing 1 % clotrimazole in Formulations 15, 16, and 17, respectively.

[0092] After 14 days of treatment the physician global assessment of this disease in all patients had significantly improved in all intertrigo patients.

[0093] Pharmaceutical stick formulations containing an antifungal drug in combination with non-drug drying agents could cure other conditions caused by fungal infections of the skin.• Tinea corporis (ringworm): A 70-year-old male was treated for tinea corporis with a pharmaceutical stick containing 1% tolnaftate in Formulation 15. After 14 days of treatment the physician global assessment of Tinea corporis had significantly improved.• Tinea versicolor (loss of pigmentation): A 49-year-old female and 57-y ear-old male were treated for tinea versicolor with a pharmaceutical stick containing 2% miconazole nitrate in Formulation 19. After 14 days of treatment the physician global assessment of Tinea versicolor had significantly improved.Example 6. Treating plantar and palmar hyperhidrosis

[0094] Formulations 21-23 (sec Tabic 11) were evaluated for the treatment of plantar hyperhidrosis. Individuals with plantar hyperhidrosis were instructed to apply the assigned formula to both feet, twice daily for 14 days. At the beginning and end of treatment, participants self-rated perspiration using a six-point scale (1 = none, 2 - mild, 3 = mild / moderate, 4 = moderate, 5 = moderate / severe, 6 = severe) similar to that of Kircik and Onumah, J Drugs Dermatol 13, 162-165 (2014). A 20% or greater reduction from baseline was observed in each of the formulations, as shown in Table 12.Table 11. Formulations for treating plantar hyperhidrosisTable 12. Self-rated sweat reduction by stick comprising drying agents

[0095] A US Division I women’s collegiate soccer player with palmar hyperhidrosis has been applying such a stick formulation with 5% A1(OH)3, 3% MgAlSiC>4, 4% MgtOHh, and 7% MgSC>4 to her hands twice daily. She reported that her condition previously interfered with her ability to function as a goaltender. Since initiating this regimen, she has experienced significant improvement over several weeks, allowing for better athletic performance and daily function.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an antifungal drug and a non-drug drying agent.

2. The composition of claim 1, wherein the antifungal drug is a squalene epoxidase inhibitor.

3. The composition of claim 2, wherein the squalene epoxidase inhibitor is tolnaftate or terbinafine.

4. The composition of claim 3, wherein the tolnaftate has a concentration of about 1%.

5. The composition of claim 3, wherein the terbinafine has a concentration of about 1%.

6. The composition of claim 1, wherein the antifungal drug is an azole.

7. The composition of claim 6, wherein the azole is miconazole nitrate or clotrimazole.

8. The composition of claim 7, wherein the miconazole nitrate has a concentration of about 2%.

9. The composition of claim 7, wherein the clotrimazole has a concentration of about 1%.

10. The composition of any one of claims 1-9, wherein the non-drug drying agent comprises a salt selected from the group consisting of A1(OH)3, MgAISiO i, Mg(OH)2, and MgSOi.

11. The composition of claim 10, wherein the non-drug drying agent comprises two or more or three or more salts selected from A1(OH)3, MgAISiOi. Mg(OH)2, and MgSOi.

12. The composition of claim 10, wherein the non-drug drying agent comprises A1(OH)3, MgAISiO i. Mg(OH)2, and MgSO4.

13. The composition of any one of claims 1-12, wherein the Al(OH)3h s a concentration of 5% or less, about 5%, about 3%, or about 1%.

14. The composition of any one of claims 1-13, wherein the MgAISiO i has a concentration of 3% or less, about 3%, about 1.8%, or about 0.6%.

15. The composition of any one of claims 1-14, wherein the MgiOHji has a concentration of 4% or less, about 4%, about 2.4%, or about 0.8%.

16. The composition of any one of claims 1-15, wherein the MgSO i has a concentration of 7% or less, about 7%, about 4.2%, or about 1.4%.

17. The composition of claim 12, comprising: about 5% A1(OH)3, about 3% MgAISiO i, about 4% Mg(OH)2, and about 7% MgSOa; or about 3% Al(OH)s, about 1.8% MgAISiOi about 2.4% Mg(OH)2, and about 4.2% MgSO4.

18. The composition of any one of claims 1-17, wherein the non-drug drying agent comprises CaCb or SiO2.

19. The composition of any one of claims 1-18, wherein the CaCh has a concentration of 5% or less.

20. The composition of any one of claims 1-19, wherein the SiChhas a concentration of 7% or less.

21. The composition of any one of claims 1-20, wherein the non-drug drying agent comprises ZnO particles.

22. The composition of claim 21, wherein the ZnO particles have a concentration of about 15%.

23. The composition of any one of claims 21-22, wherein the ZnO particles have a surface area of 3-5 m2 / g, 8-10.5 m2 / g, or 25-35 m2 / g.

24. The composition of any one of claims 1-23, further comprising a supplemental drying agent.

25. The composition of claim 1-24, wherein the supplemental drying agent is selected from magnesium oxide, magnesium carbonate, and magnesium chloride, starch, corn, tapioca, baking soda, talc, arrowroot powder, silica, magnesium carbonate, cyclomethicone, caprylic triglyceride, and clay.

26. An anhydrous dosage form comprising the composition of any one of claims 1-25.

27. The anhydrous dosage form of claim 26, further comprising cyclopentasiloxane, stearyl alcohol, PPG-17, hydrogenated castor oil, C12-15 alkyl benzoate, oleic acid, behenyl alcohol, and / or pentadecalatone.

28. The anhydrous dosage form of claim 26, further comprising cyclopentasiloxane, C12-C15 alkyl benzoate, stearyl alcohol, behenyl behenate, tocopheryl acetate, fragrance, and / or arrowroot starch.

29. The anhydrous dosage form of claim 26, further comprising about 36% cyclopentasiloxane, about 20% C12-C15 alkyl benzoate, about 10% stearyl alcohol, about 11% behenyl behenate, about 1% tocopheryl acetate, and arrowroot starch.

30. The anhydrous dosage form of any one of claims 26-29, comprising 1% tolnaftate.

31. The anhydrous dosage form of claim 30, comprising 5% Al(OH)j, 3% MgAISiO i, 4% Mg(OH)2, and 7% MgSCb.

32. The anhydrous dosage form of any one of claims 26-31, which is an anhydrous stick.

33. The anhydrous dosage form of any one of claims 26-31, which comprises an anhydrous suppository base, aerosol oleaginous spray, hydrophobic ointment, oil-in-oil emulsion, nonaqueous paste, non-aqueous microemulsions / nanoemulsion, or a non-aqueous gel.

34. The composition of any one of claims 1-25 or the anhydrous dosage form of any one of claims 26-33, which is effective in topically treating a fungal infection.

35. The composition of any one of claims 1-25 or the anhydrous dosage form of any one of claims 26-33, which does not comprise an antibiotic.

36. An anhydrous dosage form comprising two or more non-drug drying agents selected from the group consisting of A1(OH)3, MgAISiO i, Mg(OH)2, MgSO i, CaCT and SiCh.

37. The anhydrous dosage form of claim 36, comprising three or four of the non-drug drying agents.

38. The anhydrous dosage form of any one of claims 36-37, wherein the non-drug drying agents are selected from the group consisting of Al(OH)a, MgAISiO i. MglOHh, and MgSO4.

39. The anhydrous dosage form of any one of claims 36-38, further comprising cyclopentasiloxane, stearyl alcohol, PPG-17, hydrogenated castor oil, C12-15 alkyl benzoate, oleic acid, behenyl alcohol, and / or pentadecalatone.

40. The anhydrous dosage form of claims 36-39, further comprising cyclopentasiloxane, C12-C15 alkyl benzoate, stearyl alcohol, behenyl behenate, tocopheryl acetate, fragrance, and / or arrowroot starch.

41. The anhydrous dosage form of claim 40, further comprising about 36% cyclopentasiloxane, about 20% C12-C15 alkyl benzoate, about 10% stearyl alcohol, about 11% behenyl behenate, about 1% tocopheryl acetate, and arrowroot starch.

42. The anhydrous dosage form of claim 36, comprising about 5% A1(OH)3, about 3% MgAISiO i, about 4% Mg(OH)2, and about 7% MgSC>4 or about 3% AKOHh, about 1.8% MgAlSiC>4, about 2.4% Mg(OH)2, and about 4.2% MgSO4.

43. The anhydrous dosage form of any one of claims 36-42, which is effective in topically treating excessive sweating44. The anhydrous dosage form of claim 43, which is effective in topically treating plantar hyperhidrosis.

45. The anhydrous dosage form of claim 43, which is effective in topically treating palmar hyperhidrosis.

46. The anhydrous dosage form of any one of claims 36-45, which is an anhydrous stick.

47. The anhydrous dosage form of any one of claims 36-45, which comprises an anhydrous suppository base, aerosol oleaginous spray, hydrophobic ointment, oil-in-oil emulsion, nonaqueous paste, non-aqueous microemulsions / nanoemulsion, or a non-aqueous gel.

48. A method of treating a subject with a condition associated with a fungal infection of the skin comprising topically administering the composition of any one of claims 1-25 or the anhydrous dosage form or formulation of any one of claims 26-47 to the infected skin of the subject.

49. The method of claim 48, wherein the fungal infection of the skin is a dermatophytic infection.

50. The method of claim 48, wherein the subject has tinea pedis.

51. The method of claim 48, wherein the subject has intertrigo.

52. The method of claim 48, wherein the subject has tinea corporis, tinea cruris, or tinea versicolor.

53. The method of any one of claims 48-52, wherein the anhydrous stick is administered twice per day for 10 days.

54. The method of any one of claims 48-53, wherein the anhydrous stick is administered for at least 14 days, for at least 28 days, or for about 30 days.

55. A sweat reduction method sweating comprising topically administering to an individual the anhydrous dosage form of any one of claims 26-47.

56. The sweat reduction method of claim 55, wherein the individual has plantar hyperhidrosis57. The method of claim 55, wherein the individual has palmar hyperhidrosis.

58. The method of claim 55, wherein the sweat is a response to anxiety, heat, or humidity.

59. A kit comprising two of the anhydrous sticks of claim 32.

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