COMPOSITIONS FOR TREATING FUNGAL INFECTIONS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 62/897,671 filed September 9, 2019, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

[0002] The present disclosure relates to mucoadhesive antifungal patches comprising an electrospun layer and an impermeable layer. The electrospun layer can include one or more polymers and a fatty acid useful in treating a fungal infection. The disclosed patches attach to a mucosal surface for a period suitable for delivering effective amounts of the active agent to treat the disease site (for example, to treat mucosal candidiasis).

BACKGROUND

[0003] Oral candidiasis is a common condition among susceptible individuals ( e.g ., immunocompromised individuals, those on long term antibiotics and denture wearers) with the main causative organism being the fungus Candida albicans. It has been reported that C. albicans infections among the immunocompromised is now a leading cause of nosocomial infections with the incidence of oral candidiasis for these patients as high as 90-95%. Treatment is usually by antifungal therapy either orally or topically. Topical, local delivery at the site of infection by creams, gels, oral lozenges, etc. is preferred to directly target Candida growth; however, current delivery methods are transient with drug being quickly removed from the mucosal surface via mastication and salivary flow. Also problematic is growing resistance to common antifungal drugs, such as miconazole and fluconazole, which further serves to limit treatment options.

[0004] Accordingly, there is a need in the art for new antifungals and delivery systems that retain the active agent at the disease site and provide prolonged exposure of the active agent in order to effectively treat or prevent fungal infections. SUMMARY

[0005] The present disclosure relates to mucoadhesive patches that are useful in treating or preventing fungal infections (for example, oral infections). The disclosed patches adhere to a patient’s targeted tissue (for example, oral mucosa) for prolonged periods in order to deliver an effective amount of an antifungal fatty acid to the targeted tissue.

[0006] In one aspect, the present disclosure provides an antifungal patch comprising:

(a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers and a therapeutically effective amount of an antifungal fatty acid; and (b) an impermeable layer.

[0007] In some embodiments, the one or more polymers is selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

[0008] In some embodiments, the antifungal fatty acid is a C6-C12 fatty acid. In some embodiments, the antifungal fatty acid is selected from the group consisting of hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and dodecanoic acid.

[0009] In some embodiments, the impermeable layer is hydrophobic. In some embodiments, the hydrophobic impermeable layer comprises polycaprolactone.

[0010] In some embodiments, the electrospun fiber layer further comprises a therapeutically effective amount of an additional therapeutic agent. In some embodiments, the therapeutic agent is a steroid, an analgesic, a calcineurin inhibitor, a barbiturate, a benzodiazepine, or a mixture thereof. In some embodiments, the therapeutic agent is a steroid selected from the group consisting of clobetasol propionate, mometasone, fluocinonide, betamethasone, and dexamethasone. In some embodiments, the steroid is clobetasol propionate.

[0011] In one aspect, the present disclosure provides a patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, a therapeutically effective amount of a steroid and a therapeutically effective amount of an antifungal fatty acid; and (b) a hydrophobic impermeable layer. [0012] In one aspect, the present disclosure provides a patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, a therapeutically effective amount of an analgesic agent and a therapeutically effective amount of an antifungal fatty acid; and (b) a hydrophobic impermeable layer.

[0013] In one aspect, the present disclosure provides methods of treating a condition in a patient in need thereof, the method comprising administering a patch disclosed herein, wherein the condition is selected from the group consisting of recurrent aphthous stomatitis, oral lichen planus, pemphigoid, pemphigus, oral mucositis, Graft versus host disease (GvHD), Behcet’s disease, lupus erythematosus, vulva lichen planus, Lipschutz ulcers, lichen simplex chronicus, vulva psoriasis, and cancer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1A shows the growth inhibition of C. albicans strain SC5314 treated with 0.2 M C5-C12 fatty acids as measured by an agar disc diffusion assay. Fluconazole (0.8 mM) and miconazole discs (10 pg or 2.4 nmol) were used as positive controls and neat DMSO as the negative control. Results are mean ± SD (n=3). *p<0.05; **p<0.01; ***p<0.001 vs DMSO.

[0015] FIG. IB shows the growth inhibition of C. albicans strain CAR17 treated with 0.2 M C5-C12 fatty acids as measured by an agar disc diffusion assay. Fluconazole (0.8 mM) and miconazole discs (10 pg or 2.4 nmol) were used as positive controls and neat DMSO as the negative control. Results are mean ± SD (n=3). *p<0.05; **p<0.01; ***p<0.001 vs DMSO.

[0016] FIG. 1C provides visual representative images of treated agar disc diffusion plates related to the data in FIG. 1A and FIG. IB.

[0017] FIG. ID shows the growth inhibition of C. albicans strain BWP17 treated with 0.2 M (C5) to (C12) fatty acids as measured by an agar disc diffusion assay. Fluconazole (0.8 mM) and miconazole discs (10 pg or 2.4 nmol) were used as positive controls and neat DMSO as the negative control. Results are mean ± SD (n=3). *p<0.05; **p<0.01; ***p<0.001 vs DMSO.

[0018] FIG. IE provides visual representative images of treated agar disc diffusion plates related to the data in FIG. ID. [0019] FIG. 2A provides a graph showing C. albicans biofilm viability for strain SC5314 when subjected to fatty acids from heptanoic acid (C7) to dodecanoic acid (C12) ranging in concentration from 400 mM to 1.56 mM using a metabolic XTT assay. The data is normalized to untreated controls (100% viability) and mean ± SD (n=3).

[0020] FIG. 2B provides a graph of the live/dead image analysis data showing the viability of C. albicans biofilms from strain SC5314 treated with 50 mM fatty acid in a fluorescent stain experiment.

[0021] FIG. 2C shows representative fluorescence live (green), dead (red), and composite images for media, C9, and C12 applied to biofilms from C. albicans strain SC5314. Scale bar = 50 mM.

[0022] FIG. 3 provides representative scanning electron microscope (SEM) images of PCL and PVP RSI 00 electrospun patches containing no fatty acid (placebo), nonanoic (C9), or dodecanoic (C12) acid. Scale bar in bottom right applies to all images.

[0023] FIG. 4A shows the molecular structure of poly(caprolactone) (PCL) and dodecanoic acid with the hydrogen groups alphabetized and numbered and related to ¾ peaks in FIG. 4B.

[0024] FIG. 4B provides 'H NMR spectra of the PCL electrospun patch (no fatty acid), C12 neat, and C9 and C12 electrospun PCL patches. The peaks used to determine the fatty acid content in PCL fibers by comparing relative peak areas are circled in red (note: the ¾ NMR spectrum of neat C9 is almost identical to that of neat C12 and therefore not shown).

[0025] FIG. 4C shows the C9 and C12 content in PCL electrospun patches determined by 'H NMR as w/w% of patch (mean of n=2).

[0026] FIG. 4D shows the C9 and C12 content in PVP/RS100 electrospun patches determined by GC/MS as w/w% of patch (mean ± SD, n=5).

[0027] FIG. 5A shows the growth inhibition of C. albicans strain SC5314 treated with PCL and PVP/RS100 fibers containing nonanoic (C9) or dodecanoic (Cl 2) acid as measured by an agar disc diffusion assay. PCL and PVP/RS100 fibers without fatty acid were used as placebo controls. Results are mean ± SD (n=3). p-values above SD bars are compared to PCL or PVP RSI 00 placebo patch and comparison between PCL and PVP/RS100 patch with the same fatty acid are given. **p<0.01; ***p<0.001. [0028] FIG. 5B provides visual representative images of treated agar disc diffusion plates related to the data in FIG. 5A.

[0029] FIG. 5C provides SEM images of the electrospun patches once removed from C. albicans streaked agar plate. The round shapes along the fibers indicate the yeast Candida cells, which are present in all PCL patch conditions and in the PVP/RS100 placebo patch. Scale bar = 20 pm.

[0030] FIG. 6A provides a graph showing C. albicans biofilm viability for strain SC5314 when subjected to PCL patches containing either C9 or C12 fatty acid. Viability was compared to medium alone and PCL patch without fatty acid. Results are mean ± SD (n=3). *p<0.05; **p<0.01 compared to placebo electrospun patch.

[0031] FIG. 6B provides a graph showing C. albicans biofilm viability for strain CAR17 when subjected to PCL patches containing either C9 or C12 fatty acid. Viability was compared to medium alone and PCL patch without fatty acid. Results are mean ± SD (n=3). *p<0.05; **p<0.01 compared to placebo electrospun patch.

[0032] FIG. 6C provides a graph showing C. albicans biofilm viability for strain SC5314 when subjected to PVP/RSIOO patches containing either C9 or C12 fatty acid. Viability was compared to medium alone and PVP/RSIOO patch without fatty acid. Results are mean ± SD (n=3). *p<0.05; **p<0.01 compared to placebo electrospun patch.

[0033] FIG. 6D provides a graph showing C. albicans biofilm viability for strain CAR17 when subjected to PVP/RSIOO patches containing either C9 or C12 fatty acid. Viability was compared to medium alone and PVP/RSIOO patch without fatty acid. Results are mean ± SD (n=3). *p<0.05; **p<0.01 compared to placebo electrospun patch.

DEFINITIONS

[0034] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0035] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0036] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0037] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0038] “Optional” or “optionally” means that the subsequently described element, event or circumstances may or may not occur, and that the description includes instances where said event, element, or circumstance occurs and instances in which it does not. [0039] As used herein, "subject" include vertebrates, more specifically a mammal (e.g., a human, horse, pig, rabbit, dog, sheep, goat, non-human primate, cow, cat, guinea pig or rodent), a fish, a bird or a reptile or an amphibian. In some embodiments, the subject is a human subject. Unless otherwise specified, the term subject does not denote a particular age or sex. In some embodiments, the subject may be a geriatric subject, a pediatric subject, a teenage subject, a young adult subject, or a middle-aged subject. In some embodiments, the subject is less than about 18 years of age. In some embodiments, the subject is at least about 18 years of age. In some embodiments, the subject is about 5-10, about 10-15, about 15-20, about 20-25, about 25-30, about BO SS, about 35-40, about 40-45, about 45-50, about 50-55, about 55-60, about 60-65, about 65-70, about 70-75, about 75-80, about 85-90, about 90-95, or about 95-100 years of age. In some embodiments the subject is a male subject. In some embodiments the subject is a female subject. In some embodiments, the subject is diagnosed with or is considered at risk of having or developing a fungal infection. In some embodiments, the subject has been diagnosed with or is considered at risk of having or developing a

C. albicans infection. The terms “subject” and “patient” are used interchangeably throughout the present application.

[0040] As used herein, the term “impermeable layer” refers to a coating or barrier layer in a layered patch configuration that prevents or substantially limits the passage of water through the layer. The impermeable layer can also prevent or substantially limit the passage of the active ingredients (e.g., antifungal fatty acids) through the layer.

[0041] As used herein, the term “treating” with regard to a patient, refers to improving at least one symptom of the patient’s disorder. Treating can be curing, improving, or at least partially ameliorating a disorder. The term “therapeutic effect” as used herein refers to a desired or beneficial effect provided by the method and/or the composition. For example, the method for treating fungal infection provides a therapeutic effect when the method reduces at least one symptom of the fungal infection in a patient.

[0042] As used herein, the term “preventing” with regard to a patient refers to reducing or eliminating the onset of the symptoms or complications of a disease, condition or disorder. In some embodiments, the symptoms or complications are reduced or eliminated in a patient that is predisposed to the disease, condition, or disorder. As understood in the art, patients treated with topical steroids for oral lichen planus ( see

D.R. Marble, et al. “Oral candidiasis following steroid therapy for oral lichen planus” Oral. Dis. 2016, 22(2), 140-147) can develop oral candidiasis. The patches of the present disclosure are capable of preventing or treating such fungal infections.

[0043] All documents cited herein are incorporated by reference in their entirety for all purposes.

DETAILED DESCRIPTION

[0044] Drug-delivery systems (e.g., gels, creams, and lozenges) to the mucosa (such as, oral mucosa) are often ineffective due to short drug/tissue contact times and, in the case of fungal infections, because of increased prevalence of drug-resistant strains.

[0045] Highly mucoadhesive oral patches that attach to mucosal surfaces and deliver an active agent, e.g., the anesthetic lidocaine or the steroid clobetasol propionate, are described in International Publication Nos. WO2015/189212, WO2017/085264, W02018/133910, and WO2018/133909; U.S. Patent No. 10,052,291; and U.S. Publication Nos. 2019/0254985, 2019/0254986, and 2019/0351662, which are hereby incorporated by reference in their entireties for all purposes.

[0046] Certain fatty acids exhibit antifungal activity (see Pohl, C. H. et al. (2011) Antifungal Free Fatty Acids: A Review. Sci. Microb. Pathog. Curr. Res. Technol. Adv. 1, 61-71).

[0047] The present disclosure provides patches containing an effective amount of an antifungal fatty acid (such as, medium-chain fatty acids) that are suitable for application to the mucosa. As described herein, the disclosed patches adhere to the disease site and release a therapeutically effective amount of a fatty acid compound to treat or prevent a fungal infection in a subject in need thereof.

Patches of the Present Disclosure

[0048] In some embodiments, the present disclosure provides an antifungal patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, and a therapeutically effective amount of an antifungal fatty acid; and (b) an impermeable layer. The electrospun fiber layer and impermeable layer are joined to provide a patch using methods that are known to those skilled in the art, for example, the methods disclosed in International Publication No. WO/2018/133909. [0049] In some embodiments, the present disclosure provides a patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, and a therapeutically effective amount of a steroid, and a therapeutically effective amount of an antifungal fatty acid; and (b) a hydrophobic impermeable layer.

[0050] In some embodiments, the present disclosure provides a patch comprising: (a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, and a therapeutically effective amount of an analgesic agent, and a therapeutically effective amount of an antifungal fatty acid; and (b) a hydrophobic impermeable layer.

[0051] In order to provide effective treatment, the patches of the present disclosure should adhere to the disease site (e.g., tissue, mucosa, etc.) for a period of time sufficient to provide (i.e., release) an effective amount of an antifungal fatty acid. Accordingly, in some embodiments, the patch adheres to the disease site for a period greater than 2 h, greater than 4 h, greater than 8 h, greater than 12 h, greater than 16 h, greater than 24 h, greater than 30 h, greater than 36 h, greater than 42 h, or greater than 48 h.

[0052] Without being bound by any particular theory, the impermeable layer, e.g., a hydrophobic impermeable layer, protects the patch from saliva and other sources of moisture in order to prevent it from detaching from the application site (skin or mucosa) prematurely. In addition, the impermeable layer facilitates the application of the patch to the mucosa by providing a non-adhesive surface that will not stick the fingers.

[0053] In some embodiments, the patch provides a therapeutically effective amount of an antifungal fatty acid for at least about 2 h, at least about 4 h, at least about 6 h, at least about 8 h, at least about 10 h, at least about 12 h, at least about 14 h, at least about 16 h, at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h following application to a patient in need thereof. In some embodiments, the patch provides a therapeutically effective amount of antifungal fatty acid for at least about 4 h following application to a patient in need thereof. In some embodiments, the patch provides a therapeutically effective amount of antifungal fatty acid for at least about 8 h following application to a patient in need thereof. In some embodiments, the patch provides a therapeutically effective amount of antifungal fatty acid for at least about 12 h following application to a patient in need thereof. [0054] In some embodiments, a patch is applied to the disease site of a patient twice a day (b.i.d.), three times per day (t.i.d.), or four times a day (q.i.d.). In some embodiments, a patch is applied to the disease site of a patient twice a day. In some embodiments, a patch is applied to the disease site of a patient three times per day. In some embodiments, a patch is applied to the disease site of a patient four times per day.

[0055] In some embodiments, a patch is applied to the disease site of a patient twice a day for a period of about 2 to 8 weeks. In some embodiments, a patch is applied to the disease site of a patient three times per day for a period of about 2 to 8 weeks. In some embodiments, a patch is applied to the disease site of a patient four times per day for a period of about 2 to 8 weeks. In some embodiments, a patch is applied to the disease site of a patient twice a day for a period of about 2 to 4 weeks. In some embodiments, a patch is applied to the disease site of a patient three times per day for a period of about 2 to 4 weeks. In some embodiments, a patch is applied to the disease site of a patient four times per day for a period of about 2 to 4 weeks.

Electrospun Fiber Layer

[0056] In the present context, the term “electrospun fibers” is meant to encompass fibers that are obtained by a method that involves electrostatics. The methods, referred in the art as electrohydrodynamic (EHD) methods, include electrospinning, coaxial electrospinning, coaxial electrospraying, emulsion electrospinning, and the like. Any such method can be used to prepare the fibers of the present disclosure. Accordingly, the term “electrospun fibers” is not limited to fibers obtained by electrospinning, but instead refers to fibers obtained by electrohydrodynamic methods known in the art.

[0057] In general, the electrospun fibers of the present disclosure are provided in a layer, which when applied to the skin, mucosa or a humid internal surface of the body can adhere to the surface. In some embodiments, the drug substance (i.e., antifungal fatty acid or additional active agent) can be homogeneously distributed in the electrospun fibers, whereby the concentration of drug substance per surface area of the layer is constant and a dose of the drug substance can easily be determined by using a measured area of the layer.

[0058] In some embodiments, the electrospun fibers of the present disclosure comprise one or more polymers, a therapeutically effective amount of an antifungal fatty acid, and, optionally, an additional active agent, each of which is described in more detail below.

Polymers of the Electrospun Fibers

[0059] In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of dextran, polyethylene oxides, alginate, tragacanth, carrageenan, pectin, gelatin, guar, xanthan, gellan, fibronectin, collagen, hyaluronic acid, chitosan, cellulosic polymers such as methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, cellulose acetates, carboxymethylcellulose and alkali salts thereof, polymers of acrylic acids (PAA derivatives), chitosan, lectins, thiolated polymers, poly ox WSRA, PAA-co-PEG (PEG is polyethylene glycol), polylactic acid, polyglycolic acid, poly(butylene succinate), and mixtures thereof.

[0060] In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone (PVP), acrylates and acrylic copolymers (e.g., Eudragit®), ethylcellulose (EC), hydroxypropylcellulose (HPC), polyvinyl alcohol, carboxymethylcellulose, and mixtures thereof. In some embodiments, the one or more polymers is selected from polyvinylpyrrolidone (PVP), hydroxypropylcellulose (HPC) and mixtures thereof. In some embodiments, the one or more polymers is polyvinyl alcohol or carboxymethylcellulose.

[0061] In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, polycaprolactone (PCL), dextran and gelatin. In some embodiments, the electrospun fibers comprise one or more polymers selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin.

[0062] In some embodiments, the one or more polymers comprise: (a) polyvinylpyrrolidone and an ammonio methacrylate copolymer; (b) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol; (c) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide; (d) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran; (e) polyvinylpyrrolidone and gelatin; (f) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin; (g) polyvinylpyrrolidone and polyacrylate; (h) polyvinylpyrrolidone and sodium polyacrylate; (i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyacrylate; (j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and sodium polyacrylate; (k) polyvinylpyrrolidone and polyvinyl alcohol; (1) polyvinylpyrrolidone and polyethylene glycol; (m) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol; (n) polyvinylpyrrolidone and polyethylene oxide; or (o) polyvinylpyrrolidone and dextran. [0063] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and ammonio methacrylate copolymer. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer in the electrospun fibers is about 0.1 to about 10, including, about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about

4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer is about 0.5 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer is about 0.5 to about 2.

[0064] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene glycol in the electrospun fibers is about 0.15 to about 10, e.g., including 0.15, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.25 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.5 to about 2.

[0065] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyethylene oxide. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene oxide in the electrospun fibers is about 0.3 to about 10, including, about 0.3, about 0.5, about 0.75, about 1, about 1.5, about 2, about

2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene oxide is about 0.3 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyethylene oxide is about 0.5 to about 2.

[0066] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and dextran. In some embodiments, the weight ratio of polyvinylpyrrolidone to dextran in the electrospun fibers is about 0.3 to about 10, including about 0.3, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about

7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to dextran is about 0.3 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to dextran is about 0.5 to about 2.

[0067] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and gelatin. In some embodiments, the weight ratio of polyvinylpyrrolidone to gelatin in the electrospun fibers is about 0.6 to about 10, including about 0.6, about 0.8, about 1, about 1.5, about 2, about 2.5, about 3, about

3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about

8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to gelatin is about 0.6 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to gelatin is about 1 to about 3.

[0068] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyvinyl alcohol. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol in the electrospun fibers is about 0.5 to about 10, including about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 0.5 to about 5. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 1 to about 3. [0069] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and polyacrylate. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyacrylate in the electrospun fibers is about 0.1 to about 10, including about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to polyacrylate is about 0.5 to about 2.

[0070] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone and sodium polyacrylate. In some embodiments, the weight ratio of polyvinylpyrrolidone to sodium polyacrylate in the electrospun fibers is about 0.1 to about 10, including about 0.1, about 0.25, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5, or about 10, including all ranges and values therebetween. In some embodiments, the weight ratio of polyvinylpyrrolidone to sodium polyacrylate is about 0.5 to about 2.

[0071] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 6, including all ranges and values therebetween.

[0072] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene oxide in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 3, including all ranges and values therebetween.

[0073] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to dextran in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 3, including all ranges and values therebetween. [0074] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to gelatin in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 1.5, including all ranges and values therebetween.

[0075] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyacrylate. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyacrylate in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 6, including all ranges and values therebetween.

[0076] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and sodium polyacrylate. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to sodium polyacrylate in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 6, including all ranges and values therebetween.

[0077] In some embodiments, the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol. In some embodiments, the weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyvinyl alcohol in the electrospun fibers is about 1 : 0.5 : 0.1 to about 1 : 2 : 2, including all ranges and values therebetween.

[0078] In some embodiments, the electrospun fibers of the present disclosure comprise one or more polymers (as described herein), typically including hydrophilic polymers, which provide various desirable properties, e.g., providing for rheological properties suitable for electrospinning, physical properties (e.g., strength, flexibility, etc.) to provide a patch that is sufficiently durable for handling during manufacturing and use and sufficiently flexible such that it can conform to a mucosal surface, and a suitable degree of hydrophilicity for application to mucosal surfaces. Such polymers can provide bioadhesive properties to aid in adhesion to a mucosal surface. As desired, one or more additional polymers can be added to improve bioadhesion. In particular embodiments, the electrospun fibers of the present disclosure comprise polyvinylpyrrolidone and acrylic copolymers (e.g., Eudragit® copolymers), in combination with polyethylene oxide polymers. Such electrospun fiber compositions are described, for example, in US Patent No. 10,052,291, US Patent Publication Nos. 2019/0254985, and 2019/0254986, 2019/0351662.

[0079] When polyvinylpyrrolidone is used as a polymer in the electrospun fibers, it can be used in a grade having an approximate molecular weight of from 2,500 Da to 3,000,000 Da. PVP can be purchased as Kollidon® having a variety of molecular weight ranges as shown below.

[0080] Ethylcellulose is sold under the trademark ETHOCEL™ (Dow Chemical Company) and is available in different grades. Dependent on its ethoxyl content, ethylcellulose may have different softening point and melting point temperatures. Ethylcellulose is also produced in a number of different viscosities (see Table below). [0081] Acrylates and acrylic acid derivative include polymethacrylates, methacrylate copolymers, acrylic copolymers and methacrylate polymers, and include acrylates sold as EUDRAGIT as well as acrylates/octaacrylamide sold as DERMACRYL 79. Non limiting example of such acrylates are EUDRAGIT®E 12,5 (amino methacrylate copolymer), EUDRAGIT® E100 (amino methacrylate copolymer; basic butylated methacrylate copolymer), EUDRAGIT®E PO ((amino methacrylate copolymer), EUDRAGIT®L 100-55, EUDRAGIT®L 100 (methacrylic acid - methyl methacrylate copolymer 1:1), EUDRAGIT®S 100 (methacrylic acid-methyl methacrylate copolymer 1:2), EUDRAGIT®RL 100, EUDRAGIT®RL 100 (ammonio methacrylate copolymer type A), EUDRAGIT®RL PO, EUDRAGIT®RS 100 (ammonio methacrylate copolymer type B), EUDRAGIT®RS PO. EUDRAGIT®E is a cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters: EUDRAGIT®L and S are methacrylic acid copolymers and are cationic copolymerization products of methacrylic acid and methyl methacrylate. EUDRAGIT®RL or RS is ammonio methacrylate copolymers synthesized from acrylic acid and methacrylic acid.

[0082] Carboxymethylcellulose is available in a broad selection of viscosity grades. In some embodiments, the viscosity of carboxymethylcellulose in the electrospun fibers ranges from 10 to 100,000 mPa*s. In some embodiments, the carboxymethylcellulose is a sodium salt.

[0083] Methylcellulose is sold under the name METHOCEL™ (Dow Chemical Company) and is available in a wide range of viscosity grades. In some embodiments, the viscosity grade of methylcellulose in the electrospun fibers is from less than about 3 to greater than about 100,000 mPA*s.

[0084] HPMC is sold under the names Methocel® and Klucel®. In some embodiments, HPMC of the electrospun fibers has an average molecular weight of from about 80,000 to about 140,000.

[0085] In some embodiments, polyvinyl alcohol has a molecular weight ranging from about 20,000 Da to about 200,000. In some embodiments, polyvinyl alcohol has a molecular weight ranging from about 100,000 Da to about 200,000.

[0086] In some embodiments, polyethylene oxide (PEO) is used in grade having an approximate molecular weight of from about 100,000 to about 7,000,000. In some embodiments, the average molecular weight of from about 700,000 to about 4,000,000. Polyethylene oxide is sold under the name POLYOX™ (Dow Chemical Company) with molecular weights ranging from about 100,000 to about 7,000,000 Da.

[0087] In some embodiments, the PEO has a molecular weight of from about 100,000 to about 4,000,000 Da. In some embodiments, the PEO has a molecular weight of from about 100,000 to about 700,000 Da. In some embodiments, the PEO has a molecular weight of from about 100,000 to about 400,000 Da. In some embodiments, the PEO has a molecular weight of about 200,000 Da. In some embodiments, the PEO has a molecular weight greater than about 2,000,000 Da. In some embodiments, the PEO has a molecular weight of from about 2,000,000 Da to about 7,000,000 Da.

[0088] In some embodiments, dextran is used in grade having a molecular weight of from about 400,000 Da to about 2,000,000 Da. In some embodiments, dextran has a molecular weight of from about 500,000 Da to about 2,000,000 Da, e.g., about 700,000 Da to about 800,000 Da or from about 1,000,000 Da to about 2,000,000 Da.

[0089] In some embodiments, the one or more polymers is present in an amount ranging from about 30% to about 99.9% by weight of the electrospun fibers, including about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99.9%, including all ranges and values therebetween. In some embodiments, the one or more polymers is present in an amount ranging from about 50% to about 99.9% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 99.9% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 95% by weight of the electrospun fibers. In some embodiments, the one or more polymers is present in an amount ranging from about 75% to about 90% by weight of the electrospun fibers.

Antifungal Fatty Acids

[0090] As disclosed herein, the electrospun fibers comprise a therapeutically effective amount of a fatty acid. In some embodiments, the fatty acid is an antifungal fatty acid, i.e., a fatty acid capable of treating a fungal infection such as oral candidiasis.

[0091] In some embodiments, the antifungal fatty acid is a medium-chain fatty acid. In some embodiments, the fatty acid is a C6-12 fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is a saturated fatty acid.

[0092] In some embodiments, the fatty acid is selected from the group consisting of butanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tetradecanoic acid, and palmitic acid. In some embodiments, the fatty acid is selected from the group consisting of hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and dodecanoic acid. In some embodiments, butenoic acid (4:1), hexenoic acid (6:1), heptenoic acid (7:1), octenoic acid (8:1), nonenoic acid (9:1), decenoic acid (10:1), undecenoic acid (11:1), dodecenoic acid (12:1), myristoleic acid (14:1), palmitoleic acid (16:1), heptadecenoic acid (17:1), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), stearidonic acid (18:4), eicosapentaenoic acid (20:5) and docosapentaenoic acid (22:5). In some embodiments, the fatty acid is selected from the group consisting of hexenoic acid (6:1), heptenoic acid (7:1), octenoic acid (8:1), nonenoic acid (9:1), decenoic acid (10:1), undecenoic acid (11:1), and dodecenoic acid (12:1). In some embodiments, the fatty acid is selected from the group consisting of octenoic acid (8:1), nonenoic acid (9:1), decenoic acid (10:1), undecenoic acid (11:1), and dodecenoic acid (12:1).

[0093] In some embodiments, the fatty acid is about 0.1% to about 15.0% (wt./wt.%) of the electrospun fiber layer. In some embodiments, the fatty acid is about 1.0% to about 10.0% (wt./wt.%) of the electrospun fiber layer.

[0094] The present disclosure contemplates electrospun fibers combining any of the fatty acids described herein with any of the aforementioned polymers

Therapeutically Active Agents

[0095] In some embodiments, the electrospun fibers of an antifungal patch further comprise a therapeutically effective amount of an additional therapeutic agent.

[0096] In some embodiments, the additional therapeutic agent is a steroid, an analgesic, a calcineurin inhibitor, a barbiturate, a benzodiazepine, or a mixture thereof. In some embodiments, the additional therapeutic agent is a steroid. In some embodiments, the additional therapeutic agent is an analgesic. In some embodiments, the additional therapeutic agent is a calcineurin inhibitor. In some embodiments, the additional therapeutic agent is a barbiturate. In some embodiments, the additional therapeutic agent is a benzodiazepine.

[0097] In some embodiments, the additional therapeutic agent is about 0.01% to about 10.0% (wt./wt.%) of the electrospun fiber layer, including about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, including all ranges and values therebetween. In some embodiments, the additional therapeutic agent is about 0.05% to about 5.0% (wt./wt.%) of the electrospun fiber layer.

[0098] In some embodiments, the electrospun fibers of the present disclosure comprise a steroid selected from the group consisting of amcinonide, betamethasone, budesonide, clobetasol, clobetasone, cortisone, desonide, desoxy cortisone, desoximethasone, dexamethasone, diflucortolon, diflorasone, flucortisone, flumethasone, flunisolide, fluocinonide, fluocinolon, fluorometholone, fluprednisolone, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, meprednisone, methylprednisone, mometasone, paramethasone, prednicarbate, prednisone, prednisolone and triamcinolone or a pharmaceutically acceptable ester or acetonide thereof. In some embodiments, the steroid is selected from the group consisting of betamethasone, budesonide, clobetasol, clobetasone, desoximethasone, diflucortolon, diflorasone, fluocinonide, fluocinolon, halcinonide, halobetasol, hydrocortisone, mometasone and triamcinolone or a pharmaceutically acceptable ester thereof. In some embodiments, the steroid is selected from the group consisting of clobetasol propionate, mometasone, fluocinonide, betamethasone, and dexamethasone. In some embodiments, the steroid is clobetasol propionate. In some embodiments, the steroid is mometasone.

[0099] In some embodiments, the electrospun fibers of the present disclosure comprise an analgesic selected from the group consisting of local anesthetics (e.g., lidocaine, benzocaine, and the like), acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), benzamidine hydrochloride, etomidate, ketamine, propofol, gabapentin, tramadol, and pregabalin. In some embodiments, the analgesic is selected from the group consisting of lidocaine, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin, naproxen, ibuprofen, diclofenac, etc.), etomidate, ketamine, propofol, gabapentin, tramadol, and pregabalin. In some embodiments, the NSAID is selected from the group consisting of diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin. In some embodiments, the NSAID is selected from the group consisting of aspirin, naproxen, ibuprofen, and diclofenac. In some embodiments, the analgesic is a topical analgesic. In some embodiments, the analgesic is selected from the group consisting of lidocaine, benzocaine, prilocaine, xylocaine, tetracaine, capsaicin, menthol, or methyl salicylate. In some embodiments, the analgesic is lidocaine or articaine. In some embodiments, the analgesic is lidocaine.

[0100] In some embodiments, the electrospun fibers of the present disclosure comprise a calcineurin inhibitor selected from the group consisting of tacrolimus, picrolimus, pimecrolimus, cyclosporine, or voclosporin. In some embodiments, the calcineurin inhibitor is selected from the group consisting of tacrolimus, picrolimus, and cyclosporine.

[0101] In some embodiments, the electrospun fibers of the present disclosure comprise a barbiturate selected from the group consisting of secobarbital, butabarbital, methobarbital, pentobarbital, phenobarbital, aprobarbital, primidone, amobarbital, methohexital, thiamylal, and thiopental. In some embodiments, the barbiturate is selected from the group consisting of amobarbital, methohexital, thiamylal, and thiopental.

[0102] In some embodiments, the electrospun fibers of the present disclosure comprise a benzodiazepine selected from the group consisting of alprazolam, bentazepam, bromazepam, brotizolam, camazepam, chlordiazepoxide, clobazam, clonazepam, clonazolam, clorazepate, clotiazepam, diazepam, flumazenil, flunitrazepam, flurazepam, halazepam, loprazolam, lorazepam, medazepam, mexazolam, midazolam, oxazepam, prazepam, quazepam, temazepam, triazolam, zaleplon, and zolpidem. In some embodiments, the benzodiazepine is selected from the group consisting of diazepam, lorazepam, and midazolam.

Impermeable Layer

[0103] To prevent premature detachment from the skin or mucosal surface as well as other therapeutic benefits, the patches of the present disclosure comprise an impermeable layer. [0104] In some embodiments, the impermeable layer is provided as a coating disposed on a drug-containing layer. In some embodiments, the impermeable layer is co-spun with the drug-containing, and is therefore integrated into the electrospun fibers.

[0105] In some embodiments, the impermeable layer is a hydrophobic impermeable layer.

[0106] In some embodiments, the impermeable layer protects the drug-containing layer(s) from moisture or saliva. In some embodiments, the impermeable layer protects the drug-layer from being washed away from the application site, which results in the desired local therapeutic effect being reduced or eliminated. In some embodiments, the impermeable layer functions as an occlusive layer, which drives the penetration of drug substance into the skin or mucosa.

[0107] In some embodiments, the impermeable layer comprises one or more biodegradable polyesters. In some embodiments, the biodegradable polyester is an aliphatic polyester. In some embodiments, the biodegradable polyester is an aromatic polyester. In some embodiments, the impermeable layer comprises one or more polymers selected from the group consisting of poly(caprolactone), poly(glycolic acid), poly(lactic acid), poly(lactide-co-glycolide), poly(butylene succinate), poly(butylene succinate-co-adipate), poly(p-dioxanone), or poly(trimethylene carbonate). In some embodiments, the impermeable layer comprises one or more polymers selected from the group consisting of poly(caprolactone), poly(glycolic acid), poly(lactic acid), and poly(lactide-co-glycolide). In some embodiments, the impermeable layer comprises poly(caprolactone).

[0108] In some embodiments, the impermeable layer comprises polyethylene-co-vinyl acetate, ethylcellulose, poly(caprolactone), carbothane or polysoftane. In some embodiments, the impermeable layer comprises acrylates/octylacrylamide copolymer (sold under the name DERMACRL® 79), amino methacrylate copolymer (EUDRAGIT®), dimethylaminoethyl methacrylate, methacrylate, methyl methacrylate (e.g. EUDRAGIT ®E 100), or other acrylates.

[0109] In some embodiments, the impermeable layer comprises about 5-70% by weight of the patch, including about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, or about 70%, including all values and ranges therebetween, by weight of the patch. In some embodiments, the impermeable layer comprises about 5-50% by weight of the patch. In some embodiments, the impermeable layer comprises about 10-30% by weight of the patch.

Methods of Treatment

[0110] In some embodiments, the present disclosure provides methods of treating or preventing a fungal infection in a patient in need thereof by administering a patch of the present disclosure. In some embodiments, the fungal infection is a mucosal candidiasis infection. The patches of the present disclosure may be administered by, for example, placing the patch on a mucosal surface in need of treatment with the antifungal fatty acid containing electrospun fiber layer contacting the mucosal surface. The patch may be applied by hand or using an applicator.

[0111] In some embodiments, the present disclosure provides methods of treating a condition (such as oral lichen planus) by administering a patch that contains therapeutically effective amounts of an antifungal fatty acid and an additional therapeutic agent (such as a steroid or analgesic) suitable for treating the condition.

[0112] In some embodiments, the present disclosure provides a method of treating a condition in a patient in need thereof, the method comprising administering a patch of the present disclosure, wherein the condition is selected from the group consisting of recurrent aphthous stomatitis, oral lichen planus (OLP), pemphigoid, pemphigus, oral mucositis, Graft versus host disease (GvHD), Behcet’s disease, lupus erythematosus, vulva lichen planus (VLP), Lipschutz ulcers, lichen simplex chronicus, vulva psoriasis, and cancer.

[0113] In some embodiments, a patch of the present disclosure useful for treating recurrent aphthous stomatitis, oral lichen planus, pemphigoid, pemphigus, Graft versus host disease (GvHD), Behcet’s disease, lupus erythematosus, vulva lichen planus, Lipschutz ulcers, lichen simplex chronicus, vulva psoriasis, and cancer comprises a steroid (e.g., clobetasol propionate or mometasone) described herein as an active agent.

[0114] In some embodiments, a patch of the present disclosure useful for treating aphthous stomatitis, Behcet’s disease, oral mucositis, Lipschutz ulcers comprises an analgesic described herein (e.g., lidocaine) as an active agent. [0115] In some embodiments, a patch of the present disclosure useful for treating GvHD comprises a calcineurin inhibitor described herein (e.g., tacrolimus or cyclosporine) as an active agent.

[0116] In some embodiments, a patch of the present disclosure useful for treating lupus erythematosus comprises an analgesic described herein (e.g., an NSAID such as naproxen or ibuprofen) as an active agent.

[0117] In some embodiments of the present method, the patient being treated for one or more of the aforementioned diseases (e.g., OLP or VLP) also has a fungal infection. In some embodiments, the fungal infection is a mucosal candidiasis infection. In some embodiments, the fungal infection is an oral candidiasis infection.

[0118] In some embodiments, the patient being treated for one or more of the aforementioned diseases (e.g., OLP and VLP) is susceptible to development of a fungal infection. In some embodiments, the patient being treated for one or more of the aforementioned diseases is immunocompromised. In some embodiments, the fungal infection is a mucosal candidiasis infection. In some embodiments, the fungal infection is an oral candidiasis infection.

[0119] As described herein, the patches of the present disclosure are capable of treating or preventing a fungal infection (e.g., mucosal candidiasis) in a patient in need thereof.

[0120] In some embodiments, the patch is administered twice a day. In some embodiments, the patch is administered twice a day for a period of about 1-8 weeks. In some embodiments, the patch is administered twice a day for a period of about 2-4 weeks. In some embodiments, the patch is administered three times a day. In some embodiments, the patch is administered three times a day for a period of about 1-8 weeks. In some embodiments, the patch is administered three times a day for a period of about 2-4 weeks. In some embodiments, the patch is administered four times a day. In some embodiments, the patch is administered four times a day for a period of about 1-8 weeks. In some embodiments, the patch is administered four times a day for a period of about 2-4 weeks. In some embodiments, the patch is administered for at least a week. In some embodiments, the patch is administered for about 2-4 weeks. In some embodiments, the patch is administered for at least a month. EXAMPLES

[0121] Example 1

[0122] In Vitro Yeast Growth Inhibition of Wild-type and Azole-resistant C albicans Strains Treated with Medium-Chain Fatty Acids

[0123] The growth inhibition properties of a range of fatty acid solutions (used at 0.2 M) were tested on both wild type (SC5314, BWP17) and an azole-resistant clinical strain (CAR17) of C. albicans using an agar disc diffusion assay.

[0124] C. albicans wild type strains used for the susceptibility test were SC5314 and BWP17. The azole resistant clinical strain used for the susceptibility test was CARl 7. All strains were cultured on 1% w/v yeast extract, 2% w/v peptone and 2% w/v dextrose (YPD) agar at 37 °C and stored at 4 °C. Two to three colonies of each strain were inoculated in 15 mL YPD broth and incubated at 30 °C overnight. The colonies were then counted and resuspended in PBS or RPMI-1640 for further experimentation. [0125] Agar disk diffusion tests on YPD agar plates were performed using strains SC5314, BWP17 and CAR17. Fatty acids with chain lengths C5 to C12 were prepared at 0.2 M in DMSO (Sigma-Aldrich, Poole, UK). 200 pL of 2 x 105 colony forming units (CFU) per mL of C. albicans were diluted in PBS, spread across the agar plate. 20 pL of each fatty acid solution was pipetted onto filter paper susceptibility discs that were then placed on the C. albicans streaked agar plate in triplicate. Fluconazole (5 pg/disc; purchased in powder form and prepared in DMSO, Sigma-Aldrich, Poole, UK) and miconazole (10 pg/disc; used as purchased from ThermoFisher Scientific, Altrincham, UK) were used as positive controls and DMSO the negative control. Agar plates were incubated overnight at 37 °C, imaged and zone of inhibition measured using Fiji imaging software. Agar diffusion was also used to determine the antifungal effects of fatty acid-containing electrospun patches. In this case, 12.7 mm diameter discs were punched from fatty acid-containing patches, placed onto C. albicans-streaked plates, incubated overnight at 37 °C and analyzed as previously described. Patches containing no fatty acid were used as controls.

[0126] Results

[0127] For SC5314 Candida, growth inhibition zones that were significantly different from those of DMSO controls were observed for heptanoic (C7), octanoic (C8) and nonanoic (C9) acid (p < 0.05), with octanoic and nonanoic acid showing similar levels of inhibition to that of the commonly used clinical antifungal drugs fluconazole and miconazole (FIG. 1A and FIG. 1C). Similar data was observed for strain BWP17 that appeared to be even more susceptible to treatment with octanoic and nonanoic acid than the SC5314 strain FIG. ID and FIG. IE).

[0128] The CAR17 strain was confirmed as being azole-resistant as treatment with either fluconazole or miconazole failed to inhibit Candida growth (FIG. IB and FIG. 1C). However, significant zones of inhibition were observed upon treatment with fatty acids ranging from hexanoic (C6) to decanoic (CIO) acid (p < 0.01; FIG. IB and FIG. 1C)

[0129] These data indicate that several short medium-chain fatty acids have the ability to inhibit the growth of susceptible forms of C. albicans and for the first time azole- resistant forms of C. albicans as well. The results with nonanoic acid are surprising and unexpected as only even numbered carbon chain length fatty acids were previously found to be effective against C. albicans. These findings are significant given the rapid rise of antifungal resistance in many clinical isolates of C. albicans.

[0130] Example 2

[0131] Determining the Viability of Pre-formed C albicans Biofilms Treated with Medium-Chain Fatty Acids

[0132] Candida in vivo mainly exists as biofilm structures that are often much less susceptible to antifungal treatment. Therefore, an XTT assay was used to determine whether fatty acids were able to affect the viability of pre-formed in vitro cultured biofilms, where changes in metabolism were used as a surrogate measure of Candida viability.

[0133] C. albicans biofilms were prepared by adding 100 pL of a 1 x 10 ⁶ CFU per mL of SC5314 in RPMI-1640 Candida suspension into each well of a 96-well plate and incubating overnight at 37 °C. Wells were then washed with PBS and incubated for 18 h at 37 °C with a concentration series of each fatty acids (C7 to C12, prepared in 0.8 M DMSO as carrier and further diluted in RPMI-1640) ranging from 0.0015 to 0.4 M. Biofilms treated with equivalent concentrations of DMSO were used as controls. Biofilms were washed with PBS, then 50 pL of sodium 3 -[l-(phenylaminocarbonyl)- 3,4-tetrazolium]-bis (4-methoxy- 6-nitro) benzene sulfonic acid hydrate (XTT) was added to each well, and the plate was incubated for 1 h after which the XTT reagent was removed to a new plate and OD measured at 450 nm and 690 nm for background correction (Infinite 200 Pro, Tecan, Switzerland). Data was plotted after transformation by non-linear regression and IC50 values calculated using GraphPad Prism v8 (GraphPad Software).

[0134] Results

[0135] The viability of SC5314 Candida biofilm was dose-dependent and also decreased in a fatty acid carbon chain length-dependent manner (FIG. 2A). The calculated IC50 values showed that undecanoic (Cl 1) and dodecanoic (C12) acid were approximately ten-times more active compared to heptanoic (C7) and octanoic (C8) (see Table 1).

Table 1. Growth Inhibition of Pre-formed SC5314 Biofilms Treated with Medium- Chain Fatty Acids

[0136] To confirm that the fatty acids were directly killing Candida and not just altering their cell metabolism, a live/dead fluorescent stain was performed on 50 mM fatty acid- treated biofilms.

[0137] Biofilms were prepared and treated with fatty acid preparations as described above. Biofilms were then washed and incubated with the Live/Dead™ BacLight™ viability kit (ThermoFisher Scientific) according to the manufacturer’s instructions. Microscopic images were acquired using an Axiovert 200 M inverted fluorescence microscope supported with AxioVision software (Zeiss).

[0138] Image analysis showed that decanoic (CIO), undecanoic (Cl 1) and dodecanoic (C12) acid caused significantly (p < 0.001) more cell death as determined by propidium iodide-positive staining than heptanoic (C7), octanoic (C8) and nonanoic (C9), as well as medium only controls (FIG. 2B and FIG. 2C). These results are in agreement with those obtained for the XTT biofilm assay, confirming the chain length association with Candida killing efficiency. These data also show that nonanoic (C9) acid, which was the most efficient fatty acid at killing Candida in the agar diffusion assay, was less potent at killing Candida biofilm; whereas the opposite was observed for dodecanoic (C12) acid, which was the most proficient of all fatty acids tested at reducing biofilm viability. Interestingly, fluorescence microscopy revealed that nonanoic acid mainly killed yeast forms of C. albicans whereas dodecanoic acid killed both yeast and hyphal forms within biofilm (FIG. 2C).

[0139] Example 3

[0140] Preparation of Electrospun Patches of the Present Disclosure [0141] The electrospinning setup, solution preparation and patch production for both PCL and PVP/RSIOO patches was performed as previously described by Santocildes et al. (2017) Fabrication of electrospun mucoadhesive membranes for therapeutic applications in oral medicine. ACS Appl. Mater. Interfaces. 9, 11557-11567, which is incorporated herein by reference in its entirety.

[0142] PCL-Containing Patches

[0143] PCL (Mw 80 kDa) was added at 10 wt% to a solution of dichloromethane/dimethylformamide (93:7 w/w%) and mixed at room temperature until dissolved. 0.2 M of short-to-medium-chain fatty acid including butanoic (C5), hexanoic (C6), heptanoic (C7), octanoic (C8), nonanoic (C9), decanoic (CIO), undecanoic (Cl 1) or dodecanoic (Cl 2), was added to the polymer-doped solutions prior to spinning. Spinning conditions were 17 kV, 3 ml/h with a 15 cm tip-to-collector distance.

[0144] PVP/RSlOO-Containing Patches

[0145] PVP (Kollidon 90 F, Mw 1000-1500 kDa) at 10 wt% and Eudragit RSI 00 (Mw 32 kDa) at 12.5 wt% were dissolved in 97% w/w ethanol prepared in deionized water at room temperature. 0.2 M of short-to-medium-chain fatty acid including butanoic (C5), hexanoic (C6), heptanoic (C7), octanoic (C8), nonanoic (C9), decanoic (CIO), undecanoic (Cl 1) or dodecanoic (Cl 2), was added to the polymer-doped solutions prior to spinning. Spinning conditions were 17 kV, 3 ml/h with a 15 cm tip-to-collector distance.

[0146] Samples were analyzed by scanning electron microscopy (SEM) as previously described in Santocildes et al. (2017) Fabrication of electrospun mucoadhesive membranes for therapeutic applications in oral medicine. ACS Appl. Mater. Interfaces. 9, 11557-11567. Electrospun patches were sputter coated with gold and imaged using a Philips XL20 scanning electron microscope using an emission current of 15 kV.

[0147] Example 4

[0148] Determining Morphology of Fatty Acid-Containing PCL and PVR/RS100 Electrospun Patches

[0149] Since nonanoic (C9) and dodecanoic (C12) acids were shown to impose the greatest effect on Candida viability in the agar and biofilm assays respectively, these fatty acids were chosen to incorporate into PCL and PVP/RS100 electrospun patches. SEM images showed that PCL and PVP/RS100 patches are composed of a mesh-like network of micro-fibers. The placebo patches that contained no fatty acid displayed fibers of similar width for both PCL and PVP/RS100 patches, although PVP RSI 00 fibers appeared straighter, flatter and more uniform than the PCL fibers (FIG. 3). Addition of nonanoic or dodecanoic acid to the PCL dope produced electrospun fibers with much smaller diameters resulting in a more entangled mesh compared to the placebo PCL patch, whereas this was not evident when these fatty acids were incorporated into PVP RSI 00 fibers (FIG. 3).

[0150] Example 5

[0151] Measuring Fatty Acid Content in PCL and PVP/RS100 Electrospun Patches

[0152] In the process of electrospinning, the solvent system evaporates as the fibers are produced, so it is feasible that some of the volatile short chain fatty acids may also evaporate in the procedure leading to discrepancies between the fatty acid concentration in the pre-electrospinning polymer dope and that in final electrospun patch. Therefore, it was necessary to determine the final fatty acid content in each electrospun patch. NMR spectroscopy was used to analyze PCL patches as the ¾ NMR peaks for PCL and the fatty acid component did not overlap (FIG. 4A and FIG. 4B). However, the PVP/RS100 patches displayed overlapping 'H NMR peaks and therefore GC/MS was used as the quantification method.

[0153] NMR Procedure: Proton (¾) nuclear magnetic resonance (NMR) spectra of fatty acids and PCL electrospun patches dissolved in 1 mL deuterated chloroform (CDC13) and sealed in a 5 mm tube were recorded using an AVANCE III or AVANCE III HD spectrometer (Bruker™) at 298 K and 400.2 MHz or 500.13 MHz. The quantitative spectra were recorded with eight transients using a 90° pulse and a relaxation delay of 40 s (having previously determined the longest T1 within the mixtures to be ~6.5 s), over an acquisition window of 20 ppm and 64 k acquisition points. The spectra were analyzed using TopSpin™ version 3.2 software (Bruker™). The 1H NMR peaks are representative of the number of hydrogen present at a particular resonance, where the normalized integrated signals give the relative number of hydrogen at a particular resonance. By comparing the normalized integrals of distinguishable PCL signals versus fatty acid signals the mole ratio of the two components was calculated and thereby the mass concentration of fatty acid present in the PCL electrospun fibers was established.

[0154] GS/MS procedure: Electrospun PVP/RS100 patches were weighed and dissolved in 1 mL 97% (v/v) ethanol. Standards of the fatty acids were also prepared in 97% (v/v) ethanol, ranging from 0.01 Mto 1 M. An AligentDB-WAX-UI (30 m x 0.25 mm x 0.25 pm) column was used with helium flowing through the column at 1.2 mL min-1 with a pressure of 9.15 psi. The injection volume of the sample was 1 pi and the temperature of the column was increased from 50 °C to 250 °C at 10 °C min-1 intervals. The mass spectrometer scan range was between 25-500 m/z.

[0155] Results

[0156] The mean w/w% concentration of fatty acid compared to total patch weight was 2.2% for nonanoic (C9) acid and 22% for dodecanoic (C12) acid for the PCL patches (FIG. 4C), compared to 8.1% nonanoic (C9) acid and 12% dodecanoic (C12) acid in the PVP RSI 00 patches (FIG. 4D).

[0157] As the fatty acids had been added as a molar concentration in the solvent system of the electrospinning solution, the actual percentage mass of fatty acid to the polymer mass in the polymer dope solution prior to electrospinning was 28% and 18% for dodecanoic (Cl 2) acid and 22% and 14% for nonanoic (C9) acid in PCL and PVP/RS100 solutions, respectively. Without being bound by any theory, the amide groups in PVP may hydrogen-bond to the carboxyl groups of the fatty acids, which may explain why more nonanoic acid is incorporated in the PVP/RS100 fibers compared to the PCL fibers.

[0158] Example 6

[0159] In Vitro Growth Inhibition of C. albicans by Fatty Acid-containing Electrospun Patches [0160] An agar disc diffusion assay was used to test if fatty acids could be released from electrospun patches and be inhibitory to Candida growth. PCL placebo patches did not inhibit Candida growth showing that polymers alone do not affect C. albicans viability, whereas a small zone of inhibition was observed for PVP/RS100 patches (FIG. 5 A and FIG. 5B). It was noted that the PVP/RS100 patches are much reduced in diameter at the end of the experiment compared to their PCL counterparts, even though they were both the same size (12.7 mm diameter) at the start of the experiment. This is likely related to the hydrophilicity of the PVP/RS100 patches, which swell almost instantly when placed on the agar plate as a consequence of moisture uptake from the C. albicans lawn, resulting in an increase in volume but decrease in area which may give rise to the observed false positive effect (FIG. 5B). For the PCL patches, both nonanoic ( PCL C9) and dodecanoic (PCL C12) acid displayed greater zones of inhibition compared to placebo PCL patches (p < 0.001 and p < 0.01 respectively; FIG. 5A). Moreover, the disc diffusion data clearly show that the released nonanoic acid is the most potent fatty acid causing a greater zone of inhibition than dodecanoic acid (C9: 7.2 ± 1.3 mm compared to C12: 2.3 ± 1.7 mm, p < 0.001; FIG. 5A and FIG. 5B). Similarly, nonanoic acid and dodecanoic acid-containing PVP/RS100 patches displayed greater zones of inhibition compared to placebo patches (p < 0.001 and p < 0.01 respectively; FIG. 5A). In contrast to PCL patches, dodecanoic acid-containing PVP/RS100 patches were equally as potent at inhibiting Candida growth as nonanoic acid-containing patches. Meanwhile, nonanoic acid-containing PCL patches showed improved Candida growth inhibition compared to both nonanoic and dodecanoic acid- containing PVP/RS100 patches (p < 0.01; FIG. 5A).

[0161] SEM images of the fatty acid-containing electrospun patches that had been used to inhibit C. albicans growth gave a comparative view of whether C. albicans yeast cells are still present among the fibers of the electrospun patches (FIG. 5C). In both the PCL and PVP/RS100 placebo patches, yeast forms of C. albicans can be seen adhering to the polymer fibers (FIG. 5C). In contrast, no Candida was observed in either PCL or PVP/RS100 patches loaded with nonanoic (C9) acid, in line with its antifungal activity. In dodecanoic acid-containing PCL patches, yeast forms of C. albicans were detected but were markedly less abundant than in placebo patches, whereas no Candida were seen in SEM images of dodecanoic acid-containing PVP/RS100 patches (FIG. 5C). The contrast between the PCL and PVP RSI 00 SEM images clearly shows the difference in hydrophilicity between the two polymer systems. The hydrophilicity of the PVP RS 100 patch is greater with the inclusion of the dodecanoic acid than nonanoic acid producing a collapsed fibrous structure as a result of water absorption from the moist agar plate surface and swelling (FIG. 5C). Unlike the PVP/RS100, PCL fibers remain intact.

[0162] Example 7

[0163] Determining the Viability of Pre-formed C albicans Biofilms Treated with Fatty Acid-Containing Electrospun Patches

[0164] The effect of the electrospun patches containing nonanoic (C9) or dodecanoic (C12) acid on established C. albicans biofilm viability (SC5314 and CAR17) was determined using an XTT assay.

[0165] In this experiment, C. albicans biofilms were prepared in poly-l-lysine-coated 24-well plates using strain SC5314 or CAR17. C. albicans (1 x 106 CFU in RPMI- 1640) was added to each well and plates were incubated overnight at 37 °C. Wells were washed with PBS then fatty acid-containing electrospun discs (12.7 mm ø) placed in each well followed by 200 pL RPMI-1640. Discs containing no fatty acid were used as controls. Following 18 h incubation at 37 °C, the liquid in each well was removed and 200 pL of XTT reagent was added to each well and incubated for 1 h, after which the XTT reagent was removed to a new plate, OD measured and data analyzed as previously described.

[0166] Results

[0167] Placebo patches caused a slight reduction in biofilm viability for both strains tested, especially PVP/RS100 on the CAR17 strain in which viability was reduced by 60%, although this was not statistically different from Candida treated with medium alone (FIG.s 6A-D). Dodecanoic acid (C12)-containing PCL patches caused a 17-fold reduction in SC5314 biofilm viability compared to treatment with PCL placebo patches (p < 0.001), whereas treatment with nonanoic acid (C9)-containing PCL patches showed a diminished effect (FIG. 6A). In contrast, treatment with nonanoic or dodecanoic acid-containing PCL patches significantly reduced biofilm viability of the azole-resistant CAR17 strain by 80% and 70% respectively (p < 0.01; FIG. 6B). PVP/RS100 patches loaded with dodecanoic acid reduced both SC5314 and CAR17 biofilm viability by 82% (p < 0.01, FIG. 6C) and by 74% (p < 0.05, FIG. 6D) compared to placebo controls. Nonanoic acid-containing PVP/RS100 patches also reduced biofilm viability, although the effect was reduced (FIG. 6C and FIG. 6D).

[0168] As both PCL and PVP/RS100 patches containing dodecanoic acid displayed a remarkable reduction in biofilm viability, this fatty acid is attractive for the treatment of oral candidiasis using mucoadhesive electrospun patches.

[0169] Summary

[0170] While there are no previous reports on incorporating fatty acids into electrospun patches for antimicrobial purposes, the data presented herein clearly demonstrates that medium-chain saturated fatty acids offer an effective antifungal therapy to treat C. albicans infections, for which this organism is becoming increasingly resistant. Moreover, the data shows that fatty acids such as dodecanoic acid can be successfully incorporated and released from mucoadhesive electrospun patches while retaining potent antifungal activity. The fatty acid released from the patch are surprisingly and unexpectedly able to penetrate and kill C. albicans even within resistant biofilms not susceptible to conventional azole treatment.

[0171] The electrospun patches of the present disclosure are therefore ideal vehicles to deliver fatty acids such as dodecanoic acid directly to the locally infected sites for the treatment of oral fungal infections including oral candidiasis.

[0172] The invention is further described by the following numbered embodiments:

1. An antifungal patch comprising:

(a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers and a therapeutically effective amount of an antifungal fatty acid; and

(b) an impermeable layer.

2. The antifungal patch of embodiment 1, wherein the electrospun fiber layer comprises about 0.1% to about 15.0% (wt./wt.%) of the antifungal fatty acid.

3. The antifungal patch of embodiment 2, wherein the electrospun fiber layer comprises about 1.0% to about 10.0% (wt./wt.%) of the antifungal fatty acid. The antifungal patch of any one of embodiments 1-3, wherein the patch provides a therapeutically effective amount of the antifungal fatty acid for at least about 4 h following application to a patient in need thereof. The antifungal patch of any one of embodiments 1-4, wherein the one or more polymers is selected from the group consisting of polyvinylpyrrolidone, an ammonio methacrylate copolymer, polyethylene glycol, polyethylene oxide, polyacrylate, sodium polyacrylate, polyvinyl alcohol, dextran and gelatin. The antifungal patch of any one of embodiments 1-5, wherein the one or more polymers comprise:

(a) polyvinylpyrrolidone and an ammonio methacrylate copolymer;

(b) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol;

(c) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide;

(d) polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran;

(e) polyvinylpyrrolidone and gelatin;

(f) polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin;

(g) polyvinylpyrrolidone and polyacrylate;

(h) polyvinylpyrrolidone and sodium polyacrylate;

(i) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyacrylate;

(j) polyvinylpyrrolidone, an ammonio methacrylate copolymer and sodium polyacrylate;

(k) polyvinylpyrrolidone and polyvinyl alcohol;

(l) polyvinylpyrrolidone and polyethylene glycol; (m) polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol;

(n) polyvinylpyrrolidone and polyethylene oxide; or

(o) polyvinylpyrrolidone and dextran. a. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone and an ammonio methacrylate copolymer. b. The antifungal path of any one of embodiments 6 or 6a, wherein weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer is about 0.5 to about 2. c. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone and polyethylene glycol. d. The antifungal path of any one of embodiments 6 or 6c, wherein weight ratio of polyvinylpyrrolidone to polyethylene glycol is about 0.15 to about 10.e. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone and polyethylene oxide. f. The antifungal path of any one of embodiments 6 or 6e, wherein weight ratio of polyvinylpyrrolidone to polyethylene oxide is about 0.3 to about 10.g. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone and dextran. h. The antifungal path of any one of embodiments 6 or 6g, wherein weight ratio of polyvinylpyrrolidone to dextran is about 0.3 to about 10. i. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone and gelatin. j . The antifungal path of any one of embodiments 6 or 6i, wherein weight ratio of polyvinylpyrrolidone to gelatin is about 0.6 to about 10. k. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone and polyvinyl alcohol. 1. The antifungal path of any one of embodiments 6 or 6k, wherein weight ratio of polyvinylpyrrolidone to polyvinyl alcohol is about 0.5 to about 10.m. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene glycol. n. The antifungal path of any one of embodiments 6 or 6m, wherein weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene glycol is about 1 : 0.5 : 0.1 to about 1 : 2 : 6. o. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyethylene oxide. p. The antifungal path of any one of embodiments 6 or 6m, wherein weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyethylene oxide is about 1 : 0.5 : 0.1 to about 1 : 2 : 3. o. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and dextran. p. The antifungal path of any one of embodiments 6 or 6o, wherein weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to dextran is about 1 : 0.5 : 0.1 to about 1 : 2 : 3. q. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and gelatin. r. The antifungal path of any one of embodiments 6 or 6q, wherein weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to gelatin is about 1 : 0.5 : 0.1 to about 1 : 2 : 1.5. s. The antifungal path of any one of embodiments 1-6, wherein the one or more polymers comprise polyvinylpyrrolidone, an ammonio methacrylate copolymer and polyvinyl alcohol. t. The antifungal path of any one of embodiments 6 or 6q, wherein weight ratio of polyvinylpyrrolidone to ammonio methacrylate copolymer to polyvinyl alcohol is about 1 : 0.5 : 0.1 to about 1 : 2 : 2. . The antifungal patch of any one of embodiments l-6t, wherein the impermeable layer is hydrophobic. . The antifungal patch of embodiment 7, wherein the hydrophobic impermeable layer comprises polycaprolactone. . The antifungal patch of any one of embodiments 1-8, wherein the antifungal fatty acid is a C6-C12 fatty acid. 0. The antifungal patch of any one of embodiments 1-9, wherein the antifungal fatty acid is an unsaturated fatty acid. 1. The antifungal patch of any one of embodiments 1-9, wherein the antifungal fatty acid is a saturated fatty acid. 2. The antifungal patch of any one of embodiments 1-9, wherein the antifungal fatty acid is selected from the group consisting of butanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tetradecanoic acid, and palmitic acid. 3. The antifungal patch of any one of embodiments 1-9, wherein the antifungal fatty acid is selected from the group consisting of hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and dodecanoic acid. 4. The antifungal patch of any one of embodiments 1-9, wherein the antifungal fatty acid is selected from the group consisting of butenoic acid (4:1), hexenoic acid (6:1), heptenoic acid (7:1), octenoic acid (8:1), nonenoic acid (9:1), decenoic acid (10:1), undecenoic acid (11:1), dodecenoic acid (12:1), myristoleic acid (14:1), palmitoleic acid (16:1), heptadecenoic acid (17:1), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), stearidonic acid (18:4), eicosapentaenoic acid (20:5) and docosapentaenoic acid (22:5). The antifungal patch of any one of embodiments 1-9, wherein the antifungal fatty acid is selected from the group consisting of hexenoic acid (6: 1), heptenoic acid (7:1), octenoic acid (8:1), nonenoic acid (9:1), decenoic acid (10:1), undecenoic acid (11:1), and dodecenoic acid (12:1). The antifungal patch of any one of embodiments 1-15, wherein the electrospun fiber layer further comprises a therapeutically effective amount of an additional therapeutic agent. The antifungal patch of embodiment 16, wherein the therapeutic agent is a steroid, an analgesic, a calcineurin inhibitor, a barbiturate, a benzodiazepine, or a mixture thereof. The antifungal patch of embodiment 17, wherein the steroid is selected from the group consisting of clobetasol propionate, mometasone, fluocinonide, betamethasone, dexamethasone. The antifungal patch of embodiment 18, wherein the steroid is clobetasol propionate. The antifungal patch of any one of embodiments 17-19, wherein the analgesic is selected from the group consisting of lidocaine, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, etomidate, ketamine, propofol, naproxen, ibuprofen, diclofenac, gabapentin, tramadol, and pregabalin. The antifungal patch of any one of embodiments 17-20, wherein the calcineurin inhibitor is selected from the group consisting of pimecrolimus, tacrolimus and cyclosporine. The antifungal patch of any one of embodiments 17-21, wherein the barbiturate is selected from the group consisting of amobarbital, methohexital, thiamylal, and thiopental. The antifungal patch of any one of embodiments 17-22, wherein the benzodiazepine is selected from the group consisting of diazepam, lorazepam, and midazolam. A patch comprising:

(a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, a therapeutically effective amount of a steroid and a therapeutically effective amount of an antifungal fatty acid; and

(b) an impermeable layer. A patch comprising:

(a) an electrospun fiber layer, wherein the electrospun fibers comprise: one or more polymers, a therapeutically effective amount of an analgesic agent and a therapeutically effective amount of an antifungal fatty acid; and

(b) an impermeable layer. The patch of embodiment 25, wherein the analgesic agent is lidocaine. A method of treating a condition in a patient in need thereof, the method comprising administering a patch of any one of embodiments 1-26, wherein the condition is selected from the group consisting of recurrent aphthous stomatitis, oral lichen planus, pemphigoid, pemphigus, oral mucositis, Graft versus host disease (GvHD), Behcet’s disease, lupus erythematosus, vulva lichen planus, Lipschutz ulcers, lichen simplex chronicus, vulva psoriasis, and cancer. The method of embodiment 27, wherein the patch is administered twice a day. The method of embodiment 28, wherein the patch is administered three times a day. The method of any one of embodiments 27-29, wherein the patch is administered for at least a week. The method of any one of embodiments 27-30, wherein the patch is administered for about 2-4 weeks. The method of any one embodiments 27-31, wherein the patch is administered for at least a month.