Treatment of skin disorders

Abstract

This invention provides a method for treating subjects with skin lesions. [Solution] A method is provided for treating one or more skin lesions using cantharidin and related compositions, treatment plans, kits, devices, and systems. A method for treating a subject having one or more skin lesions may involve administering a composition containing cantharidin to one or more skin lesions. The method may enable effective treatment of one or more skin lesions with minimal or no adverse side effects (e.g., severe adverse side effects, permanent damage to skin tissue, scarring, excessive blistering of the skin around the lesion, elevated plasma cantharidin concentration, systemic exposure to cantharidin). The efficacy and / or safety of the treatment may depend on the specific characteristics of the composition and / or the prolonged exposure of the skin lesion(s) to cantharidin. The methods described herein may be used for a wide variety of skin disorders, including skin disorders that primarily affect the epidermis of the skin.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 516,061, filed on Jun. 6, 2017, entitled "Treatment of Cutaneous Disorders", under 35 U.S.C. § 119(e), which is hereby incorporated by reference in its entirety for all purposes. Background Many skin disorders produce lesions on the skin. Some of these lesions are in the form of epidermal growths on the skin. As an example, warts are small epidermal skin growths caused by viral infections and are often found on the hands or feet. The most common type of wart is called a common wart, which can be caused by multiple different strains of human papillomavirus (HPV). On most parts of the body, these warts will be called common warts; however, when on the feet they will be called plantar warts, or when on the genitals they will be called genital warts or condylomas. Other epidermal viral conditions such as molluscum contagiosum are similar to warts but are caused by different viruses. These virus-mediated skin growths are unsightly and pose a significant risk for transformation into cancer and for spreading, making their removal desirable. Other surface hyperproliferative disorders are similar to warts but are caused by non-viral mechanisms and include seborrheic keratosis, actinic keratosis, and porokeratosis.

[0002] Multiple modalities are used to remove warts, molluscum contagiosum, and other skin conditions, including cryotherapy; surgical curettage; laser treatment; stimulants such as salicylic acid and zinc oxide; acids such as nitric acid and squalane; immunotherapies such as imiquimod, 2,4-dinitrochlorobenzene, and Candida antigen; and chemotherapeutic agents such as bleomycin, podophyllotoxin, and 5-fluorouracil. Many of these treatments can be painful, while others may leave unsightly scars and / or require daily application. However, perhaps the biggest concern is that many of these skin disorders persist uncontrollably even after multiple follow-up treatments. Consequently, improved therapies are needed to treat these conditions. [Overview of the Initiative]

[0003] overview Methods for treating skin lesions using cantharidin (e.g., molluscum contagiosum, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer), as well as related compositions and devices, are provided. In some cases, the subject matter of the present invention involves interrelated products, alternative solutions for specific problems, and / or multiple diverse uses of one or more systems and / or articles.

[0004] Generally, this disclosure provides cantharidin compositions for treating molluscum contagiosum and other skin diseases. The cantharidin compositions may contain cantharidin, which is an intraepiderimal blistering agent. Methods utilizing the cantharidin compositions of this disclosure may have many advantages over conventional treatments, including improved pharmacokinetics, improved safety, improved tolerance, minimal or no adverse side effects, and high efficacy in single application. Compared to cantharidin compositions used to date, the advantages of the cantharidin compositions described herein include the ability to remain on the skin for a relatively long period, improved safety, removal of highly volatile and potentially explosive solvents (e.g., highly flammable solvents), compatibility with common plastics for ease of delivery, and improved biocompatibility.

[0005] Due to the properties of the solvents used in previously described cantharidin compositions, the application of cantharidin has been limited to screw-top glass containers with numerous limitations. The devices provided herein may be used for the precise application of cantharidin formulations for the treatment of topical signs of warts and molluscum contagiosum.

[0006] One aspect of this disclosure provides a method for treating a subject having one or more skin lesions. The method may include administering a composition having improved properties compared to conventional cantharidin formulations. The treatment method of this disclosure would allow cantharidin to remain on the skin for a longer period than conventional treatment methods for certain skin disorders (e.g., surface skin disorders, skin disorders not caused by HPV). For example, the method may include leaving a cantharidin-containing composition on a skin lesion for more than 6 hours (e.g., more than 18 hours and less than or equal to about 24 hours). The treatment method of this disclosure would have enhanced safety, efficacy, pharmacokinetics, and tolerance of cantharidin compared to conventional treatment methods. In some cases, the treatment method would have minimal or no adverse side effects. For example, the treatment method would not induce blistering on the skin surrounding the skin lesion and / or on normal tissue after prolonged exposure to the cantharidin-containing composition. The treatment method would result in relatively high penetration of cantharidin into the skin lesion. Treatment methods will result in a relatively high percentage (for example, all) of treated skin lesions being removed after relatively few treatments (e.g., two, three, or four).

[0007] Another aspect of this disclosure provides cantharidin compositions. Cantharidin will be dissolved in a solvent (e.g., a non-aqueous solvent) or dispersed in a solvent. In some embodiments, the solvent in the composition may have increased long-term stability and / or stability during use compared to solvents conventionally used in cantharidin compositions, such as diethyl ether. In some such cases, the compositions described herein will be less affected by fluctuations in the concentration of cantharidin, e.g., those resulting from the evaporation of the solvent from the composition, while being stored in a device used for housing or otherwise retaining the composition for a period of time. The composition may contain cantharidin and other excipients that cause a portion of the composition (e.g., a composition lacking a certain amount of solvent) to adhere to and remain on a skin lesion after administration. The composition may adhere firmly to the skin of the subject and may adhere and remain after extended periods of normal activity and less exposure to water by the subject. The composition may be designed to allow for relatively high penetration of cantharidin into the skin lesion and retention of cantharidin within the skin lesion.

[0008] Another aspect of this disclosure provides a kit for administering a cantharidin formulation to a subject. The kit may comprise multiple individually packaged, individually removable, dosage units in liquid or gel form. In some examples, one dosage unit is contained in one delivery device or system. In some cases, one dosage unit is contained in one package unit (e.g., an ampoule).

[0009] Another aspect of this disclosure provides an applicator device for delivering a cantharidin formulation to a subject. The applicator unit can deliver the cantharidin formulation to the subject. The applicator device may be a disposable applicator.

[0010] Another aspect of this disclosure provides instructions for an optimal treatment schedule. The various doses of cantharidin, skin preparation, frequency and amount of application to the skin, how the skin is cared for after application, and the duration of contact with the skin are not intuitively obvious to a person skilled in the art, as evidenced by the variability in peer-reviewed publications. The methods described herein enable the optimal and effective treatment of molluscum contagiosum and / or other skin disorders using cantharidin compositions.

[0011] Other advantages and novel features of the present invention will be evident from the detailed description of various non-limiting embodiments of the invention below, when considered in conjunction with the accompanying figures. In cases where this specification and the documents incorporated by reference contain conflicting and / or inconsistent disclosures, this specification shall be in control.

[0012] Detailed description Methods for treating one or more skin lesions using cantharidin, as well as related compositions, treatment plans, kits, devices, and systems, are provided. In some embodiments, a method for treating a subject having one or more skin lesions would involve administering a composition containing cantharidin to the skin. As an example, the composition would be administered to one or more skin lesions on the skin (e.g., resulting from a molluscum cantagiosum infection). The method would enable effective treatment (e.g., removal) of one or more skin lesions with minimal or no adverse side effects (e.g., severe adverse side effects, permanent skin tissue damage, scarring, excessive blistering in the skin surrounding the lesion, elevated plasma cantharidin concentrations, systemic exposure to cantharidin). The efficacy and / or safety of the treatment would be attributable to certain characteristics of the composition and / or the prolonged exposure of the skin lesion(s) to cantharidin. As an example, cantharidin administered to a relatively high percentage of skin lesions(s) will remain on the skin lesions for a relatively long period (e.g., more than 6 hours). In some embodiments, compositions containing cantharidin administered to the skin will enable localized delivery of cantharidin to the composition and therefore to the skin lesions(s) (e.g., to prevent exposure of the surrounding skin to the composition or cantharidin and / or to systemic exposure to the composition or cantharidin), relatively good adhesion to the skin lesions(s), relatively high penetration of cantharidin into the skin lesions(s) over time, and / or use of cantharidin at relatively low concentrations (e.g., about 1.2% w / v or less) and / or pharmacokinetics. The methods described herein may be used for a wide variety of skin disorders, including skin disorders that primarily affect the epidermis of the skin. For example, the method may be used for molluscum cantagiosum infections, seborrheic keratosis, actinic keratosis, milia, skin cancer, age spots, and other disorders not caused by human papillomavirus.

[0013] Cantharidin is used as a blistering agent for the treatment of certain skin disorders. However, in the United States, cantharidin is also classified as an extremely dangerous substance that, if ingested, will cause severe chemical burns and toxicity. Consequently, cantharidin will cause adverse side effects (e.g., scarring) under certain conditions. Historically, for example, certain adverse effects, such as damage to skin tissue, blistering of normal skin surrounding the lesion, pain, and elevated plasma cantharidin concentrations, have occurred during the treatment of certain skin disorders using cantharidin. Current best practice for the treatment of certain skin disorders using cantharidin involves short-term exposure of the lesion to cantharidin (e.g., less than about 4 hours) to prevent these adverse side effects (e.g., severe adverse side effects).

[0014] As described herein, certain methods, compositions, and devices are typically not subject to one or more limitations associated with cantharidin compositions and their use. For example, a treatment method may expose skin lesions(s)(s) to cantharidin for a relatively long period of time (e.g., more than 6 hours, more than 12 hours, more than about 18 hours, more than about 6 hours and less than or equal to about 72 hours, more than about 18 hours and less than or equal to about 24 hours) with minimal adverse side effects (e.g., severe adverse side effects) or no adverse side effects at all (e.g., severe adverse side effects).

[0015] In some embodiments, a method for treating a subject having a skin lesion may include administering a composition containing cantharidin to the skin lesion (e.g., topically). In some embodiments, the composition may contain relatively low concentrations of cantharidin (e.g., about 1.2% w / v or less, about 1% w / v or less, about 0.5% w / v or more, and about 1% w / v or less). The cantharidin may be dissolved or otherwise dispersed in a solvent (e.g., a non-aqueous solvent). In some embodiments, the solvent in the composition may have increased long-term stability and / or stability during use compared to solvents conventionally used in cantharidin compositions, such as diethyl ether. In some such cases, the compositions described herein will be stored in a device used for housing or otherwise retain the composition for a period of time, while being less affected by fluctuations in the concentration of cantharidin, e.g., those resulting from evaporation of the solvent from the composition. As an example, the concentration of cantharidin in the device (e.g., an applicator) will remain relatively constant over time and / or after several uses. In some embodiments, the solvent in the composition is less volatile than solvents used in existing and / or conventional cantharidin compositions. In some embodiments, the solvent has a vapor pressure of about 350 mmHg or less (e.g., about 210 mmHg or less) at 20°C. In some such cases, the solvent is an alcohol (e.g., ethanol) and acetone. In some cases, the solvent is a non-ether solvent and / or does not contain diethyl ether. In some embodiments, the composition has a vapor pressure of about 210 mmHg or less (e.g., about 126 mmHg or less) at 20°C. In some cases, the composition contains a relatively small weight percentage (e.g., about 20 wt.% or less, about 10 wt.% or less) of ether, such as diethyl ether. In some embodiments, the composition may contain one or more components in addition to cantharidin and a pharmaceutically acceptable excipient (e.g., the solvent).For example, the composition may contain film-forming agents (e.g., polymers, nitrocellulose and / or hydroxypropylcellulose), plasticizers (e.g., penetration enhancers, oils, camphor and / or castor oil), pigments (e.g., gentian violet), and / or bittering agents (e.g., denatonium benzoate). In some embodiments, the viscosity of the composition may be less than 100 cps, less than 90 cps, less than 80 cps, less than 70 cps, less than 60 cps, less than 55 cps, more than 30 cps, more than 35 cps, about 30-100 cps, about 30-70 cps, about 35-60 cps, or about 40-50 cps.

[0016] In some embodiments, the composition may be administered and / or formulated such that a relatively large percentage of the composition does not spread beyond the edges of the skin lesion being treated after administration (e.g., topical administration). In some embodiments, the spread of the composition to at least a portion of the skin surrounding the lesion (e.g., normal tissue) may be minimized by delivery to a certain volume of the skin lesion and / or through the use of a certain applicator (e.g., a precision applicator tip). In some embodiments, the composition may be formulated to minimize the spread of the composition to the skin surrounding the lesion while still providing a satisfactory coverage of the lesion. Whether or not the composition spreads, the composition will result in minimal adverse side effects (e.g., severe adverse side effects) or no adverse side effects at all (e.g., severe adverse side effects).

[0017] In some embodiments, at least a portion of the composition will remain on the skin lesion for a certain period of time (e.g., more than 6 hours, more than about 18 hours, and less than or equal to about 24 hours). For example, at least some or substantially all of the solvents in the composition may evaporate, leaving a material (e.g., a film) on the skin (e.g., a skin lesion). The material may include cantharidin and a film-forming agent (e.g., nitrocellulose). In some embodiments, the material may also include other components, such as penetration enhancers, dyes, and aversive agents. In some embodiments, the remaining composition (e.g., a portion of the composition remaining on the skin lesion) will have beneficial skin adhesion, flexibility, and / or safety properties (e.g., relatively little blistering or no blistering at all on the outer edges of the lesion). For example, the remaining composition may form a film on the skin lesion. In some embodiments, the film is formed as a result of the removal (e.g., via evaporation) of the solvent (e.g., substantially all) during and / or after the administration step. In some cases, the film will adhere to and remain on the skin lesion during normal activity by the subject and / or during periods of minimal exposure to water (e.g., more than approximately 6 hours, more than approximately 8 hours, more than approximately 12 hours, more than approximately 18 hours, more than approximately 24 hours, or indefinitely). In some cases, the film is relatively flexible. For example, the film will remain relatively continuous during a period of normal activity, with relatively few or no discontinuous areas. In such cases, the film will undergo minimal peeling and / or form only slight or no cracks during normal activity.

[0018] In some embodiments, the residual composition will be safe. In some such cases, the composition will not induce blistering on the skin surrounding a skin lesion within about 12 hours or more (e.g., about 24 hours or more) after administration of the composition containing cantharidin. For example, the composition will not cause blister formation (e.g., to cause blistering) at a distance of at least about 2 mm (e.g., about 5 mm, about 10 mm, about 15 mm, about 20 mm, about 30 mm) from the edge of a skin lesion within at least 6 hours (e.g., at least about 12 hours, at least about 24 hours) after the administration step and / or continuous contact with the composition. In another example, the composition will not cause blistering outside the edge of a skin lesion and / or the site of administration after at least 6 hours (e.g., at least about 12 hours, at least about 24 hours) after the administration step and / or continuous contact with the composition. In some embodiments, when a 5 mm droplet of the composition is administered to the skin, it does not produce blisters having a diameter greater than about 10 mm (e.g., about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 40 mm, about 50 mm) at a certain distance (e.g., at least 1 mm, at least about 2 mm) from the edge of a skin lesion at least 6 hours (e.g., at least about 12 hours, at least about 18 hours, at least about 24 hours) of continuous contact with the skin. In some embodiments, when a droplet of the composition having a volume of about 10 μL or less is administered to the skin, for example, over an area of ​​5 mm in diameter on the skin, it does not produce blisters having a diameter greater than about 10 mm (for example, about 15 mm, about 20 mm, about 25 mm, about 30 mm, about 40 mm, about 50 mm) at a certain distance (for example, at least 1 mm, at least about 2 mm) from the edge of the skin lesion, at least 6 hours (for example, at least about 12 hours, at least about 18 hours, at least about 24 hours) of continuous contact with the skin.

[0019] As described above, in some embodiments, at least a portion of the composition may remain on the skin lesion for a certain period of time. In some embodiments, the composition may remain on the skin lesion for more than about 6 hours, about 8 hours or more, about 10 hours or more, about 12 hours or more, about 14 hours or more, about 16 hours or more, about 18 hours or more, about 20 hours or more, about 22 hours or more, about 24 hours or more, about 28 hours or more, about 32 hours or more, about 36 hours or more, about 40 hours or more, about 44 hours or more, about 48 hours or more, about 52 hours or more, about 56 hours or more, about 60 hours or more, about 64 hours or more, or about 68 hours or more. In some examples, the composition may remain on the skin lesion for approximately 72 hours or less, approximately 68 hours or less, approximately 64 hours or less, approximately 60 hours or less, approximately 56 hours or less, approximately 52 hours or less, approximately 48 hours or less, approximately 44 hours or less, approximately 40 hours or less, 36 hours or less, approximately 32 hours or less, approximately 28 hours or less, approximately 24 hours or less, approximately 22 hours or less, approximately 20 hours or less, approximately 18 hours or less, approximately 16 hours or less, approximately 14 hours or less, approximately 12 hours or less, approximately 10 hours or less, or approximately 8 hours or less. All combinations of the above reference range are possible. For example, the composition may remain on the skin lesion for more than approximately 6 hours and approximately 72 hours or less, more than approximately 12 hours and approximately 72 hours or less, more than approximately 18 hours and approximately 72 hours or less, more than approximately 12 hours and approximately 48 hours or less, more than approximately 18 hours and approximately 36 hours or less, or more than approximately 18 hours and approximately 24 hours or less.

[0020] It should be understood that phrases such as “on the skin,” “on a skin lesion,” “on a lesion,” etc., with respect to a composition or any of its components (e.g., cantharidin), refer to the composition or any of its components being on the top of one or more layers of skin (e.g., the outer layer of the skin), inside one or more layers of skin (e.g., contained within one or more layers of skin, contained in the skin, contained within a lesion), and / or below one or more layers of skin (e.g., the surface layer of a skin lesion, the epidermal layer of a skin lesion). In some embodiments, at least some (e.g., substantially all) of the composition or any of its components may remain on the top of a skin lesion. In some embodiments, at least some (e.g., substantially all) of the composition or any of its components may remain within a skin lesion. In some embodiments, at least some (e.g., substantially all) of the composition or any of its components may be below one or more layers of skin (e.g., the surface layer of a skin lesion, the epidermal layer of a skin lesion).

[0021] In some embodiments, at least a portion (e.g., substantially all) of the solvent is removed from the composition during and / or after the administration step. For example, at least a portion (e.g., substantially all) of the solvent is removed from the composition after the administration step (e.g., via evaporation). In some such embodiments, the remaining composition will form a film on at least a portion of the skin lesion. In some embodiments, the rate and / or total time for the removal (e.g., evaporation) of the solvent (e.g., substantially all) from the composition will be selected to produce beneficial properties. For example, the vapor pressure of the solvent and / or the composition will be selected to control the rate and / or total time for the removal (e.g., evaporation) of the solvent (e.g., substantially all) from the composition. In some embodiments, the total time for removing (e.g., by evaporation) at least a portion of the solvent from the composition (e.g., about 50% or more, about 75% or more, about 90% or more, about 95% or more, about 99% or more, 100%) may be about 60 seconds or less, about 55 seconds or less, about 50 seconds or less, about 45 seconds or less, about 40 seconds or less, about 35 seconds or less, about 30 seconds or less, about 25 seconds or less, or about 20 seconds or less. In some examples, the total time for removing (e.g., by evaporation) at least a portion of the solvent from the composition (e.g., about 50% or more, about 75% or more, about 90% or more, about 95% or more, about 99% or more, 100%) may be about 10 seconds or more, about 15 seconds or more, about 20 seconds or more, about 25 seconds or more, about 30 seconds or more, about 35 seconds or more, about 40 seconds or more, about 45 seconds or more, or about 50 seconds or more. All combinations of the above reference ranges are possible (e.g., more than about 30 seconds and less than or equal to about 60 seconds). In general, the time for the removal of at least a portion of the solvent from the composition will be slower than that for some conventional cantharidin formulations, such as those containing diethyl ether or a certain percentage of diethyl ether. In some embodiments, the removal of at least a portion of the solvent (e.g., substantially all of the solvent) may occur through passive and / or active means.

[0022] In some embodiments, a relatively large percentage of cantharidin administered to a skin lesion will penetrate into the skin lesion (e.g., the epidermis of the skin lesion). For example, in some embodiments, after the administration step and / or after remaining on the skin for a certain period (e.g., 6 hours or less, 12 hours or less, 18 hours or less), about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, or about 99% or more of the administered cantharidin may be absorbed into the tissue of the skin lesion (e.g., epidermal tissue). Consequently, the composition remaining on the skin after a certain period (e.g., a film) may contain a relatively small percentage of the administered cantharidin. For example, a composition remaining on the skin (e.g., a film) may contain administered cantharidin in amounts of approximately 75% or less, approximately 50% or less, approximately 40% or less, approximately 30% or less, approximately 20% or less, approximately 10% or less, approximately 5% or less, approximately 2% or less, approximately 1% or less, or approximately 0.5% or less.

[0023] Regardless of the percentage of administered cantharidin that penetrates into skin lesions, the plasma concentration of cantharidin in the subjects (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be relatively low. For example, the plasma concentration of cantharidin in subjects (e.g., at least some subjects, all subjects) at least 2 hours (e.g., at least 6 hours, at least 12 hours, at least 24 hours) after administration of a composition containing cantharidin was approximately ≤30 ng / ml, ≤25 ng / ml, ≤20 ng / ml, ≤15 ng / ml, ≤10 ng / ml, ≤8 ng / ml, ≤5 ng / ml, ≤4.8 ng / ml, ≤4.5 ng / ml, and ≤4. It may be 3 ng / ml or less, approximately 4 ng / ml or less, approximately 3.8 ng / ml or less, approximately 3.5 ng / ml or less, approximately 3.3 ng / ml or less, approximately 3 ng / ml or less, approximately 2.8 ng / ml or less, approximately 2.5 ng / ml or less, approximately 2.3 ng / ml or less, approximately 2 ng / ml or less, approximately 1.8 ng / ml or less, approximately 1.5 ng / ml or less, approximately 1.3 ng / ml or less, approximately 1 ng / ml or less, approximately 0.8 ng / ml or less, approximately 0.5 ng / ml or less, approximately 0.3 ng / ml or less, or approximately 0.1 ng / ml or less. For example, in embodiments in which the composition is applied to more than one skin lesion (e.g., two or more, five or more, ten or more, fifteen or more, twenty or more, twenty or more, twenty or more, fifty or more, one or more, one or more), and / or in amounts up to about 900 microliters or up to 200 mg (e.g., 170 mg) of the composition applied to the target skin lesion, the plasma concentration may be less than or equal to about 3.3 ng / mL or less or about 2.5 ng / mL or less (e.g., less than or equal to about 1 ng / mL, less than or equal to about 0.5 ng / mL, less than or equal to about 0.1 ng / mL) at least two hours (e.g., two hours, six hours, 24 hours) after administration of the composition.As another example, in embodiments in which the composition is applied to more than one skin lesion (e.g., two or more, five or more, ten or more, fifteen or more, twenty or more, twenty or more, twenty or more, fifty or more, one or more) and / or in embodiments in which up to 200 mg (e.g., 170 mg) of the composition is applied to the skin lesion in question, the plasma concentration may be approximately 3.3 ng / mL or less or approximately 2.5 ng / mL or less (e.g., approximately 1 ng / mL or less, approximately 0.5 ng / mL or less, approximately 0.1 ng / mL or less) at least two hours (e.g., two hours, six hours, 24 hours) after administration of the composition.

[0024] In some embodiments, the plasma concentration of cantharidin in a subject (e.g., the concentration at a single point in time, the concentration at all time points, the maximum concentration) may be relatively low for the number of extensive lesions, lesions per pound of body weight (i.e., lesions per pound), age, body weight, total dosage administered, and / or genital complications. As an example, the plasma concentration (e.g., the concentration at a single point in time, the concentration at all time points, the maximum concentration) may be about 3.3 ng / mL or less (e.g., about 2.5 ng / mL or less, about 2.5 ng / mL or less) about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition when the composition is administered to at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, or at least 110 skin lesions. In some embodiments, the plasma concentration may be about 3.3 ng / mL or less (e.g., about 2.5 ng / mL or less, about 1 ng / mL or less) at least about 2 hours after administration of the composition when the lesions per pound of the subject are about 0.001 or more, about 0.01 or more, about 0.1 or more, about 0.25 or more, about 0.5 or more, about 0.75 or more, about 1 or more, about 1.25 or more, about 1.75 or more, about 2 or more, about 2.25 or more, about 2.5 or more, about 2.75 or more, or about 3 or more. As an example, the plasma concentration may be about 3.3 ng / mL or less (e.g., about 2.5 ng / mL or less, about 1 ng / mL or less) at least about 2 hours after administration of the composition in embodiments where the lesions per pound of the subject are about 0.001 or more and about 3 or less (e.g., about 0.1 or more and about 2.5 or less).

[0025] In some embodiments, the plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be approximately 3.3 ng / mL or less (e.g., approximately 2.5 ng / mL or less, approximately 1 ng / mL or less) at least approximately 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of a composition of approximately 0.1 milligrams or more per pound of subject (e.g., approximately 0.25 mg or more, approximately 0.5 mg or more, approximately 0.75 mg or more, approximately 1 mg or more, approximately 1.5 mg or more, approximately 2 mg or more, approximately 2 mg or more, approximately 2.5 mg or more, approximately 3 mg or more, approximately 3.5 mg or more, approximately 4 mg or more, approximately 4.5 mg or more) For example, the plasma concentration may be about 3.3 ng / mL (for example, about 2.5 ng / mL) at least 2 hours after administration of a composition containing about 0.1 mg or more and about 6 mg or less per pound of subject (for example, about 0.5 mg or more and about 6 mg or less, or about 0.75 mg or more and about 5 mg or less).

[0026] In some embodiments, the plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be approximately 3.3 ng / mL (e.g., less than or equal to approximately 2.5 ng / mL, less than or equal to approximately 1 ng / mL) at least approximately 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of a composition of approximately 0.5 milligrams or more per lesion (e.g., more than or equal to approximately 3 mg / lesion, more than or equal to approximately 3.5 mg / lesion, more than or equal to approximately 4.5 mg / lesion, more than or equal to approximately 5.5 mg / lesion, more than or equal to approximately 6 mg / lesion, more than or equal to approximately 6.5 mg / lesion, more than or equal to approximately 7 mg / lesion, more than or equal to approximately 7.5 mg / lesion, more than or equal to approximately 8 mg / lesion, more than or equal to approximately 8.5 mg / lesion, more than or equal to approximately 9 mg / lesion, more than or equal to approximately 9.5 mg / lesion). For example, plasma concentrations may be approximately 3.3 ng / mL or less (for example, approximately 2.5 ng / mL or less and approximately 1 ng / mL or less) at least approximately 2 hours after administration to subjects with compositions of approximately 3 mg / lesion or more and approximately 10 mg / lesion or less.

[0027] In some embodiments, the plasma concentration (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be about 3.3 ng / mL or less (e.g., about 2.5 ng / mL or less, about 1 ng / mL or less) at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of about 0.01 milligram or more of cantharidin per lesion (e.g., about 0.01 mg / lesion or more, about 0.02 mg / lesion or more, about 0.03 mg / lesion or more, about 0.04 mg / lesion or more, about 0.05 mg / lesion or more, about 0.06 mg / lesion or more, about 0.07 mg / lesion or more, about 0.08 mg / lesion or more, about 0.09 mg / lesion or more, about 0.1 mg / lesion or more, about 0.2 mg / lesion or more, about 0.3 mg / lesion or more, about 0.4 mg / lesion or more, about 0.5 mg / lesion). As an example, the plasma concentration may be about 3.3 ng / mL or less (e.g., about 2.5 ng / mL or less, about 1 ng / mL or less) at least about 2 hours after administration of about 0.01 mg / lesion or more and about 0.5 mg / lesion or less (e.g., about 0.07 mg / lesion or more and about 0.1 mg / lesion or less) of cantharidin to a subject.

[0028] In some embodiments, the plasma concentration of cantharidin in a subject (e.g., concentration at a single time point, concentration at all time points, peak concentration) may be relatively low and uniform in subjects with relatively low body weight and / or age. For example, the plasma concentration may be about 3.3 ng / mL or less (e.g., about 2.5 ng / mL or less, about 1 ng / mL or less) at least about 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition to subjects with a body weight of about 200 lb. or less, about 175 lb. or less, about 150 lb. or less, about 125 lb. or less, about 100 lb. or less, about 90 lb. or less, about 80 lb. or less, about 70 lb. or less, about 60 lb. or less, about 50 lb. or less, about 40 lb. or less, or about 30 lb. or less) in subjects having a body weight of about 200 lb. or less, about 175 lb. or less, about 150 lb. or less, about 125 lb. or less, about 100 lb. or less, about 90 lb. or less, about 80 lb. or less, about 70 lb. or less, about 60 lb. or less, about 50 lb. or less, about 40 lb. or less, or about 30 lb. or less. In some embodiments, plasma concentrations may be approximately 3.3 ng / mL or less (e.g., approximately 2.5 ng / mL or less, approximately 1 ng / mL or less) at least approximately 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition to subjects aged approximately 20 years or younger, approximately 18 years or younger, approximately 15 years or younger, approximately 12 years or younger, approximately 10 years or younger, approximately 8 years or younger, approximately 5 years or younger, or approximately 3 years or younger. In some embodiments, plasma concentrations may be approximately 3.3 ng / mL or less (e.g., approximately 2.5 ng / mL or less, approximately 1 ng / mL or less) at least approximately 2 hours (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition to subjects having one or more skin lesions in the genital area.

[0029] In some embodiments, the method may include repeated administration of the composition. For example, the method may include administering a composition containing a second cantharidin to at least a portion of a skin lesion. In some embodiments, the second composition may have substantially the same percentage (w / v) of cantharidin as the composition. In some embodiments, the second composition may be substantially the same as the first composition. In some embodiments, the second composition may be administered after administration of the first composition at some time interval (e.g., about 1 day or more, about 3 days or more, about 5 days or more, about 1 week or more, about 2 weeks or more, about 3 weeks or more). For example, the second composition may be administered after administration of the first composition at about 14 days or more and about 28 days or less (e.g., about 17 days or more and about 25 days or less, about 18 days or more and about 24 days or less, about 19 days or more and about 23 days or less, about 20 days or more and about 22 days or less, 21 days). For example, the second composition may be administered approximately three weeks after the administration of the first composition.

[0030] In general, the administration step may be repeated any number of times suitable for the time required to treat the skin disorder. For example, the administration step may be repeated two or more times, three or more times, four or more times, five or more times, six or more times, seven or more times, eight or more times, nine or more times, or ten or more times. In one embodiment, the total number of administration steps within a time frame (e.g., January, February, March, April, June, August, October, December) and / or until a certain endpoint is reached (e.g., a certain percentage reduction in the number of lesions, a percentage reduction in the total volume of lesions(s) or more) may be about two or more and about ten or less, about three or more and about ten or less, about two or more and about eight or less, about two or more and about six or less, or about three or more and about five or less. For example, the method may include performing two administration steps during a 6-week period. As another example, the method may include performing four administration steps during a 12-week period.

[0031] In some embodiments, the time intervals between each administration step (e.g., the first and second administrations) may be selected as desired. In some embodiments, at least some (e.g., each) time intervals between administration steps may be substantially the same. As an example, at least some (e.g., each) time intervals between administration steps may be days (e.g., about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days), weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks), months (e.g., January, February, March, April, May, June, July, August, September, October, November), or years (e.g., 1 year, 2 years, or more). For example, the method may include administering a composition containing cantharidin about every 3 weeks (e.g., every 21 ± 4 days) for about 12 weeks. In some embodiments, at least some (e.g., each) time intervals between administration steps may be different.

[0032] In some embodiments in which the administration step is repeated, the step of causing is also repeated. In some embodiments, the step of causing is repeated after each administration. In some embodiments, the step of causing is repeated after at least some, but not all, of the administration steps. In general, the repeated step(s) of causing may be as described herein.

[0033] In general, the treatment methods described herein will result in the separation of at least some epidermal tissue from the skin tissue within a skin lesion without removing and / or damaging the skin tissue. In some embodiments, the treatment methods described herein will have relatively high efficacy. For example, the administration of one or more compositions and / or the presence of compositions after one or more administrations will result in the removal of skin lesions or a substantial reduction in the volume of lesions. In some embodiments in which more than one skin lesion is present in the subject and the composition is administered to at least some of the lesions (for example, substantially each), a relatively high percentage (for example, about 90% or more, about 95% or more, about 99% or more, 100%) of the treated lesions will be removed and / or the total volume of the lesions will be reduced by a relatively high percentage (for example, about 50% or more, about 60% or more, about 75% or more, about 90% or more, about 99% or more, 100%). In some embodiments, the volume of a single skin lesion will be reduced by a relatively high percentage (for example, over 50%, over 60%, over 75%, over 90%, over 99%, and 100%).

[0034] It should be understood that the methods, compositions, and devices described herein may be used to treat one or more skin lesions in subjects caused by one or more skin disorders. References to single skin lesions are for the sake of clarity. In general, the methods, compositions, and devices described herein will be used to treat multiple skin lesions (e.g., two or more, five or more, ten or more, fifteen or more, twenty or more, thirty or more, forty or more, fifty or more, seventy or more, one hundred or more, two or more) in subjects having a skin disorder to be treated, such as a molluscum contagiosum infection.

[0035] As described above, in some embodiments, the composition may have beneficial properties in at least part that contribute to the effectiveness and / or safety of the methods described herein. In some embodiments, the composition may contain a relatively low concentration of cantharidin and have a relatively low vapor pressure (e.g., about 210 mmHg or less at 20°C, and about 126 mmHg or less at 20°C). For example, the composition may contain a relatively low concentration of cantharidin (e.g., about 1.2% (w / v) or less), a non-aqueous solvent (e.g., ethanol and acetone), a film-forming agent (e.g., nitrocellulose and / or hydroxypropylcellulose), and a plasticizer (e.g., camphor and / or castor oil). In some embodiments, the composition may also contain a dye (e.g., gentian violet) and / or a bittering agent (e.g., denatonium benzoate).

[0036] In one example, the composition contains cantharidin (for example, by weight per volume percent of about 0.1 or more and about 1.2 or less, by weight per volume percent of about 0.7 or more and about 0.9 or less, and by weight per volume percent of 0.7), acetone (for example, by weight per weight percent of about 55 or more and about 65 or less, by weight per weight percent of about 58 or more and about 62 or less), ethanol (for example, by weight per weight percent of about 25 or more and about 35 or less, by weight per weight percent of about 28 or more and about 32 or less), castor oil (for example, by weight per weight percent of about 0.5 or more and about 2 or less, by weight per weight percent of about 1.2 or more and about 1.6 or less), and nitrocellulose (for example, by weight per weight percent of about 2 or more and about 10 or less, by weight per volume percent of about 3 or more and about 6 or less) It may also contain nitrocellulose (in amounts of nitrocellulose per unit weight), hydroxypropylcellulose (in amounts of about 0.1 to about 2 per weight percent), camphor (for example, in amounts of about 0.1 to about 2 per weight percent, and about 0.5 to about 1.5 per weight percent), denatonium benzoate (for example, in amounts of about 0.001 to about 0.01 per weight percent, and about 0.004 to about 0.008 per weight percent), and / or gentian violet (for example, in amounts of gentian violet per weight percent of about 0.0001 to about 0.001, and about 0.002 to about 0.0008 per weight percent).

[0037] In some embodiments, the solvent as a whole and / or composition may have a certain vapor pressure that gives the composition beneficial properties. For example, the solvent as a whole and / or composition in the composition may have a vapor pressure of about 210 mmHg or less, about 200 mmHg or less, about 175 mmHg or less, about 150 mmHg or less, or about 126 mmHg or less at 20°C. In some embodiments, the vapor pressure of the solvent as a whole and / or composition may be about 100 mmHg or more and about 210 mmHg or less at 20°C (for example, about 100 mmHg or more and about 200 mmHg or less, about 100 mmHg or more and about 175 mmHg or less, or about 100 mmHg or more and about 150 mmHg or less). In some embodiments, the solvent as a whole and / or composition in the composition may have a flash point of about 4°C or higher. In some embodiments, the solvent as a whole and / or composition in the composition will not form peroxides upon decomposition, or will not have a tendency to form peroxides.

[0038] In one aspect, one or more solvent components in the whole solvent (for example, all solvent components), the whole solvent and / or composition, at 20°C, are approximately 350 mmHg or less, approximately 340 mmHg or less, approximately 330 mmHg or less, approximately 320 mmHg or less, approximately 310 mmHg or less, approximately 300 mmHg or less, approximately 290 mmHg or less, approximately 280 mmHg or less, approximately 270 mmHg or less, approximately 260 mmHg or less, approximately 250 mmHg or less, approximately 240 mmHg or less, and approximately 230 mmHg or less. It may have a vapor pressure of approximately 220 mmHg or less, approximately 210 mmHg or less, approximately 200 mmHg or less, approximately 190 mmHg or less, approximately 180 mmHg or less, approximately 170 mmHg or less, approximately 160 mmHg or less, approximately 150 mmHg or less, approximately 140 mmHg or less, approximately 130 mmHg or less, approximately 120 mmHg or less, approximately 110 mmHg or less, approximately 100 mmHg or less, approximately 90 mmHg or less, approximately 80 mmHg or less, approximately 70 mmHg or less, approximately 60 mmHg or less, or approximately 50 mmHg or less. In some examples, one or more solvent components in the whole solvent, the whole solvent and / or compositions may have a vapor pressure of about 20 mmHg or more, about 25 mmHg or more, about 30 mmHg or more, about 35 mmHg or more, about 40 mmHg or more, about 50 mmHg or more, about 60 mmHg or more, about 70 mmHg or more, about 80 mmHg or more, about 90 mmHg or more, about 100 mmHg or more, about 110 mmHg or more, or about 120 mmHg or more at 20°C. All combinations within the above reference range are possible. In some embodiments, one or more solvent components in the whole solvent (e.g., all solvent components), the whole solvent and / or compositions may have a vapor pressure of about 210 mmHg or less at 20°C (e.g., about 200 mmHg or less, 185 mmHg). In some embodiments, one or more solvent components in the whole solvent (e.g., all solvent components) may have a flash point of about 4°C or higher. In one embodiment, the composition may not contain any solvent components having a flash point of about 4°C or lower. In another embodiment, the composition may contain about 20 wt.% or less of solvent components having a flash point of about 4°C or lower.In some aspects, one or more solvent components in the entire solvent (for example, all solvent components) will not form peroxides during decomposition, or will not have a tendency to form peroxides.

[0039] In some embodiments, the composition may contain a relatively low percentage of diethyl ether (e.g., about 20% w / w or less, about 15% w / w or less, about 10% w / w or less, about 5% w / w or less, about 1% w / w or less, about 0.1% w / w or less, about 0.01% w / w or less) or may not contain diethyl ether. In some embodiments, the composition may contain a relatively low percentage of water (e.g., about 10% w / w or less, about 5% w / w or less, about 1% w / w or less, about 0.1% w / w or less, about 0.01% w / w or less) or may not contain water.

[0040] In some embodiments, the methods described herein may include administering the composition using a disposable applicator. In some embodiments, the methods described herein may include administering the composition using a multi-use applicator. Suitable applicators are described and incorporated by reference in International Publication No. PCT / US2014 / 052184, filed August 21, 2014, and entitled “Compositions, Methods, and Systems for the Treatment of Cutaneous Disorders,” and in U.S. Provisional Application No. 62 / 520,0504, filed June 15, 2017, and entitled “Devices and Methods for the Treatment of Cutaneous Disorders.” International publication number PCT / US2015 / 066487, filed on 17 December 2015, and titled "Commercially Viable Synthesis of Cantharidin and Bioactive Cantharidin Derivatives," and international publication number PCT / US2016 / 014139, filed on 20 January 2016, and titled "Quantification and Preparation of Pharmaceutical Grade Cantharidin," are also incorporated as references in their entirety.

[0041] In some embodiments, the disclosure provides a method for treating epidermal warts, molluscum contagiosum, or other skin diseases in a subject by using an applicator device comprising a reservoir and an applicator unit for administering a cantharidin preparation to the subject. The reservoir may contain the cantharidin preparation. The applicator unit may be in fluid communication with the reservoir. The cantharidin preparation may contain at least about 0.001% (w / v) cantharidin. In some cases, the cantharidin preparation may contain at least about 0.01%, 0.1%, 0.5%, 1.0%, 1.2%, or 1.5% cantharidin. The cantharidin preparation may contain about 1% (w / v) or more of excipients. The epidermal lesions may be removed from the subject within two weeks after delivery of the cantharidin preparation.

[0042] In some embodiments, the Disclosure provides a kit for administering a cantharidin formulation to a subject. The kit may comprise a plurality of individually packaged, individually removable, dosage units in liquid or gel form. In some examples, one dosage unit is contained in one delivery device or system. In some cases, one dosage unit is contained in one package unit (e.g., an ampoule).

[0043] In some situations, a dose unit may contain an amount of cantharidin preparation ranging from approximately 0.1 mL to approximately 10 mL. The cantharidin preparation contains at least approximately 0.001% cantharidin. In some cases, the cantharidin preparation may contain at least approximately 0.01%, 0.1%, or 1% cantharidin. The kit may be used to administer each of the active dose units. A dose unit containing the cantharidin preparation may be therapeutically effective in treating epidermal warts or other lesions in a subject. The kit may contain at least 3 package units. A dose unit containing the cantharidin preparation may be therapeutically effective in reducing epidermal warts or other lesions by at least approximately 50% in volume over a period of approximately 7 days.

[0044] In some embodiments, this disclosure provides instructions for an optimal treatment schedule. The various doses of cantharidin, skin preparation, frequency and amount of application to the skin, how the skin is cared for after application, and the duration of contact of cantharidin with the skin are not intuitively obvious to a person skilled in the art, as these have not been thoroughly tested elsewhere and are evidenced by the variability in peer-reviewed publications. The methods described herein enable the optimally effective treatment of warts, molluscum contagiosum, and / or other skin disorders using cantharidin formulations.

[0045] In some embodiments, the average treatment time per lesion for a subject may be relatively short. For example, the average treatment time per lesion may be approximately 30 seconds or less, approximately 25 seconds or less, approximately 15 seconds or less, approximately 10 seconds or less, or approximately 5 seconds or less. The average treatment time can be determined by measuring the period from the start of treatment of the first lesion to the end of treatment of the last lesion for a given administration step, and dividing the period by the number of lesions treated. For example, the average treatment time for a subject with 10 lesions treated over a period of 50 seconds is 5 seconds.

[0046] In some situations, cantharidin preparations may be administered such that the average treatment time and / or duration is approximately 30 seconds or less. Cantharidin preparations may be administered such that the average treatment time and / or duration is approximately 20 seconds or less. Cantharidin preparations may be administered such that the average treatment time and / or duration is approximately 10 seconds or less. Cantharidin preparations may be administered such that the average treatment time and / or duration is approximately 5 seconds or less.

[0047] In some situations, cantharidin preparations may be administered in volumes of approximately 10 μL or less. In other situations, cantharidin preparations may be administered in volumes of approximately 5 μL or less.

[0048] In some embodiments, the disclosure provides a kit for administering a cantharidin preparation to a subject, comprising a plurality of individually packaged, individually removable, liquid or gel-based dose units, wherein the dose units may be in package units, each dose unit containing an amount of the cantharidin preparation ranging from about 0.01 mL to 10 mL. The cantharidin preparation may contain at least about 0.001% (w / v) of cantharidin. In some cases, the cantharidin preparation may contain at least about 0.01%, 0.1%, or 1% of cantharidin.

[0049] In some situations, the kit may further include instructional materials for administering the cantharidin preparation. The instructional materials may be designed to leave at least a portion of the composition on the skin lesion for a period of time (e.g., more than about 6 hours). The instructional materials may allow the subject to self-administer the cantharidin preparation. The instructional materials may be designed for treating epidermal warts in the subject. The kit may include at least 3 package units. The cantharidin preparation may be suitable for removing epidermal warts from the subject within two weeks after delivery of the dosage unit containing the cantharidin preparation.

[0050] In some embodiments, the Disclosure provides formulations comprising at least about 0.001% (w / v) of cantharidin, a flavorant that can induce bitterness in the subject upon ingestion of the formulation, and a colorant that can enable the subject to visually detect the formulation. The formulation may have a volume of at most about 10 milliliters (mL).

[0051] In some circumstances, a cantharidin preparation may contain at least about 0.001% cantharidin. A cantharidin preparation may contain at least about 0.01%, 0.1%, 0.5%, or 1% cantharidin. Flavorants and / or colorants may be present in concentrations of at most about 1% (w / v). The volume may be about 5 mL or less. The preparation may have a Reynolds number of less than about 1500 at 25°C. The preparation may further contain a gelling agent. The preparation may have a manganese or magnesium ion concentration of less than about 1%. The flavorant may be selected from the group consisting of denatonium, amarogentin, gentiopicrin, octaacetylsucrose, quercetin, brucine, and quacin. The colorants may be selected from the group consisting of D&C violet, isosulfan blue, methylene blue, methyl red, methyl orange, Congo red, alizarin yellow, bromocresol green, FD&C green 3, FD&C yellow 5, and gentian violet.

[0052] In some embodiments, the Disclosure provides a method for treating a skin disease (e.g., warts) of the skin (or a site on the skin) of a subject, comprising: a) providing a cantharidin formulation comprising (i) at least about 0.001% (w / v) cantharidin; (ii) a flavorant that can induce a bitter taste in the subject upon ingestion of the formulation by the subject; and a colorant that can enable the subject to visually detect the formulation; and b) providing the cantharidin formulation to the skin of a site containing or suspected to contain a skin disease. The formulation may have a volume of at most about 10 milliliters (mL).

[0053] In some circumstances, the cantharidin preparation may contain at least about 0.001% cantharidin. The cantharidin preparation may contain at least about 0.01%, 0.1%, 0.5%, or 1% cantharidin. The flavorant and / or colorant may be at a maximum concentration of about 1% (w / v). The volume may be about 5 mL or less. The preparation may have a Reynolds number of less than about 1500 at 25°C. The method may further include a gelling agent. The preparation may have a manganese or magnesium ion concentration of less than about 1%. The flavorant may be selected from the group consisting of denatonium, amarogentin, gentiopicrin, octaacetylsucrose, quercetin, brucine, and quacin. The colorants may be selected from the group consisting of D&C violet, isosulfan blue, methylene blue, methyl red, methyl orange, Congo red, alizarin yellow, bromocresol green, and gentian violet. The skin diseases may be selected from the group consisting of warts, molluscum contagiosum, seborrheic keratosis, and actinic keratosis.

[0054] When used herein, the terms “treatment” or “to treat” generally refer to an approach to obtain a beneficial, intended or desired outcome, including, but not limited to, therapeutic and / or preventive benefits. Therapeutic benefits mean the eradication or improvement of the underlying disorder being treated, e.g., a skin disease or illness, e.g., warts. Therapeutic benefits may also be achieved by the eradication or improvement of one or more physiological signs associated with the underlying disorder, such that improvement is observed in the patient, even if the patient would still suffer from the underlying disorder. Treatment may include the diagnosis of a health condition, e.g., warts.

[0055] As used herein, the term "cantharidin" generally refers to compounds having the following structures, or derivatives thereof having similar activity with respect to protein phosphatase inhibition. Compounds in which boron is substituted in place of carbon will also be considered cantharidins. Compounds having different proportions of carbon isotopes will also be considered cantharidins (for example, C14 Compounds with different proportions of oxygen isotopes would also be considered cantharidins (for example, O 17 Compounds with different proportions of hydrogen isotopes would also be considered cantharidins (H 3 Compounds having different proportions of carbon, oxygen, hydrogen isotopes, or combinations thereof will also be considered cantharidin. Cantharidin may contain one or more unstable radioactive elements. Cantharidin does not have to contain one or more unstable radioactive elements. Cantharidin may contain pharmaceutically acceptable salts. Cantharidin does not have to contain pharmaceutically acceptable salts. [ka] [ka]

[0056] Non-limiting examples of cantharidin derivatives include cantharidic acid, norcantharidin, parasonin, endotal, fostriesin, and okadaic acid (see above). Other species that have or are expected to be broken down or metabolized to species containing exo,exo-disparic acid, with or without substitution, would also be considered "cantharidin." Other compounds that serve as inhibitors of phosphoproteins 1, 2A, 4, or 5 would also be considered "cantharidin." Cantharidin preparations may contain cantharidin alone or in combination with one or more other species, such as one or more excipients. [ka]

[0057] Non-limiting examples of substituted exo,exo-dicarboxylates include: 2,3-trimethylene anhydride; unsubstituted anhydride; 5,6-dehydro-anhydride; endo-5-methyl; mono-4-chloralinide; endo-5-carboxy; 5,6-dehydro; 2-bromo; endo-5-hydroxymethyl.

[0058] Cantharidin may be produced by one or more blister beetle insects, including, but not limited to, Spanish fly, false blister beetle, red-winged beetle, soldier beetle, Chinese blister beetle, or a combination thereof. The amount of cantharidin produced per blister beetle insect may be about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, or about 6 mg. The amount of cantharidin produced per insect of the family Meloidae may be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 mg or more. The amount of cantharidin produced per insect of the family Meloidae may be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6 mg or less. Cantharidin may be produced by biosynthesis. In some cases, the biosynthesis of cantharidin derivatives, norcantharidin, cantharidiimide, or norcanthalimide, produces similar therapeutic effects in the user or patient. Alternatively, cantharidin can be produced entirely synthetically or semi-synthetically, for example, using naturally occurring raw materials.

[0059] As used herein, the term “excipient” generally refers to an inert component as part of a formulation. Examples of excipients include, but are not limited to, dyes, flavors, binders, emollients, fillers, lubricants, antioxidants, skin penetration enhancers, and preservatives. In some cases, excipients may be selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, crystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In some embodiments, excipients may be salicylic acid and / or podophyllotoxin.

[0060] As used herein, the term “user” generally refers to her or himself, or another individual, for example, an individual using a delivery device or system to administer a cantharidin formulation to a subject.

[0061] As used herein, the term “Subject” generally refers to an individual who is suspected of having, diagnosed with, or under treatment for a disease (e.g., a skin disease). For example, a Subject may be under treatment by another individual or may be administered the cantharidin formulations of this Disclosure by himself or by another individual, such as a healthcare provider (e.g., a physician, a physician performing the procedure, a physician's assistant, a nurse) or a care provider. A Subject may include asymptomatic and symptomatic individuals, such as patients. In some cases, a Subject may be diagnosed with a skin disease.

[0062] As used herein, the term “about” means within plus or minus (+ / -) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the indicated amount.

[0063] In some embodiments, the disclosure provides cantharidin formulations for treating skin conditions, diseases and / or disorders, such as skin warts. Cantharidin formulations may contain a therapeutically effective amount of cantharidin.

[0064] In general, compositions containing cantharidin are administered topically. For example, a composition may be administered to a specific site of a target, such as the skin, rather than systemically. In some such cases, a topically administered composition will be therapeutically effective at or around the site of administration, but not therapeutically effective elsewhere. In some embodiments, a composition is administered topically to the skin, and after topical administration, cantharidin is present in relatively small amounts systemically (e.g., plasma concentrations of approximately 3.3 ng / mL or less, approximately 2.5 ng / mL or less, approximately 1 ng / mL or less) or not present at all. In some cases, a cantharidin preparation for topical delivery contains cantharidin and excipients suitable for topical delivery of cantharidin to the target. The amount of cantharidin in a cantharidin preparation is not particularly limited. The amount of the preparation will be limited to a therapeutic amount. In some circumstances, it is advantageous to include an amount of cantharidin far exceeding the nominal therapeutic amount, for example, to maximize the concentration of cantharidin. In other embodiments, it would be advantageous to limit the amount of cantharidin based on toxicity to the target.

[0065] In some cases, cantharidin preparations may contain at least about 50% (w / v) cantharidin, at least about 10% (w / v) cantharidin, at least about 5% (w / v) cantharidin, at least about 1% (w / v) cantharidin, at least about 0.75% (w / v) cantharidin, at least about 0.5% (w / v) cantharidin, at least about 0.1% (w / v) cantharidin, at least about 0.01% (w / v) cantharidin, or at least about 0.001% (w / v) cantharidin. Cantharidin may be present in amounts between about 0.001% and 50% by weight, or between about 1% and 10% by weight, or between about 0.001% and 1% by weight. Cantharidin may be present in amounts of approximately 0.001, 0.01, 0.1, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or approximately 15 grams per ml. Cantharidin may be present in amounts of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15 grams or more per ml. Cantharidin may be present in amounts of approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 grams or less per ml.

[0066] The cantharidin preparation has concentrations of approximately 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5.0 mg / mL, 5.1 mg / mL, 5.2 mg / mL, 5.3 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.6 mg / mL, 5.7 mg / mL, 5.8 mg / mL, 5.9 mg / mL, 6.0 mg / mL, 6.1 mg / mL, 6.2 mg / mL, 6.3 mg / mL, 6.4 mg / mL, 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, 7.5 mg / mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL, 8.3 mg / mL, 8.4 mg / mL, 8.5 mg / mL, 8.6 mg / mL, 8.7 mg / mL, 8.8 mg / mL, 8.9 mg / mL, 9.0 mg / mL, 9.1 mg / mL, 9.2 mg / mL, 9.3 mg / mL, 9.4 mg / mL, 9.5 mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10.0 mg / mL, 10.1 mg / mL, 10.2 mg / mL, 10.3 mg / mL, 10.4 mg / mL, 10.5 mg / mL, 10.6 mg / mL, 10.7 mg / mL, 10.8 mg / mL, 10.9mg / mL, 11.0mg / mL, 11.1mg / mL, 11.2mg / mL, 11.3mg / mL, 11.4mg / mL, 11.5mg / mL, 11.6mg / mL, 11.7mg / mL, 11.8mg / mL, 11.9mg / mL, 12.0mg / mL, 12.1mg / mL, 12.2mg / mL, 12.3 mg / mL, 12.4mg / mL, 12.5mg / mL, 12.6mg / mL, 12.7mg / mL, 12.8mg / mL, 12.9mg / mL, 13.0mg / mL, 13.1mg / mL, 13.2mg / mL, 13.3mg / mL, 13.4mg / mL, 13.5mg / mL, 13.6mg / mL, 13.7m The cantharidin may have concentrations of g / mL, 13.8 mg / mL, 13.9 mg / mL, 14.0 mg / mL, 14.1 mg / mL, 14.2 mg / mL, 14.3 mg / mL, 14.4 mg / mL, 14.5 mg / mL, 14.6 mg / mL, 14.7 mg / mL, 14.8 mg / mL, 14.9 mg / mL, 15.0 mg / mL, 15.5 mg / mL, 16.0 mg / mL, 16.5 mg / mL, 17.0 mg / mL, 17.5 mg / mL, 18.0 mg / mL, 18.5 mg / mL, 19.0 mg / mL, 19.5 mg / mL, or 20.0 mg / mL (milligrams (mg) cantharidin / milliliter (mL) formulation). In some cases, cantharidin concentrations range from 0.5 milligrams (mg) to 20 mg per milliliter (ml), or from 1 mg to 10 mg per ml.

[0067] Alternatively, the cantharidin preparation is at least about 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.1 mg / mL, 2.2 mg / mL, 2.3 mg / mL, 2.4 mg / mL, 2.5 mg / mL, 2.6 mg / mL, 2.7 mg / mL, 2.8 mg / mL, 2.9 mg / mL, 3.0 mg / mL, 3.1 mg / mL, 3.2 mg / mL, 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, 3.8 mg / mL, 3.9 mg / mL, 4.0 mg / mL, 4.1 mg / mL, 4.2 mg / mL, 4.3 mg / mL, 4.4 mg / mL, 4.5 mg / mL, 4.6 mg / mL, 4.7 mg / mL, 4.8 mg / mL, 4.9 mg / mL, 5.0 mg / mL, 5.1 mg / mL, 5.2 mg / mL, 5.3 mg / mL, 5.4 mg / mL, 5.5 mg / mL, 5.6 mg / mL, 5.7 mg / mL, 5.8 mg / mL, 5.9 mg / mL, 6.0 mg / mL, 6.1 mg / mL, 6.2 mg / mL, 6.3 mg / mL, 6.4 mg / mL, 6.5 mg / mL, 6.6 mg / mL, 6.7 mg / mL, 6.8 mg / mL, 6.9 mg / mL, 7.0 mg / mL, 7.1 mg / mL, 7.2 mg / mL, 7.3 mg / mL, 7.4 mg / mL, 7.5 mg / mL, 7.6 mg / mL, 7.7 mg / mL, 7.8 mg / mL, 7.9 mg / mL, 8.0 mg / mL, 8.1 mg / mL, 8.2 mg / mL, 8.3 mg / mL, 8.4 mg / mL, 8.5 mg / mL, 8.6 mg / mL, 8.7 mg / mL, 8.8 mg / mL, 8.9 mg / mL, 9.0 mg / mL, 9.1 mg / mL, 9.2 mg / mL, 9.3 mg / mL, 9.4 mg / mL, 9.5 mg / mL, 9.6 mg / mL, 9.7 mg / mL, 9.8 mg / mL, 9.9 mg / mL, 10.0 mg / mL, 10.1 mg / mL, 10.2 mg / mL, 10.3 mg / mL, 10.4 mg / mL, 10.5 mg / mL, 10.6 mg / mL, 10.7 mg / mL, 10.8mg / mL, 10.9mg / mL, 11.0mg / mL, 11.1mg / mL, 11.2mg / mL, 11.3mg / mL, 11.4mg / mL, 11.5mg / mL, 11.6mg / mL, 11.7mg / mL, 11.8mg / mL, 11.9mg / mL, 12.0mg / mL, 12.1mg / mL, 12 .2mg / mL, 12.3mg / mL, 12.4mg / mL, 12.5mg / mL, 12.6mg / mL, 12.7mg / mL, 12.8mg / mL, 12.9mg / mL, 13.0mg / mL, 13.1mg / mL, 13.2mg / mL, 13.3mg / mL, 13.4mg / mL, 13.5mg / mL, 13 It may have cantharidin concentrations of 0.6 mg / mL, 13.7 mg / mL, 13.8 mg / mL, 13.9 mg / mL, 14.0 mg / mL, 14.1 mg / mL, 14.2 mg / mL, 14.3 mg / mL, 14.4 mg / mL, 14.5 mg / mL, 14.6 mg / mL, 14.7 mg / mL, 14.8 mg / mL, 14.9 mg / mL, 15.0 mg / mL, 15.5 mg / mL, 16.0 mg / mL, 16.5 mg / mL, 17.0 mg / mL, 17.5 mg / mL, 18.0 mg / mL, 18.5 mg / mL, 19.0 mg / mL, 19.5 mg / mL, or 20.0 mg / mL (mg cantharidin / mL formulation). In some situations, cantharidin preparations may have cantharidin concentrations of approximately 40 mg / mL, 30 mg / mL, 20 mg / mL, 10 mg / mL, 5 mg / mL, or less than 1 mg / mL.

[0068] The cantharidin used in the formulation may be of sufficient purity to induce a therapeutic effect without toxicity. The purity of the cantharidin used in the formulation may be between 50% and 100%. The purity of the cantharidin used may be approximately 70%, 80%, 90%, 95%, 98%, 99%, or 99.9% or higher.

[0069] In some embodiments, cantharidin can be formulated into solid, semi-solid, gel, or liquid preparations suitable for topical or local administration, such as gels, water-soluble jellies, creams, lotions, suspensions, solutions, foams, powders, slurries, ointments, oils, capsules, tablets, pastes, suppositories, sprays, emulsions, saline solutions, or dimethyl sulfoxide (DMSO)-based solutions. High-density carriers may provide prolonged exposure to the active ingredient in the area. In contrast, solvent / solution formulations may provide more rapid exposure of cantharidin to the selected area.

[0070] Cantharidin formulations may also include suitable solid, semi-solid, gel, or liquid-phase carriers or excipients, which are compounds that can provide increased penetration of therapeutic molecules across the skin's stratum corneum permeability barrier or alter their delivery. Examples of such carriers and excipients include, but are not limited to, destructive agents (e.g., bases, acids, oxidizing agents), crosslinking agents (e.g., formalin or formaldehyde), wetting agents (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0071] Cantharidin preparations may contain acids or combinations of acids, including but not limited to salicylic acid, trichloroacetic acid, hydrochloric acid, formic acid, squalic acid, or nitric acid. Cantharidin preparations may contain podophyllotoxin. Cantharidin preparations may contain zinc oxide. Cantharidin preparations may contain immunotherapeutic agents such as imiquimod, 2,4-dinitrochlorobenzene, and / or Candida antigen. Cantharidin preparations may contain chemotherapeutic agents such as bleomyosin, podophyllotoxin, and / or fluorouracil. Cantharidin preparations may contain oxidizing agents such as hydrogen peroxide.

[0072] Cantharidin formulations may contain solubilizers to ensure good solubilization and / or dissolution of cantharidin and to minimize precipitation of cantharidin in the formulation. Solubilizers may be added to increase the solubility of cantharidin and / or to maintain the composition as a stable or homogeneous solution, emulsion, or dispersion.

[0073] Examples of suitable solubilizers include, but are not limited to, one or more of the following: alcohols and polyols such as acetone, ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and its isomers, glycerol, pentaerythritol, sorbitol, mannitol, transktol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives; ethers of polyethylene glycol having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycoflor) or methoxyPEG; and 2-pylori. Amides and other nitrogen-containing compounds such as 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, and water.

[0074] Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, polyethylene glycol 200-100, glycoflor, transktol, propylene glycol, dimethyl isosorbide, sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycoflor, and propylene glycol.

[0075] The amount of a given solubilizer may be limited to a biotolerable amount. In some situations, for example, to maximize the concentration of the drug, it may be advantageous to include an amount of solubilizer exceeding the biotolerable amount, and the excess solubilizer is removed before providing the composition to the subject using conventional techniques such as distillation or evaporation. The solubilizer, if present, may be in a weight ratio of 10% by weight, 25% by weight, 50% by weight, 100% by weight, or up to about 200% by weight, based on the combined weight of cantharidin and other excipients. Alternatively, substantially small amounts of solubilizer may also be used, such as 5% by weight, 2% by weight, or 1% by weight or less of the cantharidin preparation. In some examples, the solubilizer may be present in amounts of about 1% by weight to about 100% by weight, or about 5% by weight to about 25% by weight, of the cantharidin preparation. In some cases, the cantharidin preparation contains less than a biotolerable amount.

[0076] Cantharidin formulations may contain one or more film-forming agents. Cantharidin formulations may not contain one or more film-forming agents. Some examples of film-forming agents may include, but are not limited to, nitrocellulose, nitrocellulose derivatives, polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose, and other film-forming agents or combinations thereof. Film-forming agents may be soluble in solvents. Film-forming agents may be soluble in one or more solvents. Cantharidin formulations may contain one or more solvents. Solvents include ethanol, acetone, methanol, isopropyl alcohol, butyl alcohol, pentanol, ether, water, dimethyl sulfoxide, ethyl lactate, ethyl acetate, butyl acetate, isopropanol, acetonitrile, food-grade oils (e.g., olive oil, canola oil, sunflower oil), wax-based chlorobutanol, beeswax, lanolin, petrolatum, silicone oil, or combinations thereof, or other solvents. In some embodiments, the solvent is a pharmaceutically acceptable solvent. In some cases, the solvent is not diethyl ether, or does not contain it. The solvent may be acetone. In some embodiments, the solvent includes acetone and alcohol (e.g., ethanol). The cantharidin formulation may contain one or more plasticizers. The cantharidin formulation may not contain one or more plasticizers. Examples of such plasticizers may include, but are not limited to, camphor and castor oil. The cantharidin formulation may contain one or more water-mediated polymerization agents. The cantharidin formulation may not contain one or more water-mediated polymerization agents. Examples of water-mediated polymerization agents may include, but are not limited to, 2-octyl cyanoacrylate and butyl cyanoacrylate. In some cases, the inclusion of film-forming agents, plasticizers, water-mediated polymerization agents, or combinations thereof provides the final cantharidin formulation with viscosity, flexibility, durability, rigidity, robustness, and / or film-forming properties.

[0077] In some cases, one or more film-forming agents are present in the cantharidin preparation at a weight-to-volume concentration between approximately 0.1% and approximately 10%. In some cases, one or more film-forming agents are present in the cantharidin preparation at a weight-to-volume concentration of approximately 1.25%. In some cases, one or more film-forming agents are present in the cantharidin preparation at a weight-to-volume concentration of approximately 2%. In some cases, one or more film-forming agents are present in the cantharidin formulation at a weight-to-volume concentration of approximately 0.001, 0.01, 0.1, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 21, 22, 23, 24, or 25%. In some cases, one or more film-forming agents are present in the cantharidin formulation at a weight-to-volume concentration greater than approximately 0.001, 0.01, 0.1, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 21, 22, 23, 24, or 25% or more. In some cases, one or more film-forming agents are present in the cantharidin formulation at a weight-to-volume concentration less than approximately 0.001, 0.01, 0.1, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 21, 22, 23, 24, or 25% or less.

[0078] In some cases, one or more solvents are present in the cantharidin preparation at a weight-to-volume concentration of approximately 10% to approximately 95%. In some cases, one or more solvents are present in the cantharidin preparation at a weight-to-volume concentration of approximately 13%. In some cases, one or more solvents are present in the cantharidin preparation at a weight-to-volume concentration of approximately 87%. In some cases, one or more solvents are present in the cantharidin preparation at a weight-to-volume concentration of approximately 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%. In some cases, one or more solvents are present in the cantharidin preparation at a weight-to-volume concentration greater than approximately 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95% or more. In some cases, one or more solvents are present in the cantharidin formulation at a weight-to-volume concentration less than approximately 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95%.

[0079] When applied to the skin, cantharidin solutions can dry rapidly within, for example, 1 second, 10 seconds, 30 seconds, 1 minute, 5 minutes, or 10 minutes. In the example, the assay used to evaluate the drying time of the cantharidin preparation involves evenly applying 4 microliters of the cantharidin preparation to a 3 mm diameter circle of skin using a pipette. In the example, the cantharidin preparation dries in less than 2 minutes or 30 seconds.

[0080] In some cases, one or more plasticizers are present in the cantharidin formulation at a weight-to-volume concentration between approximately 0.001% and approximately 5%. In some cases, no plasticizers are present in the cantharidin formulation. In some cases, one or more plasticizers are present in the cantharidin formulation at a weight-to-volume concentration of approximately 5% or less. In some cases, plasticizers are present in the cantharidin formulation at weight-to-volume concentrations of approximately 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5%. In some cases, plasticizers are present in cantharidin formulations at weight-to-volume concentrations greater than approximately 0.001, 0.01, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% or more. In some cases, plasticizers are present in cantharidin formulations at weight-to-volume concentrations less than approximately 0.001, 0.01, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% or less.

[0081] Cantharidin preparations may contain dyes. Cantharidin preparations may contain one or more dyes. Cantharidin preparations do not need to contain dyes. Dyes may be acridine, anthraquinone, arylmethane, azo, diazonium, nitro, phthalocyanine, quinoneimine, tetrazolium, thiazole, xanthene, acid, base, direct, mordant, natural or solvent dye, used in concentrations sufficient to adjust the color of the cantharidin preparation.

[0082] The pigments are: acridine orange, acriflavin, anthracene blue SWR, alizarin, alizarin red S (moldanto red 3), nucleaf fast red, auramine O, chromoxanthan cyanine R, pararosanilin, rosanilin, magenta II, new fuchsin, methyl violet 2B, methyl violet 6B, crystal violet, Hoffmans violet, methyl green, ethyl green, acid fuchsin (acid violet 19), fast red B, Fast Blue B, diazonium chloride, diazonium sulfate, alkyl diazonium sulfate, diazonium chloride, diazonium fulvorate, or diazonium benzenesulfonate, picric acid, Alcian Blue, Luxol Fast Blue, Toluidine Blue O, thionine, Azure A, Azure B, Azure C, Neutral Red, Safranin O, Gallocyanine, Galamine Blue, Iodonitrotetrazolium, Nitrobluetetrazolium, Thioflavin T, Pyronin Y, Pyro Nin B, Rhodamine B, Maltius Yellow (Acid Yellow 24), Eosin Y (Acid Red 87), Beebrich Scarlet (Acid Red 66), Sulfonated Paralosanillin (Basic Red 9), Paralosanillin (Basic Red 9), Methylene Blue (Basic Blue 9), Congo Red (Direct Red 28), Ellie Garnet (Direct Red 10), Sirius Red F3B (Direct Red 80), Hematein (Natural Black 1), Romoxanthan Cyanine R (Moldant Blue 3), Celestine Blue B (Moldant Blue 14), Kermes (Natural Red 3), Carmine (Natural Red 3), Lac (Natural Red 25), Hematine (Natural Black 1), Saffron (Natural Yellow 6), Sudan III (Solvent Red 23), Sudan IV (Solvent Red 24), Oil Red O (Solvent Red 27), Sudan Black B (Solvent Black 3), or others.

[0083] The pigment may contain phase-change pigments. The pigment may contain multiple phase-change pigments. The pigment does not have to contain phase-change pigments. Some examples of phase-change pigments are D&C Orange, NeoZapon Red 492, Orasol Red G, Direct Brilliant Pink B, Direct Red 3BL, Suprano Brilliant Red 3BW, Lemon Yellow 6G, Lightfast Yellow 3G, Eisenspyron Yellow C-GNH, Bemacrom Yellow GD Sub, Cartasol Brilliant Yellow 4GF, Sibanon Yellow 2G, Orasol Black RLI, Orasol Black CN, Savinyl Black RLSN, Pyrazole Black BG, Morfast Black 101, and Diazo. This may include, but is not limited to, colors such as: Luxor Black RN, Thermoplast Blue 670, Orasol Blue GN, Savvinyl Blue GLS, Luxor Fast Blue MBSN, Sebron Blue 5GMF, Bath Acid Blue 750, Keyplast Blue, Neo Zapon Black X51, Classic Solvent Black 7, Sudan Blue 670, Sudan Yellow 146, Sudan Red 462, Neptune Red Base NB543, Neopen Blue FF-4012, Fat Sol Black BR, Molton Moplas Magenta 36, ​​or others.

[0084] The dye may include the role of an indicator dye. The dye may include multiple indicator dyes. The dye may not include any indicator dyes. Some examples of indicator dyes may include, but are not limited to, D&C violet, isosulfan blue, methylene blue, methyl red, methyl orange, Congo red, alizarin yellow, bromocresol green, gentian violet, or others. The dye may include one or more phase-change dyes and one or more indicator dyes or a combination thereof. The indicator dye(s) may be used in a concentration sufficient to define the boundaries of the area treated with the cantharidin preparation.

[0085] Cantharidin preparations may contain fluorescent dyes. Cantharidin preparations may contain multiple fluorescent dyes. Cantharidin preparations do not need to contain fluorescent dyes. Fluorescent dyes may indicate the presence of minerals (e.g., magnesium, calcium, zinc, copper, iron, lead, cadium, mercury, nickel, cobalt, aluminum, or lanthanides). Fluorescent dyes may indicate the presence of magnesium. Fluorescent dyes may indicate the presence of intracellular magnesium. Cantharidin preparations may contain fluorescent dyes that fluoresce under ultraviolet light. Examples of fluorescent indicators that fluoresce under ultraviolet light may include, but are not limited to, mag-indo-1 or mag-fluo-2. Cantharidin preparations may contain fluorescent dyes that fluoresce under visible light. Examples of fluorescent indicators that fluoresce under visible light may include, but are not limited to, magnesium green or mag-fluo-4.

[0086] Cantharidin preparations may contain one or more fluorescent dyes, one or more dyes, or a combination thereof. In some cases, one or more fluorescent dyes or one or more dyes were present in the cantharidin preparation at approximately 0.00001, 0.00005, 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 It is present at weight-to-volume concentrations of 0.9, 1, or 10%. In some cases, one or more fluorescent dyes or one or more dyes were present in the cantharidin preparation at approximately 0.00001, 0.00005, 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 It is present at weight-to-volume concentrations greater than 0.9, 1, or 10% or more. In some cases, one or more fluorescent dyes or one or more dyes were present in the cantharidin preparation at approximately 0.00001, 0.00005, 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 They are present in weight-to-volume concentrations less than 0.9%, 1%, or 10%. In some cases, one or more fluorescent dyes or dyes are present in the cantharidin preparation in weight-to-volume concentrations between approximately 0.00001% and approximately 1%.In some cases, one or more fluorescent dyes or one or more pigments are present in the cantharidin preparation at a weight-to-volume concentration of approximately 0.005%.

[0087] Cantharidin preparations may contain one or more aversive agents, such as bittering agents or oral deterrents. Bittering agents are an example of flavorants. Bittering agents or oral deterrents may be used to prevent or inhibit oral ingestion of the preparation. Bittering agents or oral deterrents may be used to prevent or inhibit licking and / or ingestion of the preparation before, during, or after application to the skin. Bittering agents or oral deterrents may include, but are not limited to, denatonium (e.g., denatonium benzoate, denatonium sugars), amarogentin, gentiopicrin, sucrose octaacetate, quercetin, brucine, and quacin. Denatonium benzoate, a bittering agent, may be added to cantharidin preparations.

[0088] Aversive agents may be present in cantharidin preparations at concentrations of approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or approximately parts per 20 million (ppm). In some cases, aversive agents are present in cantharidin preparations at concentrations greater than approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ppm or higher. In some cases, aversive agents are present in cantharidin preparations at concentrations less than approximately 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ppm. In some cases, aversive agents are present in cantharidin preparations at concentrations between approximately 0.01 ppm and approximately 20 ppm.

[0089] In some cases, the aversive agent is present in the cantharidin preparation at a weight-to-volume concentration of approximately 0.00001% to approximately 1% of the total liquid volume. In some cases, the aversive agent is present in the cantharidin preparation at a weight-to-volume concentration of approximately 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 1%, or approximately 2%. In some cases, the aversive agent is present in the cantharidin preparation at a weight-to-volume concentration greater than approximately 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 1%, or 2% or more. In some cases, the aversive agent is present in the cantharidin preparation at a weight-to-volume concentration of less than approximately 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.01%, 0.1%, 1%, or 2%. The aversive agent may be present in the cantharidin preparation at a weight-to-volume concentration of approximately 0.0006%. The aversive agent may be present in the cantharidin preparation at a weight-to-volume concentration of approximately 0.0001% to approximately 0.001%.

[0090] Cantharidin formulations may contain one or more pharmaceutically acceptable additives or excipients. Such additives or excipients may include, but are not limited to, antifogging agents, defoaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, isotonic agents, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0091] In some cases, cantharidin preparations were approximately 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7 0.6, approximately 7.7, approximately 7.8, approximately 7.9, approximately 8.0, approximately 8.1, approximately 8.2, approximately 8.3, approximately 8.4, approximately 8.5, approximately 8.6, approximately 8.7, approximately 8.8, approximately 8.9, approximately 9.0, approximately 9.1, approximately 9.2, approximately 9.3, approximately 9.4, approximately 9.5, approximately 9.6, approximately 9.7, approximately 9.8, approximately 9.9, approximately 10.0, approximately 10 It may have a pH of 0.1, approximately 10.2, approximately 10.3, approximately 10.4, approximately 10.5, approximately 10.6, approximately 10.7, approximately 10.8, approximately 10.9, approximately 11.0, approximately 11.1, approximately 11.2, approximately 11.3, approximately 11.4, approximately 11.5, approximately 11.6, approximately 11.7, approximately 11.8, approximately 11.9, or approximately 12.0.As an alternative, cantharidin preparations are available in amounts of at least approximately 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, and 7. 6, approximately 7.7, approximately 7.8, approximately 7.9, approximately 8.0, approximately 8.1, approximately 8.2, approximately 8.3, approximately 8.4, approximately 8.5, approximately 8.6, approximately 8.7, approximately 8.8, approximately 8.9, approximately 9.0, approximately 9.1, approximately 9.2, approximately 9.3, approximately 9.4, approximately 9.5, approximately 9.6, approximately 9.7, approximately 9.8, approximately 9.9, approximately 10.0, approximately 10. It may have a pH of approximately 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, or 12.0.

[0092] Cantharidin formulations may be in liquid form. Liquid forms may have resistance to fluid flow. Liquid forms may have Reynolds numbers of approximately 4000, 3000, 2000, 1500, 1000, 500, 400, 300, 200, or less than 100. Liquid forms may have Reynolds numbers of approximately 0.1, 1, 5, 10, 25, 50, 75, 100, 250, 500, 1000, 1250, 1500, 1750, or approximately 2000. Liquid forms may have Reynolds numbers of approximately 2000, 1750, 1500, 1250, 1000, 500, 400, 300, 250, 200, 150, 100, 75, 50, 25, 10, 5, 1, or less than 0.1.

[0093] In some cases, cantharidin formulations may have Reynolds numbers of approximately 4000, 3000, 2000, 1500, 1000, 500, 400, 300, 200, or less than 100 at a temperature of approximately 25°C. Liquid forms may have Reynolds numbers of approximately 1, 5, 10, 25, 50, 75, 100, 250, 500, 1000, 1250, 1500, 1750, or approximately 2000 at a temperature of approximately 25°C. Liquid forms may have Reynolds numbers of approximately 2000, 1750, 1500, 1250, 1000, 500, 400, 300, 250, 200, 150, 100, 75, 50, 25, 10, 5, or less than 1 at a temperature of approximately 25°C.

[0094] The liquid form may have high viscosity. The liquid form may be substantially viscous so that the liquid cannot splash, drip, flow, discharge, leak, or aerosolize from the applicator unit. The liquid form may be substantially viscous so that the cantharidin formulation remains at the site of the patient or user to whom it was administered. The liquid form may be substantially viscous so that the cantharidin formulation cannot flow, splash, drip, flow, discharge, or leak from the site of the patient or user to whom it was administered.

[0095] One or more gelling agents, such as dextran, nitrocellulose, hydroxypropylcellulose, ethylcellulose, or others, may be added to the liquid form to increase viscosity. The viscosity of the liquid form under ambient conditions (e.g., 25°C) is approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5 ,000, 6,000, 7,000, 8,000, 9,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80 It may be 1,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 200,000, 250,000, 500,000, 1,000,000, 1,500,000, or approximately 2,000,000 centipoise.The viscosity of the liquid form under ambient conditions is approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 3 10, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,00 It may be 0, 7,000, 8,000, 9,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 200,000, 250,000, 500,000, 1,000,000, 1,500,000, or greater than 2,000,000 centipoise.The viscosity of the liquid form under ambient conditions is approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 3 10, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 600, 700, 800, 900, 1,000, 2,000, 3,000, 4,000, 5,000, 6,00 It may be smaller than 0, 7,000, 8,000, 9,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 200,000, 250,000, 500,000, 1,000,000, 1,500,000, or less than 2,000,000 centipoise. In some cases, the viscosity is between approximately 10 centipoise and 10,000 centipoise.

[0096] Cantharidin preparations contain magnesium ions (Mg 2+ Cantharidin preparations may not contain, or may have reduced levels of, manganese ions (Mn 2+ ) or reagents that can generate manganese ions may be absent, or may contain reduced levels thereof. Cantharidin preparations may be absent, or may contain reduced levels thereof, of magnesium ions and manganese ions or reagents that can generate magnesium ions and manganese ions. Mg 2+ and / or Mn 2+Magnesium ions may interact with cantharidin, limiting its activity (e.g., therapeutic efficacy). Cantharidin preparations may contain approximately 30, 20, 15, 10, 5, 4, 3, 2, 1, or approximately 0.1% magnesium ions. Cantharidin preparations may contain approximately 30, 20, 15, 10, 5, 4, 3, 2, 1, or less than 0.1% magnesium ions. Cantharidin preparations may contain magnesium ions between approximately 0.1% and 1%. Cantharidin preparations may contain less than approximately 0.1% magnesium ions. Cantharidin preparations may contain magnesium ions between approximately 5% and 0.1%. Cantharidin preparations may contain magnesium ions. Cantharidin preparations may not contain magnesium ions. For similar reasons, cantharidin preparations may be free of manganese, calcium, sodium, and potassium ions, or may contain reduced levels thereof. For example, a cantharidin preparation may contain approximately 30, 20, 15, 10, 5, 4, 3, 2, 1, or approximately 0.1% manganese ions. A cantharidin preparation may contain approximately 30, 20, 15, 10, 5, 4, 3, 2, 1, or less than 0.1% manganese ions. A cantharidin preparation may contain manganese ions between approximately 0.1% and 1%. A cantharidin preparation may contain less than approximately 0.1% manganese ions. A cantharidin preparation may contain manganese ions between approximately 5% and 0.1%. A cantharidin preparation may contain manganese ions. A cantharidin preparation does not need to contain manganese ions.

[0097] The cantharidin formulations of this disclosure may include other topical agents. These topical agents include, but are not limited to, topical anesthetics, topical analgesics, antibacterial agents, bactericides, disinfectants, antiseptics, antibiotics, antifungal agents, bacteriostatic agents, cleansing agents, anti-inflammatory agents, anti-infective agents (e.g., gentian violet), emollients, astringents, anti-acne agents, antiviral agents, antifungal agents, antifungal agents, antipsoriatic agents, anthelmintics, and steroid hormones such as corticosteroids.Examples of topical medications include Altavax (letapamlin), Amevib (alefacept), Avitagel, Bactroban cream, benzamycin, erythromycin, Botox, cefazolin, dextrose, Chloraprep (chlorhexidine gluconate), clindamycin phosphate, Condilox (pocophyllox), Desonate (desonide), Difarin (adapalene), Dynabac, Elidel, Elibedge (bismodegib), Estrostep, norethindrone acetate, and ethinyl Estradiol, Extina (ketoconazole), Fiasea (azelaic acid), Finevin, Firazyr (icatibant), Gralyz (gabapentin), Folizan (gapabentine enacarbil), hydrochloride, hydrogen peroxide, Iamine, Inbanz, Iontokine, Ivyblock, Claron (sulfacetamide sodium), Lamisil (terbinafine hydrochloride), Rabiv (azphycel-T), Lustra, Luxis (betamethasone valerate), Mentax (butenafine HCl), Me Toro Lotion, Minoxidil, Noritate, Nitrate, Omnicef, Orthotricycle, Norgestimate, Picato (Ingenol Mebutate), Propecia, Protopic (Tacrolimus), Condylox (Podophotoxin), Regranex (Becaprelmin), Renova, Tratinoin, Salagen, Sandalwood Oil, Salicylic Acid, Scrice (Ivermectin), Stelara (Ustekinumab), Sulfamilon, Cilatron (Peginterferon Alpha-2b), Tazola This includes, but is not limited to, cephthaloline fosamil, taromide, trichloroacetic acid, tigacil (tigecycline), vertin (clindamycin phosphate), tretinoin, vergen (sincatechins), verdeso (desonide), vivativ (teravancin), vivativ (teravancin), zeizal (levoctyrizine dihydrochloride), yarvoy (ipilimumab), zelboraf (vemurafenib), and ziclara (imiquimod).

[0098] Cantharidin preparations may have the following components: Table 1: Examples of cantharidin preparations [Table 1] Table 2: Examples of cantharidin preparations that may be useful for treating severely keratinized skin. [Table 2] Table 3: Examples of DMSO-based cantharidin formulations visible under ultraviolet (UV) light that may be useful for treating cosmetic lesions on the face. [Table 3] Table 4: Examples of low-viscosity cantharidin formulations that may be useful for treating larger lesions [Table 4] Table 5: Examples of easily visualized concentrated cantharidin formulations that may be useful when adhesion is the priority. [Table 5] Table 6: Examples of fast-drying cantharidin formulations that may be useful as chemical peels. [Table 6] Table 7: Examples of cantharidin preparations for the treatment of warts and molluscum contagiosum [Table 7] Table 8: Examples of cantharidin preparations [Table 8] Table 9: Examples of cantharidin preparations [Table 9]

[0099] The cantharidin solutions listed in Tables 7-9 can be prepared by the following methods: Acetone, ethanol, and nitrocellulose are added to a glass vial to form a mixture. A stirring bar coated with polytetrafluoroethylene (PTFE) is added, and the mixture may be mixed until a uniform viscous mixture is formed. Castor oil and camphor are added to the mixture and stirred until uniform. A 1% denatonium benzoate solution in ethanol can be added to the glass vial. A 1% gentian violet solution in ethanol can be added to the glass vial. Cantharidin powder with a purity of over 95% can be added to the glass vial. The mixture may be mixed until uniform. Hydroxypropyl cellulose is added, and the mixture may be mixed until it is completely gelled and uniform.

[0100] Another aspect of this disclosure provides a method for delivering a cantharidin formulation to a subject, which may be used to treat a skin condition, disease, and / or disorder, such as a wart or skin lesion. The method for treating a subject may include using an applicator device, system, or kit of this disclosure to deliver a cantharidin formulation to a subject having or suspected of having a skin condition, disease, or disorder, such as a wart.

[0101] The methods disclosed herein include users to whom cantharidin preparations are delivered, or recipients to whom cantharidin preparations are delivered.

[0102] The subject may be diagnosed with a skin disease. This skin disease may cause epithelial warts or other skin lesions. An applicator device may be used to deliver the cantharidin preparation to the epithelial wart or skin lesion. Delivery of the cantharidin preparation may eliminate the epithelial wart or skin lesion from the subject.

[0103] After the cantharidin formulation is delivered to the subject, epithelial warts may be removed from the subject within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, weeks, or months. The cantharidin formulation may be delivered to the subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day, week, or month.

[0104] The amount of cantharidin delivered to a subject in a single dose may be between approximately 0.001 mg and 100 mg, approximately 0.1 mg and 50 mg, approximately 0.1 mg and 10 mg, approximately 0.5 mg and 10 mg, approximately 0.5 mg and 5 mg, approximately 1 mg and 5 mg, or approximately 1 mg and 2 mg.

[0105] The cantharidin formulation delivered to the target may contain at least approximately 0.001% (w / volume), 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, or 50% cantharidin. In some cases, the cantharidin formulation delivered to the target may contain up to approximately 50% (w / v), 40%, 30%, 20%, 10%, or 1% cantharidin.

[0106] The cantharidin formulation delivered to the target may contain approximately 50% (w / v), approximately 20% (w / v), approximately 10% (w / v), approximately 5% (w / v), approximately 1% (w / v), approximately 0.5% (w / v), or approximately 0.1% (w / v) or more of excipients.

[0107] Using a delivery device or system, approximately 0.00 mg / day, 0.01 mg / day, 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 2.5 mg / day, 3.0 mg / day, 3.5 mg / day, 4.0 mg / day, 4.5 mg / day, 5.0 mg / day Cantharidin preparations can be delivered to the target population at doses of up to 20 mg / day, including 5.5 mg / day, 6.0 mg / day, 6.5 mg / day, 7.0 mg / day, 7.5 mg / day, 8.0 mg / day, 8.5 mg / day, 9.0 mg / day, 9.5 mg / day, 10.0 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, or 20 mg / day. Alternatively, use a delivery device or system to administer at least approximately 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 2.5 mg / day, 3.0 mg / day, 3.5 mg / day, 4.0 mg / day, 4.5 mg / day, 5.0 mg / day, 5. Cantharidin preparations can be delivered to the target population in doses of 5 mg / day, 6.0 mg / day, 6.5 mg / day, 7.0 mg / day, 7.5 mg / day, 8.0 mg / day, 8.5 mg / day, 9.0 mg / day, 9.5 mg / day, 10.0 mg / day, 11 mg / day, 12 mg / day, 13 mg / day, 14 mg / day, 15 mg / day, 16 mg / day, 17 mg / day, 18 mg / day, 19 mg / day, or 20 mg / day.

[0108] The delivery devices or systems of this disclosure may be used to deliver cantharidin formulations to a target (for example, to a skin area of ​​a target having or suspected of having warts or skin lesions) from once a day to once a month or more. Alternatively, or in addition thereto, the delivery devices or systems of this disclosure may be used to deliver cantharidin formulations to a target from once a day to once a week. Alternatively, or in addition thereto, the delivery devices or systems of this disclosure may be used to deliver cantharidin formulations to a target at least once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every ten days, once every two weeks, once every three weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once a year or more. Alternatively, or in addition, the cantharidin formulation may be delivered to the subject at least once a day, or twice a day, or three times a day, or four times a day, or five times a day, or six times a day, or seven times a day, or eight times a day, or nine times a day, or ten times a day, or eleven times a day, or twelve times a day, or thirteen times a day, or thirteen times a day, or fifteen times a day, or sixteen times a day, or seventeen times a day, or eighteen times a day, or nineteen times a day, or twenty times a day, or twenty-one times a day, or twenty-two times a day, or twenty-three times a day, or twenty-four times a day, using the delivery device or system of the Disclosure. Alternatively, or in addition, the cantharidin formulation may be delivered to the subject as soon as the skin begins to epithelialize after a previous treatment, using the delivery device or system of the Disclosure. Alternatively, or in addition thereto, the cantharidin formulation may be delivered to the subject using the delivery device or system of the present disclosure as soon as the skin has partially epithelialized after a prior treatment. Alternatively, or in addition thereto, the cantharidin formulation may be delivered to the subject using the delivery device or system of the present disclosure as soon as the skin has fully epithelialized after a prior treatment.

[0109] Cantharidin preparations may be delivered to untreated, previously treated, or further treated skin of a subject using the preparations, delivery devices, or systems of this disclosure. Examples of prior treatments include, but are not limited to, removal of scar tissue, scabs, or keratinized tissue by wound cleansing, scrubbing, immersion, or surgical excision. Prior treatments may also include cryotherapy, cauterization, acid or base application, salicylic acid application, laser, surgical debridement, immersion, hydrogen peroxide, or immunotherapy. Prior treatments may also include adhesive tapes, creams, ointments, solutions, waxes, or hydrophobic barriers to limit the area of ​​skin exposed to the cantharidin preparation. Cantharidin preparations may be used before or concurrently with surgical excision, cryotherapy, cauterization, acid or base application, acid application, laser, surgical debridement, immersion, hydrogen peroxide, immunotherapy, or covering the treatment area with occlusive tape or bandages.

[0110] Cantharidin preparations and associated delivery devices or systems can be used to treat the following: periapical fibrokeratoma, acrodental dermatitis, apicokeratoid fibrosis, actinic keratosis (solar keratosis), adenomatous sebaceous gland, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Buschke-Olendorf syndrome, cervical cancer, cervical dysplasia, senile hemangioma, chronic nodular chondrodermatitis, cutaneous endometriosis, cutaneous leukemia, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, and Liere's disease, cutaneous dendritic cell hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine hemangioma hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevi (including, but not limited to, nevus sebaceous, comedone nevi, Proteus syndrome Becker nevus), epithelioid cell histiocytoma, familial myxoid angiofibroma, fungal skin diseases (including mycoses), granular cell tumors, glucaonoma syndrome, genital warts, ichthyosis (including, but not limited to, common ichthyosis, lamellar ichthyosis, X-linked ichthyosis, exfoliative hyperkeratosis, acquired ichthyosis and palmar keratosis). (and not limited to these), idiopathic guttate hypomelanosis, infantile papulosis, infantile fibromatosis, Kaposi's sarcoma, keloids, keratoacanthoma, keratocystoma, knuckle pad, mole, melanoma, microvenous hemangioma, Morton's neuroma, multifocal lymphangioendothelioma, multinucleated cell angiohistocytoma, multiple cutaneous leiomyoma, mycosis fungoides, cutaneous neuroma, schwannoma, flame nevus, superficial nevus lipoma, thicker skin, palisade encapsulated neuroma, parasitic skin diseases (including scabies, lice infestation, sand flea infestation, and hookwork-related cutaneous larvae migrans, but this is not limited to these). (but not limited to) pityriasis rubra pilaris, hemangiomyoma capillaries, reticular histiocytic neoplasm, porokeratinic eccrine pores and cutaneous nevi, progressive nodular histiocytoma psoriasis (including, but not limited to, erythrodermic psoriasis, palmoplantar psoriasis, palmoplantar pustulosis, tunbus's systemic pustular psoriasis, and geographic tongue), porokeratosis, seborrheic dermatitis, seborrheic keratosis, rhinophyma, solitary cutaneous leiomyoma, spider angioma, targeted hematosclerosing hemangioma, squamous cell carcinoma, tufted hemangioma, venous lake, pigmented urticaria, plaque paramastocytosis or zoular metastasis.

[0111] Other skin conditions, including but not limited to the following, can also be treated with cantharidin preparations: benign epidermal cysts, birthmarks, calluses, cones, eczema, blemishes, moles, pigmentation disorders (drug-induced hyperpigmentation, genetic symmetric pigmentary disorders, genetic general pigmentary disorders, familial progressive hyperpigmentation, Gari-Gari disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron metal discoloration, vitiligo, melanosis, Mukamel syndrome, Venus necklace, anemic nevi, pigmented nevi, Pallister-Killian syndrome, filoid hypomelanosis, focal albinism, reticular pigmentation, cysts of Pilar, white verrucosa, Shivat's polymorphic skin atrophy). Albinism, angiotrophic vascular atrophy, post-inflammatory hyperpigmentation, progressive macular hypomelanosis, pruritus, reticular pigment disorder of the flexures, Kitamura's reticular pigment disorder, Riehl's melanosis, Shah-Wardenburg syndrome, shiitake dermatitis, tar melanosis, titanium metal discoloration, transient neonatal pustular melanosis, vagabond albinism, vasospasmodic macules, Wende-Bacchus syndrome, X-linked reticular plaque, Yemeni deafblind hypopigmentation syndrome), scarring, pedunculated fibroma, tattoo removal, or vitiligo (including, but not limited to, non-segmental vitiligo, and / or segmental vitiligo trichrome vitiligo, quadrichrome vitiligo, and vitiligo poncté).

[0112] Furthermore, cantharidin preparations may be used in the rejuvenation of the epidermis, such as in the exfoliation or peeling of skin in people with sun damage or wrinkles.

[0113] Due to their chemotactic properties, ability to induce cell arrest and apoptosis, foaming agent activity, and other therapeutic outcomes, cantharidin formulations may be useful in combination with surgery, radiotherapy, immunotherapy, small molecule-based, antibody-based, recombinant protein-based, nucleic acid-based, or chemotherapeutic agents. Cantharidin formulations may also be useful as second-line, third-line, or fourth-line treatments for patients who have failed previous therapies. Examples of use of the cantharidin formulations, devices, and methods of this disclosure include: immediately after Mohs microsurgery in the treatment of basal cell carcinoma, or after failure of systemic chemotherapeutic agents in the treatment of mycosis fungoides, or in the treatment of actinic keratosis, or in combination with cryotherapy or destructive therapies such as hydrogen peroxide or acid or ingenol mebutate as first-line treatment in the treatment of porokeratosis or seborrheic keratosis.

[0114] The formulations, delivery devices, or systems of the Disclosure may be used to treat warts, molluscum contagiosum, actinic keratosis, seborrheic keratosis, or other hyperproliferative disorders of the skin that have failed or become resistant to previous treatment. Alternatively, the formulations, delivery devices, or systems of the Disclosure may be used as a first-line treatment. Alternatively, the formulations, delivery devices, or systems of the Disclosure may be used in combination with another first-line treatment.

[0115] Cantharidin preparations can be used to treat patients with cancer. For example, cantharidin preparations can be used to inhibit tumor growth and / or directly kill cancer cells. In some cases, cantharidin preparations can be used to kill cancer stem cells. In some cases, cantharidin preparations can be used to treat benign cancerous lesions. For example, cantharidin preparations can be used to kill cancer cells with a multidrug-resistant phenotype. In some situations, norcantharidin, cantharidimide, or analogs of norcantharidimide or cantharidin may be used instead of cantharidin.

[0116] Cantharidin preparations, devices, systems, and methods may be used for other purposes, such as in the production of autologous or allogeneic skin that can be used for skin grafts, or as a blister model for drug testing, or as an approach for removing residual cancer cells after surgery.

[0117] example

[0118] This example illustrates pharmacokinetic results from a Phase II clinical trial for the treatment of skin lesions caused by molluscum contagiosum. Patients received administration of the cantharidin compositions listed in Table 9 to molluscum contagiosum lesions every 21 days for up to four sessions or until complete clearance. Blood samples for systemic exposure assessment were collected on day 1 before drug application, and at 2 hours (±30 minutes), 6 hours (±1 hour), and 24 hours (±3 hours) after application. The mean age of the subjects was 7 ± 3.5 years. The mean body weight of the subjects was 58 ± 34.6 lb. The mean number of lesions per subject was 43.7 ± 24.2.

[0119] Only one of the 17 subjects had a plasma concentration of cantharidin exceeding the lower limit of quantification (i.e., 2.5 ng / ml). For all subjects, the plasma concentration of cantharidin was less than 3.3 ng / ml at all time points sampled. Furthermore, subjects who (i) were 2 years old, (ii) had more than 100 lesions, (iii) had genital lesions, and (iv) had as many as 2.26 lesions per lb had plasma concentrations of cantharidin below the lower limit of quantification. Table 10 shows the subjects of the clinical trial by sex, age, weight, number of lesions, genital complications, systemic exposure, lesions per pound of subject, mg of composition used per treatment session, mg of composition per lesion, and mg of composition per pound of subject. Table 10: Population statistics and pharmacokinetic data of the target population. [Table 10-1] [Table 10-2] [Table 10-3]

[0120] While certain aspects of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such aspects are provided only as examples. The present invention is not intended to be limited by the specific examples provided herein. Although the present invention has been described with reference to the above specification, the descriptions and figures of the aspects herein are not intended to be constrained. Without departing from the present invention, numerous variations, modifications, and substitutions will come to mind for those skilled in the art. Furthermore, it should be understood that all aspects of the present invention are not limited to the specific descriptions, configurations, or relative proportions described herein, which depend on various conditions and variables. It should be understood that various substitutes for the aspects of the present invention described herein may be used when carrying out the present invention. Accordingly, the present invention is considered to cover any of such substitutes, modifications, variations, or equivalents. The following claims define the scope of the present invention, and the methods and structures within these claims, as well as their equivalents, are intended to be covered thereby.

[0121] While several aspects of the present invention have been described and illustrated herein, those skilled in the art will readily conceive of various other means and / or structures for performing the function and / or obtaining one or more of the results and / or advantages described herein, and each of such variations and / or modifications will be considered within the scope of the present invention. More generally, those skilled in the art will understand that all parameters, dimensions, materials and configurations described herein are illustrative, and that actual parameters, dimensions, materials and / or configurations will depend on the specific application in which the teachings of the present invention are used. Those skilled in the art will recognize many equivalents to the particular aspects of the present invention described herein, or can confirm this by using only routine experimentation. Thus, it should be understood that the aforementioned aspects are presented only as examples, and within the scope of the appended claims and their equivalents, the present invention can be carried out in ways other than those specifically described and claimed. The present invention covers each of the individual features, systems, articles, materials, kits and / or methods described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is included in the scope of the present invention, provided that they are not mutually inconsistent.

[0122] As used herein and in the claims, the indefinite articles "a" and "an" should be understood to mean "at least one" unless otherwise indicated.

[0123] In this specification and in the claims, the phrase “and / or” as used herein should be understood to mean “either or both” of the elements thus combined, i.e., elements that exist together in some cases and elements that exist separately in other cases. Any other elements other than those specifically identified by the “and / or” clause may exist, unless otherwise specified, regardless of whether they are related to the specifically identified elements. Thus, as a non-restrictive example, a reference to “A and / or B” when used in combination with open-ended language such as “includes” may, in one embodiment, mean A without B (optionally including elements other than B); in another embodiment, mean B without A (optionally including elements other than A); in yet another embodiment, mean both A and B (optionally including other elements), and so on.

[0124] Where used herein and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as inclusive, that is, including at least one of the number of elements or the list, but also including multiple, and optionally including additional unlisted items. Only explicitly opposite terms such as “just one” or “exactly one,” or “consisting of” where used in the claims, would refer to including the number of elements or exactly one element of the list. In general, where used herein, the term “or” shall be interpreted only as indicating an exclusive substitution (i.e., “one or the other, but not both”) when preceded by terms of exclusivity such as “either,” “one,” “just one,” or “exactly one.” Where used in the claims, “essentially consisting of” shall have its usual meaning as used in the field of patent law.

[0125] As used herein and in the claims, with respect to a list of one or more elements, the phrase “at least one” should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and all elements specifically listed in the list of elements, nor excluding any combination of elements in the list of elements. Furthermore, this definition allows for the presence of elements other than those specifically identified in the list of elements to which the phrase “at least one” refers, regardless of whether they are related to the specifically identified elements. Therefore, as a non-restrictive example, “at least one of A and B” (or equivalently “at least one of A or B” or equivalently “at least one of A and / or B”) may, in one embodiment, mean at least one (including any number) of A (and optionally including elements other than B) in which B is absent; in another embodiment, at least one (including any number) of B (and optionally including elements other than A) in which A is absent; and in yet another embodiment, at least one (including any number) of A and at least one (including any number) of B (and optionally including other elements), etc.

[0126] In the claims and the above specification, all transitional clauses such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” and “holding” should be understood as open-ended, meaning including but not limited to. Only the transitional clauses “consisting of” and “essentially consisting of” are closed or semi-closed transitional clauses, respectively, as described in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

1. Administering a composition containing cantharidin to at least a portion of a skin lesion; and To leave at least a portion of the composition on the skin lesion for more than approximately 6 hours. A method for treating subjects having skin lesions, including those mentioned above.

2. The method according to any one of the preceding claims, wherein at least a portion of the composition remains in contact with a skin lesion for more than about six hours.

3. The method according to any one of the preceding claims, wherein the composition comprises about 20% (w / w) or less of diethyl ether.

4. The method according to any one of the preceding claims, wherein the composition does not contain diethyl ether.

5. The method according to any one of the preceding claims, wherein the skin lesion is not caused by human papillomavirus.

6. The method according to any one of the preceding claims, wherein the composition remains on a skin lesion for about 12 hours or more.

7. The method according to any one of the preceding claims, wherein the composition remains on a skin lesion for about 18 hours or more.

8. The method according to any one of the preceding claims, wherein the composition remains on a skin lesion for about 24 hours or more.

9. The method according to any one of the preceding claims, wherein the composition remains in the skin lesion until the composition is removed.

10. The method according to any one of claims 1 to 5 and 9, wherein the composition remains on a skin lesion for about 6 hours or more and about 72 hours or less.

11. The method according to any one of claims 1 to 5 and 9, wherein the composition remains on a skin lesion for about 12 hours or more and about 48 hours or less.

12. The method according to any one of claims 1 to 5 and 9, wherein the composition remains on a skin lesion for about 18 hours or more and about 24 hours or less.

13. The method according to any one of the preceding claims, further comprising separating at least a portion of the epidermal tissue of a skin lesion from at least a portion of the skin tissue of the skin lesion.

14. The method according to any one of the preceding claims, wherein during the step of causing the skin tissue to be substantially removed and / or damaged.

15. Administering a composition containing cantharidin to at least a portion of a skin lesion; and At least a portion of the composition remains in the skin lesion, where approximately 10% or more of the cantharidin administered during the administration step penetrates into the skin lesion. A method for treating subjects having skin lesions, including those mentioned above.

16. The method according to any one of the preceding claims, wherein more than 90% of the cantharidin administered during the administration step penetrates into the skin lesion.

17. Administer a composition containing approximately 1.2% (w / v) or less of cantharidin and a non-aqueous solvent to at least a portion of the skin lesion, wherein the vapor pressure of the composition is approximately 210 mg Hg or less at 20°C; and The composition is left in the skin lesion, wherein the composition does not induce blistering in at least a portion of the skin surrounding the skin lesion within at least 12 hours after the administration step. A method for treating subjects having skin lesions, including those mentioned above.

18. Administer a composition containing approximately 1.2% (w / v) or less of cantharidin and a non-aqueous solvent to at least a portion of the skin lesion, wherein the vapor pressure of the composition is approximately 210 mg Hg or less at 20°C; and The composition is left in the skin lesion, wherein the composition induces blisters only on the skin lesion and optionally within approximately 2 mm of the edge of the skin lesion within at least 12 hours after the administration step. A method for treating subjects having skin lesions, including those mentioned above.

19. A method for treating a subject with a skin lesion, comprising administering a composition containing approximately 1.2% (w / v) or less of cantharidin and a non-aqueous solvent to at least a portion of the skin lesion, wherein the vapor pressure of the composition is approximately 210 mg Hg or less at 20°C.

20. A method for treating a subject having a skin lesion, comprising administering a composition containing approximately 1.2% (w / v) or less of cantharidin and a non-aqueous solvent to at least a portion of the skin lesion, wherein the composition contains approximately 20% (w / w) or less of diethyl ether.

21. The method according to any one of the preceding claims, wherein the vapor pressure of the composition is about 200 mg Hg or less at 20°C.

22. The method according to any one of the preceding claims, wherein the composition does not induce blistering in at least a portion of the skin surrounding a skin lesion within 24 hours after the administration step.

23. The method according to any one of the preceding claims, wherein the composition does not induce blistering in the skin within approximately 2 mm of the edge of a skin lesion.

24. The method according to any one of the preceding claims, wherein the composition does not induce blistering in the skin within approximately 5 mm of the edge of a skin lesion.

25. The method according to any one of the preceding claims, wherein the composition does not induce blistering in the skin within approximately 10 mm of the edge of a skin lesion.

26. Administer a composition containing approximately 1.2% (w / v) or less of cantharidin and a non-aqueous solvent to a skin lesion, wherein the vapor pressure of the composition is less than approximately 210 mm Hg at 20°C; To leave at least a portion of the composition in the skin lesion; and To reduce numerous skin lesions by more than 50%. A method for treating subjects having skin lesions, including those mentioned above.

27. The method according to any one of the preceding claims, wherein the vapor pressure of the composition is about 200 mg Hg or less at 20°C.

28. The method according to any one of the preceding claims, further comprising repeating the administration step and the inducing step at least once.

29. The method according to any one of the preceding claims, wherein the number of skin lesions is reduced by approximately 75% or more.

30. The method according to any one of the preceding claims, wherein the number of skin lesions is reduced by approximately 90% or more.

31. The method according to any one of the preceding claims, wherein the number of skin lesions is reduced by about 90% or more after at least one administration step.

32. The method according to any one of the preceding claims, wherein the composition comprises about 1.2% (w / v) or less of cantharidin.

33. The method according to any one of the preceding claims, wherein the composition comprises about 0.9% (w / v) or less of cantharidin.

34. The method according to any one of the preceding claims, wherein the composition comprises about 0.8% (w / v) or less of cantharidin.

35. The method according to any one of the preceding claims, wherein the composition comprises a weight per volume percent of cantharidin of about 0.5 or more and less than 1.

36. The method according to any one of the preceding claims, wherein the composition comprises a weight per volume percent of cantharidin of about 0.6 or more and less than 1.

37. The method according to any one of the preceding claims, wherein the composition comprises a weight per volume percent of cantharidin of about 0.7 or more and about 0.9 or less.

38. The method according to any one of the preceding claims, wherein the composition comprises a film-forming agent.

39. The method according to any one of the preceding claims, wherein the film-forming agent comprises one or more polymers.

40. The method according to any one of the preceding claims, wherein the film-forming agent comprises nitrocellulose, hydroxypropylcellulose, or a combination thereof.

41. The method according to any one of the preceding claims, wherein the composition comprises a non-aqueous solvent.

42. The method according to any one of the preceding claims, wherein the composition comprises an alcohol.

43. The method according to any one of the preceding claims, wherein the composition comprises acetone, ethanol, or a combination thereof.

44. The method according to any one of the preceding claims, wherein the composition comprises about 20% (w / w) or less of diethyl ether.

45. The method according to any one of the preceding claims, wherein the composition does not contain diethyl ether.

46. The method according to any one of the preceding claims, wherein the composition comprises about 10% (w / w) or less of water.

47. The method according to any one of the preceding claims, wherein the composition is water-free.

48. The method according to any one of the preceding claims, wherein the composition comprises a plasticizer.

49. The method according to any one of the preceding claims, wherein the plasticizer comprises oil.

50. The method according to any one of the preceding claims, wherein the plasticizer comprises camphor, castor oil, or a combination thereof.

51. The method according to any one of the preceding claims, wherein the composition comprises a bittering agent.

52. The method according to any one of the preceding claims, wherein the composition comprises an oral deterrent.

53. The method according to any one of the preceding claims, wherein the bittering agent comprises denatonium benzoate.

54. The method according to any one of the preceding claims, wherein the composition comprises a dye.

55. The method according to any one of the preceding claims, wherein the pigment is gentian violet.

56. The method according to any one of the preceding claims, wherein the composition does not contain a solvent having a flash point of less than 4°C.

57. The method according to any one of the preceding claims, wherein the composition does not contain a solvent that tends to form peroxides.

58. The method according to any one of the preceding claims, wherein the composition does not contain a solvent having a vapor pressure of about 185 mm Hg or more at 20°C.

59. The method according to any one of the preceding claims, further comprising administering a second composition containing cantharidin to at least a portion of a skin lesion, wherein the second composition has substantially the same percentage (w / v) of cantharidin as the composition.

60. The method according to any one of the preceding claims, wherein the second composition is administered approximately 17 days or more and approximately 25 days or less after administration of the composition.

61. The method according to any one of the preceding claims, further comprising repeating the administration step.

62. The method according to any one of the preceding claims, further comprising repeating the administration step and the causing step.

63. The method according to any one of the preceding claims, further comprising repeating the administration step two or more times.

64. The method according to any one of the preceding claims, further comprising repeating the administration step and the inducing step two or more times.

65. The method according to any one of the preceding claims, further comprising repeating the administration step three or more times.

66. The method according to any one of the preceding claims, further comprising repeating the administration step and the inducing step three or more times.

67. The method according to any one of the preceding claims, further comprising repeating the administration step for approximately three weeks after the administration step.

68. The method according to any one of the preceding claims, further comprising repeating the administration step and / or the inducing step two or more times over a 12-week period.

69. The method according to any one of the preceding claims, further comprising repeating the administration step and / or the inducing step three times over a 12-week period.

70. The method according to any one of the preceding claims, wherein the skin lesion is removed from the subject within one week after the administration step.

71. The method according to any one of the preceding claims, wherein blisters do not form on at least a portion of the skin surrounding the skin lesion.

72. The method according to any one of the preceding claims, wherein no blisters form on at least a portion of the skin surrounding the skin lesion for at least 12 hours after the administration step.

73. The method according to any one of the preceding claims, wherein no blisters form on at least a portion of the skin surrounding the skin lesion for at least 24 hours after the administration step.

74. The method according to any one of the preceding claims, wherein the skin lesion is caused by the human papillomavirus.

75. The method according to any one of the preceding claims, wherein the skin lesion is not caused by human papillomavirus.

76. The method according to any one of the preceding claims, wherein the skin lesion is from molluscum contagiosum, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer.

77. The method according to any one of the preceding claims, wherein the skin lesion is caused by an infection with molluscum contagiosum.

78. The method according to any one of the preceding claims, wherein the skin lesion is from a skin disorder affecting the epidermis of the skin.

79. The method according to any one of the preceding claims, wherein the composition does not cause scarring after 24 hours of continuous contact with skin lacking skin lesions.

80. The method according to any one of the preceding claims, wherein when the composition is administered in an amount of about 10 μL or less over an area of ​​5 mm in diameter on the skin, it does not produce blisters having a diameter greater than about 20 mm after 24 hours of continuous contact with the skin.

81. The method according to any one of the preceding claims, wherein when a 5 mm droplet of the composition is administered to the skin, it does not produce blisters having a diameter greater than about 20 mm after 24 hours of continuous contact with the skin.

82. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 3.3 ng / ml or less at least 2 hours after the administration step.

83. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 2.5 ng / ml or less at least 2 hours after the administration step.

84. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is about 1 ng / ml or less at least 2 hours after the administration step.

85. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 3.3 ng / ml or less at least 6 hours after the administration step.

86. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 2.5 ng / ml or less at least 6 hours after the administration step.

87. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is about 1 ng / ml or less at least 6 hours after the administration step.

88. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 3.3 ng / ml or less at least 24 hours after the administration step.

89. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 2.5 ng / ml or less at least 24 hours after the administration step.

90. The method according to any one of the preceding claims, wherein the plasma concentration of cantharidin in the subject is approximately 1 ng / ml or less at least 24 hours after the administration step.

91. The method according to any one of the preceding claims, wherein at least a portion of the composition remains firmly attached to at least a portion of the skin lesion after six hours of normal activity by the subject.

92. The method according to any one of the preceding claims, wherein at least a portion of the composition remains firmly attached to at least a portion of the skin lesion after 12 hours of normal activity by the subject.

93. The method according to any one of the preceding claims, wherein at least a portion of the composition remains firmly attached to at least a portion of the skin lesion after 24 hours of normal activity by the subject.

94. The method according to any one of the preceding claims, wherein the composition comprises a non-aqueous solvent.

95. The method according to any one of the preceding claims, comprising removing at least a portion of the non-aqueous solvent from the composition during and / or after the administration step.

96. The method according to any one of the preceding claims, wherein the removal step comprises evaporating at least a portion of the non-aqueous solvent from the composition during and / or after the administration step.

97. The method according to any one of the preceding claims, wherein at least a portion of the solvent is removed within about one minute of the administration step.

98. The method according to any one of the preceding claims, wherein approximately 10% or more of the administered cantharidin penetrates into at least a portion of the skin lesion.

99. The method according to any one of the preceding claims, wherein approximately 50% or more of the administered cantharidin penetrates into at least a portion of the skin lesion.

100. The method according to any one of the preceding claims, wherein more than 90% of the administered cantharidin penetrates into at least a portion of the skin lesion.

101. A composition, Cantharidin, where the composition comprises about 0.1 to about 1.2 by weight per volume percent of cantharidin; Acetone, where the composition comprises about 55 to about 65 by weight percentage of acetone; Ethanol, where the composition comprises about 25 to about 35 by weight percentage of ethanol; Castor oil, where the composition comprises a weight per weight percentage of castor oil of about 0.5 to about 2; Nitrocellulose, where the composition comprises a weight per weight percentage of nitrocellulose of about 2 to about 10; Hydroxypropyl cellulose, wherein the composition comprises about 0.1 to about 2 by weight percentages of hydroxypropyl cellulose; Camphor, where the composition contains a weight per weight percentage of camphor of about 0.1 to about 2; Denatonium benzoate, where the composition comprises a weight per weight percent of denatonium benzoate of about 0.001 or more and about 0.01 or less; and Gentian violet, where the composition comprises a weight per weight percentage of gentian violet of about 0.0001 or more and about 0.001 or less. The composition comprising the above.

102. A composition according to any one of the preceding claims, comprising about 0.7 or more and about 0.9 or less by weight per volume percent of cantharidin.

103. A composition according to any one of the preceding claims, comprising by weight of approximately 58 or more and approximately 62 or less of acetone per weight percent.

104. A composition according to any one of the preceding claims, comprising by weight per weight percent of ethanol of approximately 28 or more and approximately 32 or less.

105. A composition according to any one of the preceding claims, comprising by weight per weight percent of castor oil of about 1.2 or more and about 1.6 or less.

106. A composition according to any one of the preceding claims, comprising approximately 3 or more and approximately 6 or less by weight percentage of nitrocellulose.

107. A composition according to any one of the preceding claims, comprising by weight per weight percent of hydroxypropyl cellulose of about 0.1 or more and about 2 or less.

108. A composition according to any one of the preceding claims, comprising a weight per weight percentage of camphor of about 0.5 or more and about 1.5 or less.

109. A composition according to any one of the preceding claims, comprising approximately 0.004 or more and approximately 0.008 or less by weight of denatonium benzoate per weight percent.

110. A composition according to any one of the preceding claims, comprising the weight per weight percent of gentian violet of about 0.0002 or more and about 0.0008 or less.

111. A composition according to any one of the preceding claims, comprising approximately 20% (w / v) or less of diethyl ether.

112. A composition according to any one of the preceding claims, which does not contain diethyl ether.

113. A composition according to any one of the preceding claims, which does not contain a solvent having a flash point of less than 4°C.

114. A composition according to any one of the preceding claims, which does not contain a solvent that tends to form peroxides.

115. A composition according to any one of the preceding claims, which does not contain a solvent having a vapor pressure of approximately 185 mm Hg or more at 20°C.

116. A composition according to any one of the preceding claims, comprising approximately 10% (w / w) or less of water.

117. A composition according to any one of the preceding claims, which does not contain water.

118. A method for treating a skin lesion caused by molluscum contagiosum infection, comprising administering a composition according to any one of the preceding claims to at least a portion of the skin lesion.

119. A composition according to any one of the preceding claims, comprising a disposable applicator device.

120. The method according to any one of the preceding claims, wherein the composition comprises about 10% (w / w) or less of diethyl ether.

121. The method according to any one of the preceding claims, wherein the vapor pressure of the composition is less than about 210 mm Hg at 20°C.

122. The method according to any one of the prior claims, wherein the subject is approximately 15 years of age or younger.

123. The method according to any one of the preceding claims, wherein the weight of the object is approximately 100 lb or less.

124. The method according to any one of the preceding claims, wherein the subject has skin lesions of approximately 0.1 or more per pound.

125. The method according to any one of the preceding claims, wherein the administration step comprises administering about 0.75 mg or more of the composition per pound of subject.

126. The method according to any one of the preceding claims, wherein the administration step includes administering approximately 3 mg or more of the composition to a skin lesion.

127. The method according to any one of the preceding claims, wherein the administration step includes administering cantharidin at a dose of approximately 0.01 mg or more and approximately 0.5 mg or less per skin lesion.

128. The method according to any one of the preceding claims, wherein the skin lesion is located in the area of ​​the genital organs of the subject.

129. A composition according to any one of the preceding claims, comprising approximately 10% (w / w) or less of diethyl ether.

130. A composition according to any one of the preceding claims, comprising approximately 5% (w / w) or less of diethyl ether.

131. A composition according to any one of the preceding claims, wherein the vapor pressure of the composition is less than about 210 mm Hg at 20°C.

132. A composition comprising cantharidin and a solvent, wherein the vapor pressure of the composition is less than about 210 mm Hg at 20°C.

133. A composition according to any one of the preceding claims, which, when in contact with skin and / or skin lesions, does not substantially remove and / or damage skin tissue.

134. A composition according to any one of the preceding claims, which does not cause scarring when in continuous contact for at least 24 hours with skin lacking skin lesions.

135. The composition according to any one of the preceding claims, which does not cause blisters in at least a portion of the skin surrounding the skin lesion.

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