Device and method for treatment of body surface disorder

Abstract

To provide an applicator device, a kit, a system, and a method for using such a device for treating one or more body surface conditions (such as warts, Molluscum contagiosum, conjunctivitis, otitis).SOLUTION: An applicator device 1 may facilitate topical administration of a controllable amount of a pharmaceutical composition to a desired area of an affected body surface (e.g., skin, eye, ear, nose, mouth, anus, vagina). The applicator device includes an ampule 40 containing the pharmaceutical composition, the ampule being positioned within a tube 50. Squeezing the tube breaks the ampule and may release the pharmaceutical composition. The applicator device includes a filter 30 that permits passage of fluid and inhibits passage of broken ampule shards. The applicator device includes a dispensing tip through which the pharmaceutical composition passes.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 520,504, filed June 15, 2017, and entitled "Devices and Methods for the Treatment of Cutaneous Disorders," and also claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 615,429, filed January 9, 2018, and entitled "Devices and Methods for the Treatment of Cutaneous Disorders," each of which is incorporated by reference herein in its entirety. Background technology The body surface can be affected by a variety of disorders. For example, many skin disorders produce lesions on the skin. Some of these lesions take the form of epidermal growths on the skin. For example, warts are small epidermal skin growths caused by viral infections, often found on the hands or feet. The most common type of wart is called a common wart, which can be caused by several different strains of human papillomavirus (HPV). On most parts of the body, these warts would be called common warts; on the feet, however, they would be referred to as plantar warts, or, if located on the genitals, as genital warts or condyloma. Other epidermal viral conditions, such as molluscum contagiosum, resemble warts but are caused by distinct viruses. These virus-mediated skin growths are unsightly and pose a significant risk for cancerous transformation and spread, making their removal desirable. Other superficial hyperproliferative disorders resemble warts but are caused by non-viral mechanisms and include seborrheic keratosis, actinic keratosis and porokeratosis.

[0002] Multiple modalities are used for the removal of warts, molluscum contagiosum, and other skin conditions, including cryotherapy; surgical curettage; laser treatment; irritants such as salicylic acid and zinc oxide; acids such as nitric acid and squaric acid; immunotherapies such as imiquimod, 2,4-dinitrochlorobenzene, and Candida antigens; and chemotherapeutic agents such as bleomycin, podophyllotoxin, and 5-fluorouracil. Many of these treatments can be painful, while others can leave disfiguring scars and / or require daily application. However, perhaps most concerning is that many of these skin disorders remain recalcitrant, even after multiple follow-up treatments. Consequently, improved therapies are needed to treat these conditions. Summary of the Invention

[0003] Described herein is an applicator device for dispensing a composition for topical administration to a subject. In some embodiments, the composition may be a pharmaceutical composition. In some embodiments, the applicator device may be used to administer the composition topically to a subject. The applicator device may administer the composition topically to various body surfaces, including, but not limited to, skin, mucous membranes, exposed soft tissues or organs, genitals, penis, vagina, anus, nails, hair, nose, eyes, ears, or mouth, including lips, teeth, tongue, and gums. These body surfaces may be intact, abraded or injured, or exposed due to wounds or surgical exposure.

[0004] Described herein are devices, methods, kits, and systems for treating one or more conditions, such as body surface conditions. A body surface condition is a condition affecting a portion of the body that can be treated through topical administration of a composition onto the body. According to one aspect, an applicator device is used to distribute the composition to an area of ​​the body affected by the condition. The applicator device may be constructed and arranged to deliver a controllable amount of the composition to a specific location on the body without transferring the composition to other areas of the body.

[0005] According to one aspect, the applicator device can produce droplets that can be dispensed onto a body surface without creating physical contact between the applicator device and the body surface. As a result, when administering the composition, the user can avoid contacting the applicator device with the body surface (e.g., avoiding physically disturbing the body surface and / or contaminating the dispenser tip or the pharmaceutical composition), and when administering the pharmaceutical composition, hold the dispenser tip a short distance from the desired treatment site, allowing the pharmaceutical composition to be dispensed onto the body surface. This is in contrast to applicator devices with brush applicators (foam, cloth, or fuzzy) or roll-on heads, which must contact the body surface to administer the composition. Another aspect of this dispenser tip is that it minimizes the surface area and time of exposure of the solution to air, reducing the amount of solvent loss and thereby maintaining the concentration of the solution applied to the body surface compared to other applicator tips.

[0006] Another aspect of the present disclosure provides an applicator device for dispensing a pharmaceutical composition for locally treating a condition. The applicator device may include a tube, an ampoule positioned within the tube, the pharmaceutical composition contained within the ampoule, a dispenser tip attached to the tube, a dispenser tip having a tapered tip, and a filter positioned within the tapered tip of the dispenser tip. The filter may be constructed and arranged to prevent the passage of liquid and broken ampoule fragments having a particle size of at least 150 μm.

[0007] Another aspect of the present disclosure provides an applicator device for dispensing a pharmaceutical composition to locally treat a condition. The applicator device may include: a tube, the pharmaceutical composition contained within the tube, a dispenser tip connected to the tube, and a cap having an opening for receiving the dispenser tip. The cap may have a closed position in which at least a portion of the dispenser tip passes through the opening. The cap may be connected to and positioned over at least a portion of the dispenser tip. When the cap is in the closed position, venting of the dispenser tip is permitted through the opening in the cap. In some embodiments, the applicator device includes an ampoule, and the pharmaceutical composition is contained within the ampoule.

[0008] Another aspect of the present disclosure provides a method of topically administering a pharmaceutical composition to a subject, the method may include: squeezing a tube of the applicator device while a cap is in a closed position covering at least a portion of a dispenser tip of the applicator device to break an ampoule within the tube and release the pharmaceutical composition contained within the ampoule, moving the dispenser tip toward the subject, and dispensing the pharmaceutical composition from the dispenser tip to the subject.

[0009] Another aspect of the present disclosure provides a kit for dispensing a pharmaceutical composition for topically treating a condition. The kit may include multiple applicator devices. Each applicator device may include: a tube, an ampoule located within the tube, the pharmaceutical composition contained within the ampoule, a dispenser tip attached to the tube, a dispenser tip having a tapered tip, and a filter located within the tapered tip of the dispenser tip, wherein the filter is constructed and arranged to allow the passage of fluid and prevent the passage of broken ampoule fragments having a particle size of at least 150 μm. The kit may also include instructions for use. In some embodiments, the kit may include outer packaging that protects the applicator and / or the drug from light and moisture, aids for opening the applicator, and / or promotional materials. The pharmaceutical composition may include cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent.

[0010] Another aspect of the present disclosure provides a method of treating a subject having an affected body surface area, such as, but not limited to, the skin, eyes, ears, mouth, nose, vagina, or anus. The method may include squeezing a tube of an applicator device to break an ampoule in the tube while a cap is in a closed position covering at least a portion of a dispenser tip of the applicator device, releasing the pharmaceutical composition contained within the ampoule. The method may also include moving the dispenser tip toward the affected body surface area of ​​the subject and dispensing the pharmaceutical composition from the dispenser tip onto the affected body surface area.

[0011] According to one aspect, patients receive one treatment every three weeks plus or minus four days (i.e., one treatment every 17-25 days): the first treatment is at week 0, the second treatment is at week 3, the third treatment is at week 6, and the fourth treatment is at week 9.

[0012] One aspect of the present disclosure provides a method for treating a dermatological condition. The method includes applying a pharmaceutical composition to a subject, which may include squeezing a tube of an applicator device to break an ampoule within the tube and release the pharmaceutical composition contained within the ampoule, and dispensing the pharmaceutical composition from a dispenser tip onto multiple skin lesions of the subject. The method may include performing the step of applying the pharmaceutical composition four times, once every 17 to 25 days, wherein the pharmaceutical composition includes cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent.

[0013] Another aspect of the present disclosure provides a method for treating a dermatological condition. The method may include treating multiple skin lesions in a subject by dispensing a pharmaceutical composition from an applicator device onto the skin lesions, wherein the pharmaceutical composition comprises cantharidin and one or more excipients, and wherein treating the skin lesions with the applicator device removes more skin lesions than treating the skin lesions with a stick applicator in the same time period.

[0014] Another aspect of the present disclosure provides a method for treating a dermatological condition. The method may include treating multiple skin lesions in a subject by dispensing a pharmaceutical composition from an applicator device onto the skin lesions. The pharmaceutical composition may include cantharidin and one or more excipients. Treating the skin lesions with the applicator device will remove more skin lesions in the same time period than treating the skin lesions with a stick applicator.

[0015] Another aspect of the present disclosure provides an applicator device for dispensing a pharmaceutical composition for topical administration to a subject. The device may include a tube, a pharmaceutical composition contained within the tube, and a dispenser tip attached to the tube. The dispenser tip may have a tapered tip terminating in a distal opening having an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches.

[0016] Another aspect of the present disclosure provides a method for treating a dermatological condition. The method may include applying a pharmaceutical composition to a subject, which may include squeezing a tube of an applicator device. The applicator device may have a dispenser tip with a tapered tip having an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches at a distal opening. The method may also include dispensing the pharmaceutical composition from the dispenser tip onto multiple skin lesions of the subject.

[0017] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying figures. In cases where the present specification and any document are incorporated by reference containing conflicting and / or inconsistent disclosure, the present specification shall control.

[0018] Non-limiting embodiments of the present invention are described by way of example in connection with the accompanying figures, which are schematic and not intended to be drawn to scale. In the figures, each identical or illustrated nearly identical component is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor are every component of each embodiment of the present invention shown where illustration is not necessary to enable those skilled in the art to understand the invention. In the figures: [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 is a perspective view of an applicator device according to some aspects of the present invention.

[0020] [Figure 2] FIG. 2 is an exploded view of the applicator device of FIG.

[0021] [Figure 3]FIG. 3 is a side view of the applicator device of FIG.

[0022] [Figure 4] 4 is a cross-sectional view of the applicator device of FIG. 3 taken along line 4-4 of FIG.

[0023] [Figure 5] FIG. 5 is a perspective view of a dispenser tip of an applicator device according to some aspects of the present invention.

[0024] [Figure 6] FIG. 6 is a side view of a dispenser tip of an applicator device described herein.

[0025] [Figure 7] 7 is a cross-sectional view of the dispenser tip of FIG. 6 taken along line 7-7 of FIG.

[0026] [Figure 8] FIG. 8 is a detailed view of the enclosed area 8 of the dispenser tip of FIG.

[0027] [Figure 9] FIG. 9 is a detailed view of the enclosed area 9 of the dispenser tip of FIG.

[0028] [Figure 10] FIG. 10 is a perspective view of a filter of an applicator device according to some aspects of the present invention.

[0029] FIG. 10B is a side view of the filter of FIG. 10A.

[0030] FIG. 10C is a plan view of the filter of FIG. 10A.

[0031] [Figure 11] FIG. 11 is a perspective view of a cap of an applicator device according to some aspects of the present invention.

[0032] [Figure 12] FIG. 12 is a side view of the cap of FIG.

[0033] [Figure 13] FIG. 13 is a bottom view of the cap of FIG.

[0034] [Figure 14] 14 is a cross-sectional view of the cap of FIG. 13 taken along line 14-14 of FIG.

[0035] [Figure 15] FIG. 15 is a perspective view of a dispenser tip of an applicator device having multiple vents.

[0036] [Figure 16] 16 is a side view of the dispenser tip of FIG. 15. FIG.

[0037] [Figure 17] FIG. 17 is a plan view of the dispenser tip of FIG.

[0038] [Figure 18] 18 is a side view of the dispenser tip of FIG. 15. FIG.

[0039] [Figure 19] 19 is a cross-sectional view of the dispenser tip of FIG. 18 taken along line 19-19 of FIG.

[0040] [Figure 20] FIG. 20 is a detailed view of the enclosed area 20 of the dispenser tip of FIG.

[0041] [Figure 21] FIG. 21 is a detailed view of the enclosed area 21 of the dispenser tip of FIG.

[0042] [Figure 22] FIG. 22 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a traditional wood stick applicator.

[0043] [Figure 23] FIG. 23 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a conventional wood stick applicator.

[0044] [Figure 24] FIG. 24 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a conventional wood stick applicator.

[0045] [Figure 25] FIG. 25 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a conventional wood stick applicator.

[0046] [Figure 26] FIG. 26 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a conventional wood stick applicator.

[0047] [Figure 27] FIG. 27 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a traditional wood stick applicator.

[0048] [Figure 28] FIG. 28 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a conventional wood stick applicator.

[0049] [Figure 29] FIG. 29 is a graph showing that applying a pharmaceutical composition using a device applicator described herein resulted in greater skin lesion clearance compared to using a conventional wood stick applicator.

[0050] Detailed Description In one set of embodiments, an applicator device for use in dispensing a composition is provided. The applicator device may be used to topically administer the composition to a body surface of a subject. FIG. 1 depicts an illustrative embodiment of applicator device 1 having tube 50 and cap 10. FIG. 2 depicts an exploded view of applicator device 1. In some embodiments, applicator device 1 includes a reservoir 40 (e.g., an ampoule) for holding the pharmaceutical composition. In some embodiments, applicator device 1 includes a dispenser tip 20 and a filter 30. FIG. 3 depicts a side view of applicator device 1, and FIG. 4 is a cross-sectional view of the applicator device of FIG. 3 taken along line 4-4 of FIG. 3. In some embodiments, the applicator device may be used to deliver any suitable composition for topical administration of the composition to a body surface.

[0051] The relative positions of the components of applicator device 1 according to some embodiments can be seen in Figure 4. In some embodiments, ampoule 40 is located within tube 50. In some embodiments, filter 30 is located within dispenser tip 20. In some embodiments, cap 10 has a closed position in which cap 10 covers the distal opening of the dispenser tip. In some embodiments, in the closed position, the cap is removably coupled to dispenser tip 20.

[0052] In some embodiments, the pharmaceutical composition is stored in ampoule 40. Ampoule 40 may be constructed and arranged as a sealed vessel to prevent exposure of the pharmaceutical composition, particularly the active ingredient, to ambient air, which may help preserve the stability of the pharmaceutical composition and / or active ingredient. In some embodiments, the ampoule is made of glass. In some embodiments, the ampoule is made of plastic.

[0053] According to some embodiments, in use, a user may initiate release of the pharmaceutical composition by squeezing tube 50, which causes ampoule 40 to break and results in release of the pharmaceutical composition from the interior of the ampoule. In some embodiments, a user squeezes the tube to break the ampoule by squeezing a paperboard or corrugated cardboard sleeve or other ampoule-breaking device around the tube. Along with the composition being released from the ampoule, the pharmaceutical composition flows from the broken ampoule toward dispenser tip 20. In some embodiments, squeezing the tube may cause the composition to flow out of dispenser tip 20. Filter 30 may be constructed and arranged to allow passage of the pharmaceutical composition while preventing passage of debris from the broken ampoule.

[0054] In some embodiments, the user may leave cap 10 in the closed position when initiating release of the pharmaceutical composition (e.g., when squeezing tube 50 to break ampoule 40). In some embodiments, leaving cap 10 on while the ampoule is broken may help to avoid premature dispensing of the pharmaceutical composition from the dispenser tip. In other embodiments, however, the user may remove cap 10 to initiate release of the pharmaceutical composition. In some embodiments, the unit may be oriented face up, face down, or at an angle when the ampoule is broken.

[0055] In some embodiments, when a user (e.g., a medical professional) is ready to administer the pharmaceutical composition to a subject, the user removes cap 10, exposing the distal opening of dispenser tip 20. The user then moves dispenser tip 20 toward the desired treatment site on the subject's body surface. In some embodiments, the dispenser tip is constructed and arranged so that the user must exert a threshold force on the tubing (e.g., squeeze the tubing) to create a sufficient amount of pressure within the tubing to cause a quantity of the pharmaceutical composition to be expelled out of the dispenser tip. In some embodiments, air may be expelled prior to the pharmaceutical composition, resulting in the creation of an internal vacuum. In some embodiments, gravity alone is sufficient to cause the pharmaceutical composition to flow out of the dispenser tip and onto the subject's body surface.

[0056] In some embodiments, cessation of the force applied to the tube (e.g., the user stops squeezing the tube) may cause the pharmaceutical composition to be drawn back into the dispenser tip. In some embodiments, this movement of the pharmaceutical composition back into the dispenser tip may be caused by the creation of a vacuum inside the tube 50, caused by the expansion of the internal volume of the tube 50 from its initial volume when in a squeezed state to a larger volume when the tube is allowed to return to its original, stress-free shape in the case of squeezing. In some embodiments, this movement of the pharmaceutical composition back into the dispenser tip may be caused or facilitated by the geometry of the dispenser tip, which will be discussed in a later section.

[0057] In some embodiments, the applicator device is capable of generating droplets without making physical contact between the applicator device and the body surface.

[0058] In other embodiments, however, the user may contact the distal end of the dispenser tip with a body surface during administration of the pharmaceutical composition.

[0059] In some embodiments, the user dispenses a quantity of the pharmaceutical composition from the applicator device onto an intermediate applicator, such as a cotton swab stick applicator, a rod, a toothpick, a capillary tube, a cotton ball, or any other suitable applicator, which is then used to apply the pharmaceutical composition to the treatment site.

[0060] In some embodiments, the applicator device may have a dispenser tip. In some embodiments, the dispenser tip is a separate component from the tube. In some embodiments, the dispenser tip is integrally formed with the tube such that the dispenser tip and the tube form a single, integrated component. In some embodiments, the dispenser tip comprises a tapered tip through which the pharmaceutical composition flows. The dispenser tip may have a distal opening through which the pharmaceutical composition exits the applicator device.

[0061] One illustrative embodiment of a dispenser tip is shown in Figure 5. The dispenser tip 20 may include a tapered tip 22, which may include an opening 23. In some embodiments, the opening 23 is at the distal end of the tapered tip 22.

[0062] Figures 6-9 provide dimensions (shown in inches for distances and degrees for angles) for one illustrative embodiment of a dispenser tip. It should be appreciated that such dimensions are provided as an example and that an applicator device may include a dispenser tip having dimensions different from those shown in Figures 6-9.

[0063] In some embodiments, opening 23 has an outer diameter of about 0.01 inch to about 0.1 inch, about 0.015 inch to about 0.09 inch, about 0.0175 inch to about 0.05 inch, about 0.02 inch to about 0.04 inch, about 0.025 inch to about 0.035 inch, about 0.028 inch to about 0.032 inch, or about 0.032 inch. In some embodiments, opening 23 has an inner diameter of about 0.001 inch to about 0.1 inch, about 0.005 inch to about 0.05 inch, about 0.0075 inch to about 0.05 inch, about 0.01 inch to about 0.03 inch, or about 0.012 inch.

[0064] According to one aspect of the present invention, in some embodiments, the dispenser tip comprises a tapered tip, which may have an exterior surface and an interior surface. The pharmaceutical composition from the applicator device may flow through and contact the interior surface of the dispenser tip. The interior and / or exterior surfaces may taper (i.e., decrease in size) in a direction moving from the proximal end to the distal end of the dispenser tip. In some embodiments, the angle of taper of the exterior surface may be different from the angle of taper of the interior surface. In some embodiments, the angle of taper of the exterior surface varies over the length of the tapered tip. In some embodiments, the angle of taper of the interior surface varies over the length of the tapered tip. In some embodiments, a first portion of the exterior surface of the tapered tip may have a first taper angle, and a second portion of the exterior surface may have a second, different taper angle. In some embodiments, a first portion of the interior surface of the tapered tip may have a first taper angle, and a second portion of the interior surface may have a second, different taper angle. In some embodiments, the second taper angle is less than the first taper angle. In some embodiments, the interior and / or exterior surfaces have tapered and non-tapered portions.

[0065] In one illustrative embodiment shown in Figure 9, which depicts a detailed view of the enclosed region 9 of the dispenser tip of Figure 7, tapered tip 22 has an exterior surface 24 and an interior surface 26. Interior surface 26 has a tapered first portion 27 and a second portion 29 that is straight or has a different taper angle from that of the first portion. In some embodiments, the second portion may have a smaller taper angle than the first portion. As can also be seen in the embodiment of Figure 9, the taper angle of exterior surface 24 is different from the taper angle of first portion 27 of interior surface 26.

[0066] In some embodiments, the interior surface of the dispenser tip has a taper angle of about 1 to about 5 degrees, about 2 to about 4 degrees, about 2.5 to about 3.5 degrees, about 2.5 to about 4 degrees, about 2.5 to about 4.5 degrees, about 2.5 to about 5 degrees, about 2.5 to about 5.5 degrees, or about 3.00 degrees.

[0067] In some embodiments, the exterior surface of the dispenser tip has a taper angle of about 1 to about 10 degrees, about 2 to about 9 degrees, about 2.5 to about 5.5 degrees, about 2.5 to about 7 degrees, about 3 to about 8 degrees, about 4 to about 7 degrees, about 4.5 to about 5.5 degrees, about 4.7 degrees to about 5 degrees, or about 4.80 degrees.

[0068] The tapered tip may have a longitudinal axis L, as shown in Figures 6, 8, and 9. The tapered tip may be rotationally symmetric about the longitudinal axis L.

[0069] The tapered tip may have a length along the longitudinal axis L of about 0.1 to about 2 inches, about 0.3 to about 1.7 inches, about 0.5 to about 1.5 inches, about 0.7 to about 1.4 inches, about 0.8 to about 1.3 inches, about 0.9 to about 1.3 inches, about 1.1 to about 1.3 inches, or about 1.1 to about 1.2 inches.

[0070] In some embodiments, the interior surface of the dispenser tip at a distal portion of the tip has a straight-walled channel with a reduced taper or no taper compared to the remainder of the interior surface. In some embodiments, the distal portion of the tip having a straight-walled channel extends a distance along the longitudinal axis L of the dispenser tip that is about 0.01 to about 0.1 inches long, about 0.01 to about 0.05 inches long, about 0.02 to about 0.04 inches long, about 0.025 to about 0.035 inches long, or about 0.029 inches long.

[0071] According to one aspect of the present invention, the size and shape of the tapered tip aids in controlling the dispensing of droplets of the composition onto the desired area of ​​skin. In some embodiments, the tapered tip produces droplets of the composition having a size of about 0.1 mm to about 10 mm, about 0.5 mm to about 9 mm, about 0.7 mm to about 6 mm, or about 1 mm to about 4 mm. The controlled size of the droplets produced by the applicator tip may aid in keeping the dispensed composition within a small area of ​​skin and avoiding dispensing the composition onto unwanted areas of the skin, e.g., limiting treatment to only the areas of skin affected by the skin condition.

[0072] In some embodiments, the volume of each droplet of composition administered by the applicator device may be at least 1 uL, at least 2 uL, at least 3 uL, at least 4 uL, at least 5 uL, at least 6 uL, at least 7 uL, at least 8 uL, at least 9 uL, at least 10 uL, at least 15 uL, at least 20 uL, at least 30 uL, at least 50 uL, at least 100 uL, at least 200 uL, at least 300 uL, at least 500 uL, at least 800 uL, at least 900 uL, at least 1 mL, or at least 5 mL. In some embodiments, the volume of each droplet administered by the applicator device is less than 5 mL, less than 1 mL, less than 900 μL, less than 800 μL, less than 700 μL, less than 600 μL, less than 500 μL, less than 400 μL, less than 300 μL, less than 200 μL, less than 100 μL, less than 90 μL, less than 80 μL, less than 70 μL, less than 60 μL, less than 50 μL, less than 45 μL, less than 40 μL, less than 35 μL, less than 30 μL, less than 25 μL, less than 20 μL, less than 15 μL, less than 12 μL, less than 10 μL, less than 9 μL, less than 8 μL, less than 7 μL, less than 6 μL, or less than 5 μL. All combinations of the above-referenced ranges are possible. For example, the volume of each droplet administered by the applicator device may be from about 1 uL to about 5 mL, or from about 2 uL to about 1 mL, or from about 3 uL to about 900 uL, or from about 4 uL to about 900 uL, or from about 5 uL to about 500 uL, or from about 5 uL to about 400 uL, or from about 5 uL to about 200 uL, or from about 5 uL to about 100 uL, or from about 5 uL to about 50 uL, or from about 5 uL to about 20 uL, or from about 5 uL to about 10 uL.

[0073] The dispenser tip could be capable of delivering multiple droplets, for example 5, 10, 20, 30, 40, 50, 60 or more droplets.

[0074] In some embodiments, the applicator device includes a drip guard that helps prevent the pharmaceutical composition from slipping off the side of the device and into the user's hand holding the device. In some embodiments, the drip guard may be in the form of a moat with a recess for capturing the pharmaceutical composition. In some embodiments, the drip guard surrounds at least a portion of the tapered tip of the dispenser tip.

[0075] 5-8, the dispenser tip 20 includes a drip guard 26 in the form of an annular ring that forms an annular recess 36 for receiving one or more droplets that run down the side of the tapered tip 22. The recess may be sized to hold at least 1, at least 2, at least 3, at least 4, or at least 5 droplets, or any other suitable number of droplets.

[0076] As seen in FIGS. 5 and 7, a dispenser drip guard 26 surrounds the proximal portion of the tapered tip 22 .

[0077] In some embodiments, the drip guard defines the maximum outer diameter of the dispenser tip. For example, as seen in FIG. 7, the diameter of the drip guard 26 is the maximum diameter of the dispenser tip 20.

[0078] In some embodiments, the drip guard has a diameter of about 0.1 to about 1 inch, about 0.15 to about 0.8 inch, about 0.2 to about 0.6 inch, about 0.3 to about 0.5 inch, about 0.3 to about 0.45 inch, or about 0.404 inch.

[0079] In some embodiments, the applicator device allows for the ability to consistently deliver material at the same concentration as in the ampoule, and at the time of contact with the skin, the delivered material has a concentration of about 0.7% w / v.

[0080] In some embodiments, the dispenser tip 20 includes an attachment portion 28 that may mate with the tube 50. In some embodiments, the attachment portion 28 is attached to the tube 50. For example, as shown in FIG. 4 , at least a portion of the attachment portion 28 may contact at least a portion of the tube 50. The dispenser tip 20 and the tube 50 may be attached to each other via adhesive, welding, ultrasonic welding, UV adhesive, an interference fit, a mechanical interlock, a threaded connection, a snap fit, a fastener, or any other suitable arrangement. One or more intermediary components may be used to attach the dispenser tip to the tube. In some embodiments, the dispenser tip 20 and the tube 50 are attached to each other and form an airtight seal.

[0081] The tip may be made of a polymeric material, such as a plastic or thermoplastic. In some embodiments, the tip is made of a polypropylene homopolymer. In some embodiments, the tip is made of a transparent or translucent material. A transparent or translucent material will allow the user to see the composition flowing through the tip during administration. In some embodiments, the composition is colored to help the user see the composition flowing through the tip. Other parts of the applicator device, such as the tube, ampoule, and cap, may also be transparent or translucent.

[0082] In some embodiments, the applicator device comprises a filter that allows passage of the pharmaceutical composition and prevents passage of broken ampoule fragments.

[0083] The filter may filter out aggregates, particles, fragments of material, or the like, such as, but not limited to, glass particles, plastic particles, precipitates or other aggregates from liquid drug formulations.

[0084] The filter may be made from a plastic with one or more holes, or alternatively may be a mesh material. The filter may be made from polyester, polyethylene, polyethylene terephthalate (PET), coPET, or other polymer or fiber-based materials.

[0085] In some embodiments, the filter has the shape of a cylinder, a rectangular prism, a cube, or other suitable shape.

[0086] In some embodiments, the filter is a cylinder having an outer diameter and a length. In some embodiments, the filter may have an outer diameter of about 0.05 inches to about 0.5 inches, 0.1 inches to about 0.3 inches, 0.12 inches to about 0.14 inches, or about 0.135 inches. In some embodiments, the filter may have a length of about 0.1 inches to about 0.3 inches, 0.12 inches to about 0.18 inches, 0.13 inches to about 0.17 inches, 0.14 inches to about 0.15 inches, or about 0.147 inches, or about 0.169 inches.

[0087] In some embodiments, the filter has a density greater than or equal to about 2 grams per cubic inch, greater than or equal to about 2.5 grams per cubic inch, greater than or equal to about 3 grams per cubic inch. In some embodiments, the filter has a density less than about 5 grams per cubic inch, less than about 4 grams per cubic inch, or less than about 3.5 grams per cubic inch. In some embodiments, the filter may have a density of about 2 to about 4 grams per cubic inch, or about 2.5 to about 3.5 grams per cubic inch, or about 3 grams per cubic inch.

[0088] 10A, 10B, and 10C, filter 30 is in the shape of a cylinder having a length of about 0.147 inches and a diameter of about 0.135 inches. In an alternative embodiment, the filter is in the shape of a cylinder having a length of about 0.169 inches and a diameter of about 0.135 inches.

[0089] In some embodiments, the filter is constructed and arranged to allow passage of a fluid having a viscosity of 30 to 100 cps. In some embodiments, the filter is constructed and arranged to prevent passage of broken ampoule fragments having a particle size of at least 20 μm, at least 50 μm, at least 100 μm, at least 120 μm, at least 130 μm, at least 140 μm, at least 150 μm, at least 200 μm, at least 250 μm, at least 300 μm, or at least 400 μm. In some embodiments, the filter is constructed and arranged to prevent passage of broken ampoule fragments having a particle size of less than 1 mm, less than 800 μm, less than 700 μm, less than 500 μm, less than 400 μm, less than 300 μm, less than 200 μm, or less than 100 μm. In some embodiments, the filter is constructed and arranged to prevent the passage of broken ampoule fragments having a particle size of about 20 μm to about 1 mm, about 30 μm to about 800 μm, about 50 μm to about 500 μm, about 100 μm to about 300 μm, about 100 μm to about 200 μm, or about 120 μm to about 170 μm.

[0090] As used herein, the "particle size" of a particle refers to the particle's largest dimension. For example, if the longest dimension of a particle is 200 μm, but the particle also has a width of only 20 μm and a depth of only 30 μm, the particle size of such a particle would be considered its longest dimension, which is 200 μm.

[0091] The performance of a filter in blocking particles of a certain particle size may be tested in accordance with the United States Pharmacopoeia (USP) Chapter (788) "Particular Matter in injections" as of June 15, 2017.

[0092] In some embodiments, the filter is constructed and arranged to avoid absorbing a volume of more than 35 μL of the pharmaceutical composition as the composition flows through the filter.

[0093] According to one aspect of the present invention, in some embodiments, the filter is located within the dispenser tip of the applicator device. In some embodiments, the dispenser tip has a tapered tip, and the filter is located within the wall of the tapered tip. In some embodiments, the filter is retained within the tapered tip via an interference fit between the filter and the interior surface of the tapered tip.

[0094] In one example, shown in FIG. 4, the filter 30 is located within the wall of the tapered tip 22 of the dispenser tip 20 .

[0095] In some embodiments, the distal end of the filter is more compressed than the proximal end of the filter, which may help ensure that material passing through the tip (e.g., pharmaceutical composition and debris) also passes through the filter rather than around it.

[0096] In some embodiments, the dispenser tip comprises a recess for receiving a filter.

[0097] 7 and 8, dispenser tip 20 includes a recess 37 sized and shaped to receive filter 30. The recess may be flanked by narrowing channels on the distal and proximal sides of the recess, which may help to keep the filter positioned within recess 37. For example, as seen in FIG. 7, channel portion 47 at the distal end of recess 37 has a smaller diameter than that of recess 37, and channel portion 57 at the proximal end of recess 37 has a smaller diameter than that of recess 37.

[0098] In some embodiments, the applicator device has a cap. According to one aspect of the present invention, the cap is used to protect the dispenser tip from being damaged. In some embodiments, the cap does not actually create a seal when in the closed position, but instead allows venting of the dispenser tip through the cap, for example, through a through-hole opening in the cap or through an opening between the dispenser tip and the cap. In some embodiments, a vent channel in the dispenser tip allows venting of the dispenser tip from the cap. In some embodiments, unwanted pharmaceutical composition can be controllably dispensed into the cap rather than to a patient or another storage device.

[0099] In some embodiments, the cap has an opening that receives at least a portion of one or more other applicator device components. The opening of the cap may be removably coupled to at least a portion of one or more other applicator device components when in the closed position. For example, in some embodiments, the cap may receive and be coupled to at least a portion of a dispenser tip when in the closed position. In some embodiments, the cap receives and is coupled to at least a portion of a tube when in the closed position.

[0100] In the illustrative embodiment shown in FIG. 4 , cap 10 has an opening that receives a portion of dispenser tip 20 when the cap is in the closed position and is coupled to dispenser tip 20. Opening 11 can be seen in FIG. 11 . The cap may have features that will allow the cap to be coupled to another component of an applicator device. According to one aspect of the present invention, the cap may have coupling features that allow the cap to be coupled to another component of an applicator device without creating a seal with the component to which the cap is coupled. In other words, in some embodiments, the coupling features allow for venting of the dispenser tip through the cap, e.g., through a vent channel in the dispenser tip, when the cap is in the closed position.

[0101] In one illustrative embodiment, the cap's coupling feature includes one or more ribs located within the cap interior. The ribs may protrude radially inward from the inner surface of the cap. When another component of the applicator device is inserted into the opening of the cap, the ribs may contact against the surface of the component. The ribs may have an amount of clearance between them that is smaller than the area occupied by the portion of the component received into the cap. As a result, the ribs may press radially inward against the surface of the component, and the cap may be coupled to the component via an interference fit.

[0102] In the illustrative embodiment shown in Figures 4, 11, and 13, the applicator device has a cap 10 with a plurality of ribs 15. As best seen in Figure 13, the ribs 15 may be evenly spaced from one another. While this illustrative embodiment uses three ribs, it should be appreciated that any suitable number of ribs may be used, such as 2, 3, 4, 5, 6, 7, or 8 ribs.

[0103] As best seen in FIG. 4 , cap 10 interfaces with a portion of dispenser tip 20. When the dispenser tip is received within the cap, ribs 15 may press against the exterior surface of the dispenser tip to connect the cap and dispenser tip. The cap may interface with the portion of the dispenser tip that has the largest diameter. In some embodiments, the cap interfaces with drip guard 26 of the dispenser tip. Ribs 15 may press against the exterior surface of drip guard 26.

[0104] In some embodiments, the ribs do not create a seal between the cap and the dispenser tip, although the ribs create an interference fit with portions of the dispenser tip 20. In some embodiments, the ribs may be fused to the tube via ultrasonic welding.

[0105] It should be appreciated that other connection arrangements may be used, for example, the connection features may operate via a mechanical interlock, a threaded engagement, or any other suitable connection arrangement.

[0106] In some embodiments, in addition to or instead of interfacing with the dispenser tip, the cap may interlock with the tube when in the closed position, for example, the cap may press against the exterior surface of the tube and connect with the tube via corresponding threads or the like.

[0107] According to one aspect of the present invention, the cap allows ventilation through an opening that receives another component of the applicator device. In some embodiments, the cap has only one opening and no other holes besides the opening for ventilation. In such embodiments, the cap has a continuous, uninterrupted exterior surface with no holes besides the opening. In other embodiments, in addition to the opening, the cap may have one or more holes for ventilation.

[0108] In some embodiments, after a period of time, at least a portion of the pharmaceutical composition (e.g., a portion of the pharmaceutical composition in the dispenser tip located toward the distal opening) may harden to create a seal, enabling a self-sealing effect and may prevent the pharmaceutical composition from flowing out of the dispenser tip and / or may prevent the pharmaceutical composition from being exposed to atmospheric air. In some embodiments, the self-sealing effect may be caused by evaporation of a solvent (e.g., water or alcohol) from the pharmaceutical composition, which may leave a solid behind. In some embodiments, a vent feature in the cap may allow the solvent to evaporate and thus enable the self-sealing effect.

[0109] In some embodiments, the self-sealing feature may function as a safety feature, e.g., to prevent unwanted release of the pharmaceutical composition after treatment, e.g., to prevent subsequent use that could result in cross-contamination between different patients. The self-sealing feature could function as a tamper-evident feature that could prevent a user from being able to use a previously activated applicator. In some embodiments, the self-sealing feature would help prevent oxidative degradation of the active ingredient of the pharmaceutical composition.

[0110] In some embodiments, the applicator is used to treat a subject (e.g., a child) with multiple skin lesions, and the user will need to put the applicator down midway through dispensing the pharmaceutical composition. The user will need to start and stop application multiple times during a single treatment while treating the patient. In some embodiments, the applicator will not dry out for at least 1, 5, 10, 20, 30, 45, or 60 minutes when not in use, but will dry out after the first lesion is treated.

[0111] In some embodiments, the cap includes a feature that prevents rotation of the cap and the entire device applicator when the cap is in the closed position. In some embodiments, the cap may include one or more flat surfaces that prevent the cap from rotating. As seen in FIGS. 11-13, the cap 10 may include six flat surfaces 12. It should be appreciated that any number of flat surfaces may be used. In some embodiments, the cap includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any other suitable number of flat surfaces. The flat surfaces may be the same size to form a regular shape. For example, in the embodiment shown in FIGS. 11-13, the flat surfaces 12 form a hexagon.

[0112] In some embodiments, the flat surface is located at the proximal end of the cap that receives the dispenser tip.

[0113] Figures 11-14 provide dimensions (shown in inches) for one illustrative embodiment of the cap. It should be appreciated that such dimensions are provided as an example and that an applicator device may be provided with a cap having dimensions different from those shown in Figures 11-14.

[0114] In some embodiments, the cap may have a length of about 0.5 to about 3 inches, about 1 inch to about 2 inches, about 1 inch to about 1.5 inches, or about 1.28 inches.

[0115] In some embodiments, the cap may have a maximum external width (measured from one planar surface 12 to another) of about 0.1 to about 1 inch, about 0.3 to about 0.8 inch, about 0.4 to about 0.5 inch, or about 0.47 inch. In some embodiments, the cap comprises an opening and / or tube for receiving a dispenser tip. The opening may be circular and may have a diameter of about 0.1 to about 1 inch, about 0.2 to about 0.9 inch, about 0.3 to about 0.8 inch, about 0.3 to about 0.5 inch, about 0.35 to about 0.45 inch, or about 0.4 inch.

[0116] In some embodiments, the cap may be used to collect unwanted droplets - for example, if during administration of a medication the user squeezes hard enough that more droplets than desired are expelled, the cap may be used to capture the excess droplets.

[0117] In some embodiments, to aid in ventilation, one or more grooves may be present on the surface of the dispenser tip mated with the cap and / or on the surface of the cap mated with the dispenser tip. Such grooves may create one or more gaps between the dispenser tip and the cap when the cap is in the closed position to prevent sealing between the cap and the dispenser tip and to promote solvent ventilation as discussed above. In some embodiments, when the cap is in the closed position, the cap is attached to the dispenser tip and mated at an interface of the dispenser tip, such as the exterior surface of the dispenser tip drip guard. In some embodiments, the mating surface of the dispenser tip may have one or more grooves. Alternatively or additionally, the surface of the cap, for example, the interior surface of the cap that mated with the surface of the dispenser tip, may have one or more grooves.

[0118] One illustrative embodiment of a dispenser tip having one or more grooves is shown in Figures 15-17. As seen in Figure 15, groove 25 is formed in the exterior surface of drip guard 26. In some embodiments, the groove extends from distal edge 21 of drip guard 26 to proximal edge 31 of drip guard 26. However, it should be appreciated that in other embodiments, the groove may be a different length. For example, the groove may extend from the distal edge of the drip guard to a point on the surface, such that the groove extends partially across the surface rather than from the distal edge to the proximal edge. In the embodiment of Figures 15-17, the groove is linear. However, it should be appreciated that other groove shapes can be used. For example, the groove may have a serpentine, curved, or other non-linear path. As seen in Figure 17, in some embodiments, the dispenser tip includes more than one vent. The embodiment shown in Figure 17 includes three vents. However, it should be appreciated that 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 vents, or any other suitable number of vents, may be used. In some embodiments, the vents are equally spaced from one another. The vents may be radially spaced from one another around the periphery of the surface. The vents may be located on the surface of a portion of the dispenser tip having the largest diameter. As seen in FIG. 17 for three vents 25, the vents may be spaced 120 degrees from one another around the periphery of the drip guard 26. However, in other embodiments, the vents may be non-uniformly spaced from one another.

[0119] Figures 18-21 provide dimensions (shown in inches for distances and degrees for angles) for one illustrative embodiment of a dispenser tip. It should be understood that such dimensions are provided as an example and that an applicator device may be equipped with a dispenser tip having dimensions different from those shown in Figures 18-21.

[0120] As seen in FIG. 21, the opening 23 may have an outer diameter of about 0.032 inches + / - 0.002 inches and an inner diameter of about 0.012 inches + / - 0.001 inches.

[0121] Dispenser tip 20 includes a tapered tip 22 having an exterior surface and an interior surface. As seen in FIG. 21, which depicts a detailed view of enclosed region 21 of the dispenser tip of FIG. 19, tapered tip 22 has an exterior surface 24 and an interior surface 26. Interior surface 26 has a first portion 27 that is tapered and a second portion 29 that is straight, or has a different taper angle than that of the first portion. In some embodiments, the second portion may have a smaller taper angle than that of the first portion. As also seen in the embodiment of FIG. 9, the taper angle of exterior surface 24 is different from that of first portion 27 of interior surface 26. In the embodiment of FIG. 21, the interior surface has a taper angle of about 3 degrees, and the exterior surface has a taper angle of about 4.8 degrees.

[0122] 18, 20 and 21, the tapered tip has a longitudinal axis L. The tapered tip is rotationally symmetric about the longitudinal axis L.

[0123] As shown in Figure 21, the interior surface 26 of the dispenser tip at the distal portion of the tip is a straight-walled channel with reduced or no taper compared to the remainder of the interior surface. In some embodiments, the distal portion of the tip having a straight-walled interior channel extends a distance along the longitudinal axis L of the dispenser tip that is about 0.029 + / - 0.002 inches long.

[0124] The dispenser tip 20 comprises an attachment portion 28 that mates with the tubing 50. In some embodiments, the attachment portion 28 is attached to the tubing 50.

[0125] The applicator device includes a filter located within the dispenser tip of the applicator device. In the embodiment shown in Figures 19 and 20, the dispenser tip 20 includes a recess 37 sized and shaped to receive the filter 30. The recess may be flanked by narrowing channels on the distal and proximal sides of the recess to help retain the filter located within the recess 37. For example, as seen in Figures 19 and 20, the channel portion 47 at the distal end of the recess 37 has a smaller diameter than that of the recess 37, and the channel portion 57 at the proximal end of the recess 37 has a smaller diameter than that of the recess 37. In the embodiment of Figures 19 and 20, the dispenser tip also includes a funnel region 67 that serves as a transition from the smaller diameter filter recess 37 to the larger diameter chamber 77 that is inserted into the dispenser tube. In the embodiment of Figures 19 and 20, the dispenser tip further includes a straight-walled channel region 65 between the filter recess 37 and the funnel region 67.

[0126] According to one aspect, the tube is compressible, inducing a pressure increase within the tube and dispensing the pharmaceutical composition out of the dispenser tip. In some embodiments, the tube can be compressible, inducing a pressure increase within the tube in excess of about 1.0 atm, 1.1 atm, 1.2 atm, 1.3 atm, 1.4 atm, 1.5 atm, 1.6 atm, 1.7 atm, 1.8 atm, 1.9 atm, 2.0 atm, 3.0 atm, 4.0 atm, 5.0 atm, 6.0 atm, 7.0 atm, 8.0 atm, 9.0 atm, 10 atm, 20 atm, 30 atm, or 40 atm. The tube can be compressible, inducing a pressure increase within the tube of about 1.0 atm, 1.1 atm, 1.2 atm, 1.3 atm, 1.4 atm, 1.5 atm, 1.6 atm, 1.7 atm, 1.8 atm, 1.9 atm, 2.0 atm, 3.0 atm, 4.0 atm, 5.0 atm, 6.0 atm, 7.0 atm, 8.0 atm, 9.0 atm, 10 atm, 20 atm, 30 atm, or 40 atm or more. In some cases, the pressure within the tube increases by a factor of at most about 100 atm, 50 atm, 40 atm, 30 atm, 20 atm, 10 atm, or 5 atm. In some examples, the tube is compressible to induce a pressure increase within the tube of about 1 atm to 20 atm, 1 atm to 15 atm, 1 atm to 10 atm, or 1 atm to 5 atm.

[0127] In some cases, the tube may be compressible to induce a pressure within the tube that is greater than about 1.0 atm, 1.1 atm, 1.2 atm, 1.3 atm, 1.4 atm, 1.5 atm, 1.6 atm, 1.7 atm, 1.8 atm, 1.9 atm, 2.0 atm, 3.0 atm, 4.0 atm, 5.0 atm, 6.0 atm, 7.0 atm, 8.0 atm, 9.0 atm, 10 atm, 20 atm, 30 atm, or 40 atm. The tube can be compressible to induce a pressure within the tube of about 1.0 atm, 1.1 atm, 1.2 atm, 1.3 atm, 1.4 atm, 1.5 atm, 1.6 atm, 1.7 atm, 1.8 atm, 1.9 atm, 2.0 atm, 3.0 atm, 4.0 atm, 5.0 atm, 6.0 atm, 7.0 atm, 8.0 atm, 9.0 atm, 10 atm, 20 atm, 30 atm, or 40 atm or greater. In some cases, the pressure within the tube increases to at most about 100 atm, 50 atm, 40 atm, 30 atm, 20 atm, 10 atm, or 5 atm. In some examples, the tube can be compressible to induce a pressure within the tube of about 1 atm to 20 atm, 1 atm to 15 atm, 1 atm to 10 atm, or 1 atm to 5 atm.

[0128] The tube may have a shape that is primarily or substantially cylindrical or spherical. Alternatively, the tube may have a shape that is primarily or substantially rectangular. The tube may have one edge. Alternatively, the tube may have two or more edges. Additionally, the tube may have an irregular shape.

[0129] The tube may be at least partially or completely formed of a polymeric material (e.g., plastic). The plastic used may be, but is not limited to, polypropanol, low-density polyethylene, medium-density polyethylene, high-density polyethylene, or polytetrafluoroethylene, or some combination thereof. Alternatively, the tube may be at least partially or completely formed of a metallic material (e.g., stainless steel or aluminum). In some examples, a portion of the tube is formed of a polymeric material, and the remainder of the tube is formed of a metallic material.

[0130] The tube may be formed at least partially or completely from a polymeric material (e.g., plastic). Alternatively, the tube may be formed at least partially or completely from a metallic material (e.g., stainless steel or aluminum). In some examples, a portion of the tube is formed from a polymeric material and the remainder of the tube is formed from a metallic material.

[0131] In some embodiments, the tube can have a volume of about 0.1 mL to 10 mL, or about 0.2 mL to 9 mL, or about 0.3 mL to 8 mL, or about 0.4 mL to 8 mL, or about 0.5 mL to 6 mL, or about 2 mL to 4 mL or less, or equal to about 3 mL. The tube can have a volume of about 10 mL, about 8 mL, about 6 mL, about 5 mL, about 4 mL, about 3 mL, about 2.5 mL, or about 2 mL or less.

[0132] In some embodiments, the tube has a length of about 0.5 inches to about 5 inches, about 1 inch to about 4 inches, about 1.5 inches to about 3.5 inches, about 2 inches to about 3 inches, or about 2.5 inches.

[0133] In some embodiments, the tubing has an inner diameter of about 0.1 inches to about 1 inch, about 0.15 to about 0.7 inches, about 0.2 to about 0.6 inches, about 0.25 to about 0.4 inches, about 0.3 to about 0.35 inches, or about 0.31 inches.

[0134] In some embodiments, the tube may be placed within a paperboard or cardboard sleeve that protects the pharmaceutical composition from light and reduces the risk of glass puncture to the user in the event that glass shards puncture the tube.

[0135] The applicator may contain an ampoule that holds the pharmaceutical composition, which may be constructed and arranged to be broken to release the pharmaceutical composition. In some cases, the ampoule can be crushed into several pieces. In some cases, the outer tube can be compressed to crush and break the ampoule, thereby releasing the pharmaceutical composition. Figures 2 and 4 depict illustrative embodiments of ampoule 60.

[0136] In some embodiments, the force required to crush the ampoule is about 1-20 lbf, about 5-15 lbf, about 7-13 lbf, or about 9-10 lbf.

[0137] In some embodiments, the ampoule is made of USP Type I borosilicate glass, USP Type II borosilicate glass, or USP Type III borosilicate glass. Alternatively, the ampoule may be formed of a polymeric material such as plastic or rubber. As another alternative, the ampoule could be made from PTFE-lined plastic or metal foil-lined plastic. As another alternative, the ampoule could also be made from ceramic. The ampoule in such cases may be punctured, crushed, or torn open to release the pharmaceutical composition.

[0138] In some embodiments, the pharmaceutical composition may be contained in a different container other than an ampoule. For example, the container may be a flexible-walled pouch. In some embodiments, the pharmaceutical composition is held directly within the tube itself, without an additional container containing the pharmaceutical composition.

[0139] In some embodiments, the pharmaceutical composition may be separated into two or more components and combined together immediately prior to use: the user breaks the seal or other separating barrier and combines the two components together.

[0140] In some embodiments, the ampoule may have a volume of about 3000 mL or less, about 2000 mL or less, about 1000 mL or less, about 500 mL or less, about 300 mL or less, or about 100 mL or less. In some embodiments, the ampoule may have a volume of more than about 100 mL, more than about 300 mL, more than about 500 mL, more than about 1000 mL, more than about 2000 mL, or more than about 3000 mL. In some embodiments, the ampoule may have a volume of about 10 mL to 3000 mL, or about 50 mL to 2500 mL, or about 100 mL to 2000 mL, or about 200 mL to 1400 mL, or about 300 mL to 1000 mL, or about 400 mL to 800 mL, or about 500 mL to 700 mL.

[0141] In some embodiments, the ampoule contains about 100 to 2000 mL of the pharmaceutical composition.

[0142] In some embodiments, the ampoule has a length of about 10 mm to about 100 mm, about 20 mm to about 90 mm, about 30 mm to about 80 mm, about 40 mm to about 60 mm, about 45 mm to about 55 mm, or about 48.99 mm.

[0143] In some embodiments, the ampoule has an outer diameter of about 1 mm to about 15 mm, about 3 mm to about 12 mm, about 5 mm to about 9 mm, about 6 mm to about 8 mm, about 6.5 mm to about 7.5 mm, or about 7 mm.

[0144] Examples of various topical compositions that may be retained within and delivered by the device applicator include, but are not limited to, the following: vesicants such as cantharidin, ingenol melbutate, or nitrogen mustard; antibacterial agents such as mupirocin and clindamycin; antifungal agents such as anthralin, clotrimazole, ketoconazole, and terbafine; benzoyl peroxide; tea tree oil; sandalwood extract; Solanum vulgare extract; undatum extract, Arborvitae extract, Podophyllin, Podofilox, Digoxin, Furosemide, Sinecatechin, Nitric Oxide, Green Tea Extract, Salicylic Acid, Coal Tar, Corticosteroids, Retinoids, Antibiotics, Anti-inflammatory Agents, Anesthetic Agents, Decongestants, Steroids, Anti-itch Medications, Immunomodulating Skin Medications, Haptens, Contact Allergens, Squalic Acid Dibutyl Ester, Diphenylcyclopropenone, Sunscreens, Topical Cosmetics, Self-Tanning Agents, Hyaluronic Acid, Dihydroxyacetone, Hydrogen Peroxide, Tretinoin, Bichloroacetic Acid, Trichloroacetic Acid, Lactic Acid, Root acid, silver nitrate, potassium hydroxide, sodium hydroxide, diluted povidone iodine, anorectal preparations, antiseptic and antiseptic agents, dermatological preparations, anti-invectives, antirosacea agents, antihistamines, antitumor agents, antivirals, astringents, debriding agents, depigmenting agents, emollients, keratolytic agents, nonsteroidal anti-inflammatory agents, photochemotherapeutic agents, rubefacients, nasal preparations, lubricants, irrigants, ophthalmic agents, anti-angiogenic ophthalmic agents, mydriatics, glaucoma agents, otic agents, earwax water, vaginal preparations, spermicides, povidine iodine, imiquimod, oxidizing agents, hydrogen peroxide, or other Toll-like receptor agonists or antagonists.

[0145] In some embodiments, the pharmaceutical composition may include at least 20% or more of at least one non-aqueous solvent (e.g., acetone, ether, ethanol, DMSO, amyl acetate, or chloroform). In some embodiments, the ampoule may be constructed and arranged to maintain the stability of the pharmaceutical composition such that after a 1-month period, the concentration of the active ingredient is at least 98% of the starting concentration, and after a 6-month period, the concentration is at least 96% of the starting concentration.

[0146] In some embodiments, the ampoule contains an excess of an inert gas, such as nitrogen or argon.

[0147] In some embodiments, the applicator device may be used to topically administer the composition to a subject. The applicator device may administer the composition topically to various body surfaces, including, but not limited to, the skin, mucous membranes, genitals, vagina, anus, nails, hair, nose, eyes, ears, or mouth, including lips, teeth, tongue, and gums.

[0148] The applicator device may be used to treat a variety of conditions, including, but not limited to, warts, molluscum contagiosum, mucous membrane pemphigoid, nasal polyps, conjunctivitis, otitis, herpes simplex, dentin hypersensitivity, tooth discoloration, halitosis, glossitis, periodontal disease, yeast infections, fungal infections, hemorrhoids, or any other body surface condition. Examples of other body surface conditions include, but are not limited to, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, skin cancer, or other types of skin conditions. While some examples and / or embodiments described herein refer to the treatment of skin conditions, such as skin lesions, it should be appreciated that the applicator device is not limited to use on or at the skin, and may be used for topical administration of a composition to any body surface, including mucous membranes, eyes, mouth, ears, etc. The inventors have recognized the need for an applicator that can controllably administer a composition to the intended body surface of a subject.

[0149] Examples of skin conditions that may be treated by the applicator device include, but are not limited to, the following: fungal infections, athlete's foot, acne, benign epidermal cysts, nevi, carbuncles, calluses, cellulitis, cold sores, corns, cutaneous candidiasis, eczema, freckles, hemangiomas, urticaria, lupus, measles, lentigines, necrotizing fasciitis, pigmentation disorders (drug-induced hyperpigmentation, hereditary dyschromatosis contralateralis, hereditary generalized dyschromatosis, familial progressive hyperpigmentation, Gari-Gari disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron-metallic discoloration, pale skin, and the like). Macules, melanosis, Mucamer syndrome, Venus necklace, anemic nevus, depigmented nevus, Pallister-Killian syndrome, foliate hypomelanosis, mottling, reticular facial pigmentation, hair cyst, pityriasis alba, poikiloderma of Civatte, vascular poikiloderma, post-inflammatory postpigmentation, progressive macular hypomelanosis, pruritus, reticular dyspigmentation of flexures, reticular acropigmentation, Lille melanosis, Waardenburg-Schaer syndrome, shiitake dermatitis, tar melanosis, titanium metallic discoloration, transient neonatal pustular melanosis, Vagabond's leukomelanoma, vasospastic plaques, Wende-Bauckus syndrome, X-linked pigmented reticulopathy, Yemeni deaf-blind pigmentation syndrome, psoriasis, rosacea, scars, skin cancer, skin tags, tattoo removal, vitiligo (including but not limited to non-segmental vitiligo and / or segmental vitiligo, trichome vitiligo, quadrichrome vitiligo, vitiligo ponctue), warts, hypohidrosis, impetigo, cutis laxa, pressure ulcers, erysipelas, diaper rash, dyshidrotic eczema, stomatitis, herpetic stomatitis, ichthyosis vulgaris, dermatomyositis, ingrown nails, acrodermatitis, sebaceous cysts, seborrheic keratosis, pilonidal sinus, keloids, lichen planus, actinic keratosis, stasis dermatitis demertitis), calluses, tinea versicolor pemphigoid, mouth ulcers, or shingles.

[0150] Examples of ocular conditions that may be treated by the applicator device include, but are not limited to: conjunctivitis, keratitis, keratoconjunctivitis, allergic conjunctivitis, corneal ulcers, Thygeson's superficial punctate keratitis, vernal conjunctivitis, herpes simplex keratitis, ophthalmic diseases, ocular hypertension, ocular rosacea, dryness It includes keratoconjunctivitis, ocular inflammatory disease, ocular surface disease, corneal inflammation, intraocular inflammation, uveitis, cataracts, glaucoma, fungal eye infections or blepharitis.

[0151] Examples of ear conditions that may be treated with the applicator device include, but are not limited to, dermatitis of the ear canal, otitis, otitis media, otitis externa, vertigo, Meniere's disease, tympanostomy tube otorrhoea, chronic suppurative otitis media, earwax impaction, seborrheic dermatitis, seborrheic keratosis, contact dermatitis, eczematous dermatitis of the ear, acute otitis externa, fissure granuloma, actinic keratosis, skin horn, basal cell carcinoma, keloid, Hutchinson's spot, Winkler's disease, auricular chondritis, and perichondritis, cylindroma, blue nevus, supernumerary ear, Osler-Rendu-Weber disease, atopic dermatitis, or photoallergic dermatitis.

[0152] Examples of nasal conditions include, but are not limited to, nasal polyps, bacterial nasal infections, rhinitis, sinusitis, sinus infections, allergic rhinitis, chronic atrophic rhinitis, fungal sinusitis, postnasal drip, or rosacea, rhinorrhea.

[0153] Some embodiments of the applicator device or system may be used to treat the following: acral fibrokeratoma, Acrodermatitus enterpathica, acral keratoelastoid, actinic keratoses (solar keratoses), sebaceous adenoma, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Buschke-Ollendorff syndrome, cancer of the cervix, cervical dysplasia, senile hemangioma, chronic nodular chondrodermatitis, cutaneous endometriosis, leukemia cutis, cutaneous lymphoma, cutaneous meningioma, cutaneous myxoma, Darier's disease, dermal dendritic cell hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine angiomatous hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevi (including, but not limited to, sebaceous nevus, comedonal nevus, Proteus syndrome). Becker's nevus), epithelioid cell histiocytoma, familial myxovascular fibromas, fungal skin diseases (including lobomycosis), granular cell tumors, glucagonoma syndrome, genital warts, ichthyosis (including but not limited to ichthyosis vulgaris, ichthyosis lamellaria, X-linked ichthyosis, epidermolytic hyperkeratosis, and acquired ichthyosis) acquista and palmoplantar keratoderma), idiopathic guttate hypomelanosis, infantile acrocystosis, infantile fibromatosis, Kaposi's sarcoma, keloid, keratoacanthoma, keratocyst, knuckle pad, lentigo, melanoma, venular hemangioma, Morton's neuroma, multifocal lymphangioendotheliomatosis, multinucleated hemangiohistiocytoma, multiple cutaneous leiomyomas, mycosis fungoides, cutaneous neuroma, nerve cyst, nevus flammeus, superficial lipomatous nevus, pachydermodactyly, palisaded encapsulated neuroma, skin parasitosis (scabies, pediculosis, flea bites, hookworm-related) including, but not limited to, cutaneous larva migrans), Pityriasis ruba pilaris, arrector piloleiomyoma, fascicular fibrohistiocytic tumor, pore-keratinized eccrine ostium and dermal duct nevi, progressive nodular histiocytoma, psoriasis (including but not limited to erythrodermic psoriasis, palmoplantar psoriasis, palmoplantar pustulosis, generalized pustular psoriasis of the Thunbush, geographic tongue), porokeratosis, seborrheic dermatitis, seborrheic keratosis, rhinorrhea, solitary cutaneous leiomyoma, spider angiomas, target hematoside angiomas, squamous cell carcinoma, tufted angiomas, venous lakes, pigmented urticaria, xanthelasma mastocytosis, or herpes zosteriform metastases.

[0154] There may also be use for some embodiments of the device applicator in epidermal skin rejuvenation, such as exfoliating or peeling skin in individuals with sun damage or wrinkles.

[0155] In some embodiments, the pharmaceutical composition is a composition that includes cantharidin. In some embodiments, the ampoule is capable of maintaining the stability of a composition suitable for topical administration comprising a cantharidin formulation at a starting concentration of 0.1-1.5% weight to volume, wherein after a one-month period the concentration of cantharidin is at least 98% of the starting concentration, and after a six-month period the concentration of cantharidin is at least 96% of the starting concentration. In some embodiments, the ampoule is capable of maintaining the stability of a composition suitable for topical administration comprising a cantharidin formulation at a starting concentration of 0.1-1.5% weight to volume, wherein after a one-month period no significant related substances are formed, and after a six-month period no significant related substances are formed.

[0156] In some embodiments, a method for treating a subject with one or more skin lesions may include administering a composition containing cantharidin to the skin. Illustratively, the composition may be administered to one or more skin lesions on the skin (e.g., resulting from molluscum contagiosum infection, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer). The method may enable effective treatment (e.g., removal) of the skin lesion(s) with minimal or no side effects (e.g., severe side effects, permanent damage to the epidermal tissue, scarring, excessive blistering of the skin surrounding the lesion, elevated plasma cantharidin concentrations, systemic exposure to cantharidin). The efficacy and / or safety of the treatment may depend on certain features of the composition and / or prolonged exposure of the skin lesion(s) to cantharidin. For example, a relatively high percentage of cantharidin administered to a skin lesion(s) may remain on the skin lesion(s) for a relatively long period (e.g., more than 6 hours). In some embodiments, a composition containing cantharidin administered to the skin may enable local delivery of the composition, and therefore cantharidin, to the skin lesion(s) (e.g., preventing exposure of surrounding skin to the composition or cantharidin and / or preventing systemic exposure to the composition or cantharidin), relatively good adhesion to the skin lesion(s), relatively high penetration of cantharidin into the skin lesion(s) over time, and / or the use of relatively low concentrations (e.g., about 1.2% w / v or less), and / or bioavailability of cantharidin. In some embodiments, the methods described herein may be used for a wide variety of skin disorders, including those primarily affecting the epidermis of the skin. For example, the methods may be used to treat molluscum contagiosum infections, seborrheic keratosis, actinic keratosis, milia, skin cancer, age spots, and other disorders not caused by human papillomavirus.

[0157] In some embodiments, the device applicators described herein may be used to administer the compositions, and the methods described herein may include administering the compositions. Suitable compositions for use in some embodiments are described in U.S. Provisional Application No. 62 / 516,061, filed June 6, 2017, and entitled "Treatment of Cutaneous Disorders," and International Patent Application No. PCT / US18 / 36353, filed June 7, 2018, and entitled "Treatment of Cutaneous Disorders," each of which is incorporated herein by reference in its entirety. Suitable compositions for use in some embodiments are also described in International Patent Application No. PCT / US2014 / 052184, filed August 21, 2014, and entitled "Compositions, Methods, and Systems for the Treatment of Cutaneous Disorders," each of which is incorporated herein by reference in its entirety.

[0158] Cantharidin is used as a blistering agent for the treatment of certain skin disorders. However, cantharidin is also classified as a highly hazardous substance in the United States and can cause severe chemical burns and toxicity when ingested. As a result, cantharidin can cause side effects (e.g., scarring) under certain conditions. For example, historically, certain side effects, such as damage to the epidermal 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 practices for the treatment of certain skin disorders using cantharidin include short-term exposure of the lesion to cantharidin (e.g., less than about 4 hours), which prevents these side effects (e.g., serious side effects).

[0159] One aspect of the present disclosure relates to a method for treating one or more skin lesions using a pharmaceutical composition comprising cantharidin with an applicator device, resulting in improved outcomes in eliminating the skin lesions compared to applying the pharmaceutical composition with a conventional wood stick applicator. Illustratively, the composition may be administered topically to one or more skin lesions on the skin (e.g., resulting from a localized molluscum contagiosum infection) using the applicator device. In some embodiments, the method may involve administering the composition to the skin lesion(s) two or more times (e.g., three, four, five, six times) at intervals (e.g., every 2-4 weeks, every 3 weeks ± 4 days) over a relatively short period (e.g., 12 weeks, 15 weeks). The method may allow for more effective treatment (e.g., shorter treatment time, less frequent administration, complete removal, higher percentage reduction) than other methods (e.g., administration without an applicator device). For example, the current method may allow for a relatively high percentage of lesion reduction (e.g., about 50% or more, complete removal) after one or more administrations (e.g., 1, 2, 3, 4) using the applicator device. In some instances, the method may allow for complete elimination (i.e., complete removal) of lesions in a relatively large percentage of subjects (e.g., about 50% or more, about 70% or more) after six or fewer administrations (e.g., five or fewer, four or fewer) of the composition using the applicator device. The enhanced effectiveness of the treatment may depend, in part, on the ability of the applicator device to administer a composition of a given viscosity and / or phase (e.g., a liquid) directly to the skin lesion(s). The methods described herein may be used for a wide variety of skin disorders, including those primarily affecting the epidermis of the skin. For example, the methods may be used to treat molluscum contagiosum infections, seborrheic keratosis, actinic keratosis, milia, skin cancer, age spots and other disorders not caused by human papillomavirus.

[0160] In some embodiments, a method for treating a subject with a skin lesion (e.g., resulting from a molluscum contagiosum infection) may include administering a composition containing cantharidin to the skin lesion using an applicator device described herein. In some embodiments, the composition contains a relatively low concentration of cantharidin and has a relatively low vapor pressure (e.g., about 210 mmHg or less at 20°C, 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 1.5% 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 commonly used in cantharidin compositions, such as diethyl ether. In some such cases, the compositions described herein will be less susceptible to fluctuations in cantharidin concentration, e.g., due to evaporation of the solvent from the composition, while stored in an applicator device used to house or otherwise retain the composition for a period of time. Illustratively, the cantharidin concentration in the device (e.g., 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 (e.g., about 210 mmHg or less) at 20°C. In some such cases, the solvent is alcohol (e.g., ethanol) and acetone. In some cases, the solvent is a non-ether solvent and / or does not include 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 includes a relatively small weight percentage (eg, about 20 wt.% or less, about 10 wt.% or less) of an ether, such as diethyl ether.In some embodiments, the composition may contain, in addition to one or more other components, cantharidin and a pharmaceutically acceptable excipient (e.g., a solvent). Illustratively, the composition may contain a film-forming agent (e.g., a polymer, nitrocellulose, and / or hydroxypropylcellulose), a plasticizer (e.g., a penetration enhancer, oil, camphor, and / or castor oil), a dye (e.g., gentian violet), and / or a bittering agent (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, greater than 30 cps, greater than 35 cps, about 30-100 cps, about 30-70 cps, about 35-60 cps, or about 40-50 cps.

[0161] In some embodiments, the composition may have a viscosity of at least about 20 cps, at least about 30 cps, at least about 35 cps, at least about 40 cps, at least about 50 cps, at least about 55 cps, at least about 60 cps, at least about 70 cps, at least about 80 cps, at least about 90 cps, at least about 100 cps, at least about 110 cps, at least about 120 cps, or at least about 130 cps. In some embodiments, the composition may have a viscosity of about 150 cps or less, about 140 cps or less, about 130 cps or less, about 120 cps or less, about 110 cps or less, about 100 cps or less, about 90 cps or less, about 80 cps or less, about 70 cps or less, about 60 cps or less, about 55 cps or less, about 50 cps or less, about 40 cps or less, about 35 cps or less, about 30 cps or less, or about 20 cps or less. Combinations of the above-referenced ranges are also possible. For example, in some embodiments, the composition may have a viscosity of about 20 cps to about 150 cps, or about 20 cps to about 130 cps, or about 30 cps to about 100 cps, or about 30 cps to about 90 cps, or about 35 cps to about 100 cps, or about 30 cps to about 110 cps, or about 30 cps to about 70 cps, or about 35 cps to about 60 cps, or about 40 cps to about 50 cps, or about 40 cps to about 80 cps.

[0162] In some embodiments, the applicator device enables the ability to consistently deliver a material with the same viscosity as the material in the ampoule. In some embodiments, at the time of contact with the skin, the delivered material has a viscosity of at least about 20 cps, at least about 30 cps, or at least about 35 cps. In some embodiments, at the time of contact with the skin, the delivered material has a viscosity of about 120 cps or less, about 110 cps or less, about 100 cps or less, or about 50 cps or less. Combinations of the above-referenced ranges are also possible. For example, in some embodiments, at the time of contact with the skin, the delivered material has a viscosity of about 20 cps to about 120 cps, about 30 cps to about 110 cps, or about 35 cps to about 100 cps.

[0163] In some embodiments, the method includes repeated administration of the composition using an applicator device. Illustratively, the method may include a second administration of a composition comprising cantharidin to at least a portion of the skin lesion using an applicator device. The second administration may deliver substantially the same amount of cantharidin as the first administration. In some examples, the second administration is substantially the same as the first administration. In some embodiments, the second administration may occur a period of time (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) after the first administration. Illustratively, the second administration may occur about 2 weeks or more and about 4 weeks or less (e.g., about 14 days or more and about 28 days or less, 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) after the first administration. Illustratively, the second administration may occur about 3 weeks after the first administration. In some embodiments, the second administration may occur about 3 weeks ± 4 days after the first administration. In some embodiments, the second administration may occur about 3 weeks ± 6 days after the first administration. In some embodiments, the second administration may occur about 3 weeks ± 5 days after the first administration. In some embodiments, the second administration may occur about 3 weeks ± 3 days after the first administration. In some embodiments, the second administration may occur about 3 weeks ± 2 days after the first administration. In some embodiments, the second administration may occur about 3 weeks ± 1 day after the first administration.

[0164] In some embodiments, the method includes administering a third administration of a composition comprising cantharidin to at least a portion of the skin lesion using an applicator device. In some embodiments, the third administration may deliver substantially the same amount of cantharidin as one or more previous administrations. In some examples, the third administration may be substantially the same as the first and / or second administration. In some embodiments, the third administration may occur a period of time (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) after the second administration. Illustratively, the third administration may occur about 2 weeks or more and about 4 weeks or less (e.g., about 14 days or more and about 28 days or less, 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) after the second administration. Illustratively, the third administration may occur about 3 weeks after the second administration. In some embodiments, the third administration may occur about 3 weeks ± 4 days after the second administration. In some embodiments, the third administration may occur about 3 weeks ± 6 days after the second administration. In some embodiments, the third administration may occur about 3 weeks ± 5 days after the second administration. In some embodiments, the third administration may occur about 3 weeks ± 3 days after the second administration. In some embodiments, the third administration may occur about 3 weeks ± 2 days after the second administration. In some embodiments, the third administration may occur about 3 weeks ± 1 day after the second administration.

[0165] In some embodiments, the method may include administering a fourth administration of a composition comprising cantharidin to at least a portion of the skin lesion using an applicator device. In some embodiments, the fourth administration may deliver substantially the same percentage (w / v) of cantharidin as one or more previous administrations. In some examples, the fourth administration may be substantially the same as the first, second, and / or third administrations. In some embodiments, the fourth administration may occur a period of time (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) after the third administration. Illustratively, the fourth administration may occur about 2 weeks or more and about 4 weeks or less (e.g., about 14 days or more and about 28 days or less, 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) after the third administration. Illustratively, the fourth administration may occur about 3 weeks after the third administration. In some embodiments, the fourth administration may occur about 3 weeks ± 4 days after the third administration. In some embodiments, the fourth administration may occur about 3 weeks ± 6 days after the third administration. In some embodiments, the fourth administration may occur about 3 weeks ± 5 days after the third administration. In some embodiments, the fourth administration may occur about 3 weeks ± 3 days after the third administration. In some embodiments, the fourth administration may occur about 3 weeks ± 2 days after the third administration. In some embodiments, the fourth administration may occur about 3 weeks ± 1 day after the third administration.

[0166] In some embodiments, the method may include subsequent (eg, fifth, sixth) administrations to at least a portion of the skin lesion using an applicator device. In some embodiments, a subsequent administration may deliver substantially the same percentage (w / v) of cantharidin as one or more previous administrations. In some examples, a subsequent administration may be substantially the same as the first, second, third, fourth, or any other previous administration. A subsequent administration (e.g., a fifth administration) may occur a period of time (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) after the immediately previous administration (e.g., a fourth administration). Illustratively, a subsequent administration may occur about 2 weeks or more and about 4 weeks or less (e.g., about 14 days or more and about 28 days or less, 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) after the previous administration. Illustratively, a subsequent administration may occur about 3 weeks after the previous administration. In some embodiments, the subsequent administration may occur about 3 weeks ± 4 days after the previous administration. In some embodiments, the subsequent administration may occur about 3 weeks ± 6 days after the previous administration. In some embodiments, the subsequent administration may occur about 3 weeks ± 5 days after the previous administration. In some embodiments, the subsequent administration may occur about 3 weeks ± 3 days after the previous administration. In some embodiments, the subsequent administration may occur about 3 weeks ± 2 days after the previous administration. In some embodiments, the subsequent administration may occur about 3 weeks ± 1 day after the previous administration.

[0167] Generally, the administration step may be repeated any suitable number of times required to treat a skin disorder. Illustratively, the administration step may be repeated two or more times, three or more times, four 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 some embodiments, the administration step may be repeated about two or more times and six or less times (e.g., about three or more times and about five or less times). In some embodiments, the administration step may be repeated four times. In some embodiments, the administration step may be repeated five times. In some embodiments, the administration step may be repeated three times. In some examples, the administration step may be repeated six times. In some embodiments, a relatively high percentage reduction in lesions may occur after about two or more times and about six or less administrations (e.g., four administrations, five administrations, six administrations). Illustratively, the percentage reduction in lesions may be about 90% or more (e.g., about 95% or more, 97%) after four administrations. As another example, the percent reduction in lesions may be about 80% or more (e.g., about 85% or more, 86%) after two administration steps. In some embodiments, a relatively large percentage of subjects will achieve complete elimination of skin lesions after about two or more and about six or less administrations (e.g., four, five, six). Illustratively, about 50% or more (e.g., about 60% or more, about 70% or more, 75%) will achieve complete elimination after four administration steps. In some examples, about 70% or more (e.g., about 80% or more, about 90% or more, about 95% or more, 100%) will achieve complete elimination after five or more administration steps (e.g., five administration steps, six administration steps). In some embodiments, a relatively large percentage of subjects will achieve complete elimination of skin lesions after about two or more and about six or less administrations (e.g., four, five, six). Illustratively, about 70% or more (eg, about 80% or more, about 90% or more, 100%) of subjects will achieve 90% elimination after four administration steps.For example, about 100% of subjects will achieve 90% elimination after four administration steps. In some embodiments, a relatively large percentage of subjects will achieve 75% elimination of skin lesions after about 2 or more and about 6 or less administrations (e.g., 4 administrations, 5 administrations, 6 administrations). Illustratively, about 80% or more (e.g., about 90% or more, about 95%, 100%) of subjects will achieve 75% elimination after four administration steps. For example, about 100% of subjects will achieve 75% elimination after four administration steps.

[0168] In some embodiments, the total number of administration steps is performed within a certain time frame (e.g., 3 weeks, 6 weeks, 9 weeks, 12 weeks, 15 weeks, 18 weeks, 21 weeks, 6 months, 8 months, 10 months, 12 months) and / or until a certain endpoint is reached. The percent reduction in total volume of the lesion(s) may be about 2 or more and about 10 or less, about 3 or more and about 10 or less, about 2 or more and about 8 or less, about 2 or more and about 6 or less, or about 3 or more and about 5 or less. For example, the method may involve performing two administration steps in a 6-week period. As another example, the method may involve performing four administration steps in a 12-week period.

[0169] Generally, the treatment period may be any suitable time frame required to treat a skin disorder. Illustratively, the treatment period may be about 1 week or more, about 2 weeks or more, about 3 weeks or more, about 4 weeks or more, about 1 month or more, about 2 months or more, about 3 months or more, about 4 months or more, about 6 months or more, about 8 months or more, about 10 months or more, or about 12 months or more. The treatment period refers to the time from the first administration until a certain endpoint (e.g., a certain percentage reduction in the number of lesions, a percentage reduction in the total volume of the lesion(s)) is reached and / or a fixed time from the first administration. In some embodiments, the treatment period is a fixed time from the first administration. In some embodiments, the treatment period is 12 weeks. In some embodiments, the treatment period is 13 weeks. In some embodiments, the treatment period is 14 weeks. In some embodiments, the treatment period is 15 weeks.

[0170] In some embodiments, the duration of treatment may be relatively short. Illustratively, the duration of treatment may be about 18 weeks or less, about 17 weeks or less, about 16 weeks or less, about 15 weeks or less, about 14 weeks or less, about 13 weeks or less, about 12 weeks or less, about 11 weeks or less, about 10 weeks or less, about 9 weeks or less, about 8 weeks or less, about 7 weeks or less, about 6 weeks or less, about 5 weeks or less, about 4 weeks or less, or about 3 weeks or less. In some embodiments, the duration of treatment may be 12 weeks from the first administration. In some embodiments, the duration of treatment may be 15 weeks from the first administration. In some embodiments, the duration of treatment may be 18 weeks from the first administration. In some embodiments, the duration of treatment may be 9 weeks or more from the first administration. In some embodiments, the duration of treatment may be about 9 weeks or more and about 18 weeks or less (e.g., about 9 weeks or more and about 15 weeks or less, about 12 weeks or more and about 15 weeks or less, about 12 weeks or more and about 18 weeks or less).

[0171] In some embodiments, the time interval between each administration step (e.g., between the first administration and the second administration) may be selected as desired. In some embodiments, the time interval between at least some (e.g., each) administration steps may be substantially the same. Illustratively, the time interval between at least some (e.g., each) 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 or more years). In some cases, the time interval between each administration step (e.g., between the first administration, the second administration, and the third administration) may be about 3 weeks (e.g., every 21 days ± 4 days). For example, the method may include administering a composition containing cantharidin every 3 weeks (e.g., every 21 days ± 4 days) for about 9 weeks. In such cases, the method includes performing four administration steps, and the time interval between each administration step is about 3 weeks (e.g., every 21 days ± 4 days). In some embodiments, the time interval between at least some (e.g., each) administration steps may be different.

[0172] In one embodiment, the treatment method may include administering a composition containing cantharidin to one or more skin lesions on the skin (e.g., resulting from a molluscum contagiosum infection) using an applicator device. The treatment period may be about 9 weeks or more and about 15 weeks or less (e.g., about 11 weeks or more and about 13 weeks or less). In some cases, the treatment period may be 12 weeks from the first administration. The method may further include repeating the administering step. Illustratively, the method may include two or more administration steps (e.g., three or more, four or more). In some cases, the method may include four administration steps, with a treatment period that may be 12 weeks from the first administration. The time interval between each administration step may be about 1 week or more and about 6 weeks or less (e.g., about 2 weeks or more and about 4 weeks or less). In some cases, the time interval between four administrations may be about 3 weeks (e.g., 21±4 days). In some such embodiments, the composition may include cantharidin, a solvent (e.g., non-aqueous, non-ethereal, ethanol, and acetone), a film-forming agent (e.g., a polymer, nitrocellulose, and / or hydroxypropylcellulose), and a plasticizer (e.g., a penetration enhancer, oil, camphor, and / or castor oil). The composition may also optionally include a dye (e.g., gentian violet) and / or a bittering agent (e.g., denatonium benzoate).

[0173] For example, the composition may include cantharidin (e.g., at a weight percent of about 0.1 or more and about 1.2 or 1.5 or less per volume percent), acetone (e.g., at a weight percent of about 55 or more and about 65 or less per weight percent), ethanol (e.g., at a weight percent of about 25 or more and about 35 or less per weight percent), castor oil (e.g., at a weight percent of about 0.5 or more and about 2 or less per weight percent of castor oil), nitrocellulose (e.g., at a weight percent of about 2 or more and about 10 or less per weight percent), hydroxypropyl cellulose (e.g., at a weight percent of about 0.1 or more and about 2 or less per weight percent of hydroxypropyl cellulose), camphor (e.g., at a weight percent of about 0.1 or more and about 2 or less per weight percent), denatonium benzoate (e.g., at a weight percent of about 0.001 or more and about 0.01 or less per weight percent), and gentian violet (e.g., at a weight percent of about 0.0001 or more and about 0.001 or less per weight percent).

[0174] In some embodiments, the method may further include allowing the cantharidin-containing composition to remain on the skin lesion for more than 6 hours (e.g., 18 hours or more and about 24 hours or less). In some embodiments in which the administration step is repeated, the allowing step may also be repeated. In certain embodiments, the allowing step may be repeated after each administration. In some embodiments, the allowing step may be repeated after at least some, but not all, administration steps. Generally, the repeated allowing step(s) may be repeated as described herein with respect to the administration step.

[0175] In some embodiments, at least a portion of the composition will be allowed to remain on the skin lesion for a period of time (e.g., more than 6 hours, about 18 hours or more, and about 24 hours or less). For example, at least some or substantially all of the solvent in the composition may evaporate, leaving a material (e.g., a film) on the skin (e.g., the 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 a penetration enhancer, a dye, or an aversive agent. In some embodiments, the remaining composition (e.g., the portion of the composition that remains on the skin lesion) will have beneficial properties of skin adhesion, flexibility, and / or safety (e.g., relatively little or no blistering outside the edge of the lesion). For example, the remaining composition may form a film on the skin lesion. In some embodiments, the film forms as a result of 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 remain attached to the skin lesion during normal activity by the subject and / or for a period of time with little exposure to water (e.g., more than about 6 hours, more than about 8 hours, more than about 12 hours, more than about 18 hours, more than about 24 hours, indefinitely). In some cases, the film is relatively flexible. Illustratively, the film will remain relatively continuous with relatively few or no intermittent areas during a period of normal activity. In such cases, the film will undergo minimal peeling and / or will form few or no cracks during normal activity.

[0176] In some embodiments, the remaining composition may be safe. In some such cases, the composition may not induce blisters on the skin surrounding the skin lesion within about 12 hours or more (e.g., about 24 hours or more) after administration of the composition comprising cantharidin. For example, the composition may not cause blister formation (e.g., 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 the 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. As another example, the composition may not cause blisters at the edge of the skin lesion and / or outside the administration site 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, the composition does not produce blisters having a diameter of more 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 distance (e.g., at least about 1 mm, at least about 2 mm) from the edge of the skin lesion after 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 when a 5 mm drop of the composition is administered to the skin. In some embodiments, the composition does not produce blisters having a diameter of more 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 distance (e.g., at least 1 mm, at least about 2 mm) from the edge of the skin lesion after 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 when droplets of the composition having a volume of about 10 μL or less are administered to the skin, e.g., over an area on the skin with a diameter of 5 mm.

[0177] Generally, the treatment methods described herein may result in the separation of at least a portion of the epidermal tissue within a skin lesion from the outer skin tissue without removing and / or damaging the outer skin tissue. The treatment methods described herein may have relatively high efficacy. Illustratively, one or more administrations of a composition using an applicator device and / or allowing the composition to remain after one or more administrations may result in the removal of a skin lesion or a substantial reduction in the volume of the lesion. In some embodiments, the treatment methods may have higher efficacy than other treatment methods, including, for example, administration of the same composition without an applicator and administration of a different composition using the same applicator. Illustratively, the treatment methods may have a relatively high percentage of lesion reduction (e.g., about 95% or more), a relatively high percentage of complete elimination in subjects (e.g., about 75% or more), a relatively short treatment duration, and / or relatively infrequent administration.

[0178] In some embodiments, the treatment methods described herein will have a relatively high percentage reduction in lesions. In some embodiments where more than one skin lesion (e.g., resulting from a molluscum contagiosum infection) is present on a subject and a composition is administered to at least some (e.g., substantially each) of the lesions, a relatively high percentage of the treated lesions will be removed and / or the total volume of the lesions will be reduced by a relatively high percentage (e.g., by about 50% or more, about 70% or more, about 90% or more). Illustratively, if more than one skin lesion is present on a subject and one or more compositions (e.g., one composition, two or more compositions, three compositions, or more, such as four or more compositions) are administered to at least some (e.g., substantially each) of the lesions, about 40% or more, about 45% or more, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, about 98% or more, about 99% or more, or about 100% of the treated lesions will be removed. In some embodiments, about 40% or more (e.g., about 45% or more, about 50% or more) of the treated lesions will be removed after the first administering and / or enabling step. In some embodiments where repeated administrations are performed, about 60% or more (e.g., about 70% or more, about 80% or more) of the treated lesions will be removed after the second administration and / or enabling step. In some embodiments where repeated administrations are performed, about 80% or more (e.g., about 85% or more, about 90% or more) of the treated lesions will be removed after the third administration and / or enabling step. In some embodiments where repeated administrations are performed, about 90% (e.g., about 92% or more, about 95% or more) of the treated lesions will be removed after the fourth administration and / or enabling step. In some such embodiments, the treatment method comprises performing four administration steps and may have a 12-week period. In some examples, the interval between each administration step may be about 3 weeks (e.g., 21±4 days).

[0179] In some embodiments, administering the composition one or more times (e.g., two or more times, three or more times, four or more times) and / or allowing the composition to remain after one or more administrations will result in complete elimination (i.e., complete removal) of skin lesions in a relatively high percentage of subjects. Illustratively, in some embodiments, about 50% or more, about 55% or more, about 60% or more, about 65% or more, about 70% or more, or about 75% or more of subjects will have complete elimination of skin lesion(s) after two or more treatments (e.g., four or more treatments). In some examples, about 70% or more of subjects will have complete elimination of skin lesion(s) after two or more treatments (e.g., four or more treatments). In some embodiments, between about 50% and about 100% of subjects (e.g., between about 50% and about 90%, between about 50% and about 100%) will have complete clearance of skin lesion(s) after two or more treatments (e.g., four or more treatments). In some such embodiments, the treatment method includes administering four administration steps and may have a 12-week duration.

[0180] In some embodiments, the volume of a single skin lesion may be reduced by a relatively high percentage (e.g., about 50% or more, about 60% or more, about 75% or more, about 90% or more, about 99% or more, 100%).

[0181] It should be appreciated that throughout the methods, the compositions and devices described herein can be used to treat one or more body surface conditions, and reference to a single skin lesion is for ease of explanation. Generally, the methods, compositions, and devices described herein can be used to treat multiple skin lesions (e.g., 2 or more, 5 or more, 10 or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 75 or more, 100 or more, 200 or more) on a subject with a skin disorder, such as a molluscum contagiosum infection.

[0182] In some embodiments, certain methods and compositions do not suffer from one or more limitations typically associated with cantharidin and its use. Illustratively, certain treatment methods may involve exposing skin lesion(s) to cantharidin for a relatively long period of time (e.g., more than 6 hours, 12 hours or more, about 18 hours or more, about 6 hours or more and about 72 hours or less, about 18 hours or more and about 24 hours or less) with minimal or no side effects (e.g., serious side effects).

[0183] In some embodiments, the composition may be administered using an applicator device and / or may be formulated so that a relatively large percentage of the composition does not spread outside the boundaries of the treated body surface area after administration (e.g., topical administration). In some embodiments, spread of the composition to at least a portion of the body surrounding the affected area (e.g., normal tissue) may be minimized by delivery of a volume to the affected area and / or through the use of an applicator (e.g., a precision applicator tip). In some embodiments, the composition may be formulated to minimize spread of the composition to portions of the body surrounding the affected area while allowing suitable coverage of the affected area. Regardless of whether the composition spreads, the composition will cause minimal or no side effects (e.g., serious side effects).

[0184] In some embodiments, at least a portion of the composition will be allowed to remain on the affected body area for a period of time (e.g., more than 6 hours, about 18 hours or more, and about 24 hours or less). For example, at least some or substantially all of the solvent in the composition evaporates, leaving a material (e.g., a film) on the affected body area (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, aversive agents, etc. In some embodiments, the remaining composition (e.g., the portion of the composition remaining on the affected body area) may have beneficial adhesion, flexibility, and / or safety properties (e.g., relatively low or no blistering outside the boundary of the lesion). For example, the remaining composition may form a film on the skin lesion. In some embodiments, the film forms as a result of removal (e.g., via evaporation) of the solvent (e.g., substantially all) during and / or after the administration step. In some cases, the coating may remain attached to the affected body area during normal activity by the subject and / or during light exposure to water for a period of time (e.g., more than about 6 hours, more than about 8 hours, more than about 12 hours, more than about 18 hours, more than about 24 hours, indefinitely). In some cases, the coating is relatively flexible. Illustratively, the coating will remain relatively continuous with relatively few or no intermittent areas during a period of normal activity. During normal activity, the coating will undergo minimal peeling and / or will form few or no cracks.

[0185] In some embodiments, the remaining composition will be safe. In some such cases, the composition will not induce blisters on the body parts surrounding the affected body area for about 12 hours or more (e.g., about 24 hours or more) after administration of the composition comprising cantharidin. For example, the composition will not cause blister formation (e.g., 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 the affected body area 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. As another example, the composition will not cause blisters at the edge of the affected body area and / or outside the site of administration for 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, the composition, when a 5 mm drop of the composition is administered to the skin, does not produce blisters having a diameter of more 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 distance (e.g., at least about 1 mm, at least about 2 mm) from the edge of the affected body area after 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.

[0186] As described above, in some embodiments, at least a portion of the composition may be left on the affected body area for a period of time, such as 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 instances, the composition may be left on the affected body area for about 72 hours or less, about 68 hours or less, about 64 hours or less, about 60 hours or less, about 56 hours or less, about 52 hours or less, about 48 hours or less, about 44 hours or less, about 40 hours or less, about 36 hours or less, about 32 hours or less, about 28 hours or less, about 24 hours or less, about 22 hours or less, about 20 hours or less, about 18 hours or less, about 16 hours or less, about 14 hours or less, about 12 hours or less, about 10 hours or less, or about 8 hours or less. All combinations of the above reference ranges are possible. For example, the composition may be left on the affected body area for more than about 6 hours and less than about 72 hours, more than about 12 hours and less than about 72 hours, more than about 18 hours and less than about 72 hours, more than about 12 hours and less than about 48 hours, more than about 18 hours and less than about 36 hours, or more than about 18 hours and less than about 24 hours.

[0187] It should be understood that phrases such as "on the affected body area," "on the skin," "on the skin lesion," "on the lesion," and the like, with respect to the composition or any of its components, may refer to the composition or any of its components being on top of one or more layers of the skin (e.g., the outside of the skin), inside one or more layers of the skin (e.g., contained within one or more layers of the skin, contained in the skin, contained within the lesion), and / or below one or more layers of the skin (e.g., the superficial layer of the skin lesion, the epidermal layer of the skin lesion). In some embodiments, at least a portion (e.g., substantially all) of the composition or any of its components may remain on top of the affected body area. In some embodiments, at least a portion (e.g., substantially all) of the composition or any of its components may remain within the affected body area. In some embodiments, at least a portion (e.g., substantially all) of the composition or any of its components may be below one or more layers of the affected body area (e.g., the superficial layer of the skin lesion, the epidermal layer of the skin lesion).

[0188] 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. Illustratively, 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 affected body area. In some embodiments, the rate and / or total time for removal (e.g., substantially all) of the solvent from the composition (e.g., evaporation) may be selected to produce beneficial properties. Illustratively, the vapor pressure of the solvent and / or composition may be selected to control the rate and / or total time for removal (e.g., substantially all) of the solvent from the composition (e.g., evaporation). In some embodiments, the total time for removal (e.g., evaporation) of at least a portion (e.g., about 50% or more, about 75% or more, about 90% or more, about 95% or more, about 99% or more, 100%) of the solvent from the composition 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 instances, the total time for removal (e.g., evaporation) of at least a portion (e.g., about 50% or more, about 75% or more, about 90% or more, about 95% or more, about 99% or more, 100%) of the solvent from the composition 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-mentioned reference ranges are possible (for example, more than about 30 seconds and less than about 60 seconds).Generally, the time for removing at least a part of the solvent from composition can be slower than that of some conventional cantharidin compositions, such as those that contain diethyl ether or a certain percentage of diethyl ether.In some embodiments, the removal of at least a part of the solvent (for example, substantially all of the solvent) can be through passive and / or active means.

[0189] In some embodiments, when cantharidin is used as the administered composition, a relatively large percentage of the composition (e.g., cantharidin) administered to an affected body area (e.g., a skin lesion) will penetrate into the affected body area (e.g., the epidermis of the skin lesion). Illustratively, in some embodiments, after administration and / or remaining on the skin for a period of time (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 (e.g., the epidermal tissue) of the skin lesion. As a result, the composition (e.g., a film) remaining on the skin after a period of time may contain a relatively small percentage of the administered cantharidin. Illustratively, the composition remaining on the skin (e.g., a film) may contain less than about 75%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 2%, less than about 1%, or less than about 0.5% of the administered cantharidin.

[0190] In some embodiments in which cantharidin is used as an administered composition, regardless of the percentage of the administered cantharidin that penetrates into the skin lesion, the plasma concentration of cantharidin in the subject (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be relatively low. Illustratively, the plasma concentration of cantharidin in the subject (e.g., at least some subjects, all subjects) may be about 30 ng / ml or less, about 25 ng / ml or less, about 20 ng / ml or less, about 15 ng / ml or less, about 10 ng / ml or less, about 8 ng / ml or less, about 5 ng / ml or less, about 4.8 ng / ml or less, about 4. ... It may be 3 ng / ml or less, about 4 ng / ml or less, about 3.8 ng / ml or less, about 3.5 ng / ml or less, about 3.3 ng / ml or less, about 3 ng / ml or less, about 2.8 ng / ml or less, about 2.5 ng / ml or less, about 2.3 ng / ml or less, about 2 ng / ml or less, about 1.8 ng / ml or less, about 1.5 ng / ml or less, about 1.3 ng / ml or less, about 1 ng / ml or less, about 0.8 ng / ml or less, about 0.5 ng / ml or less, about 0.3 ng / ml or less, or about 0.1 ng / ml or less. For example, in embodiments in which the composition is applied to more than one skin lesion (e.g., 2 or more, 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, 50 or more, 100 or more), and / or up to about 900 microliters or up to 200 mg (e.g., 170 mg) of the composition is applied to a skin lesion of the subject, the plasma concentration may be about 3.3 ng / mL or less or about 2.5 ng / mL or less (e.g., about 1 ng / mL or less, about 0.5 ng / mL or less, about 0.1 ng / mL or less) at least 2 hours (e.g., 2 hours, 6 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., 2 or more, 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, 50 or more, 100 or more), and / or up to 200 mg (e.g., 170 mg) of the composition is applied to the subject's skin lesions, the plasma concentration may be about 3.3 ng / mL or less or about 2.5 ng / mL or less (e.g., about 1 ng / mL or less, about 0.5 ng / mL or less, about 0.1 ng / mL or less) at least 2 hours (e.g., 2 hours, 6 hours, 24 hours) after administration of the composition.

[0191] In some embodiments, the plasma concentration of cantharidin in a subject (e.g., concentration at a single time point, concentration at all time points, maximum concentration) may be relatively low for a wide range of lesions, lesions per pound of body weight (i.e., lesions per pound), age, body weight, total administered dosage, and / or genital complications. Illustratively, 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 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 subject has 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 lesions per pound. Illustratively, 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 subject has about 0.001 or more and about 3 or less lesions per pound (e.g., about 0.1 or more and about 2.5 or less).

[0192] 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 0.1 milligrams per pound of subject or more (e.g., about 0.25 mg or more, about 0.5 mg or more, about 0.75 mg or more, about 1 mg or more, about 1.5 mg or more, about 2 mg or more, about 2.5 mg or more, about 3 mg or more, about 3.5 mg or more, about 4 mg or more, about 4.5 mg or more). Illustratively, the plasma concentration may be about 3.3 ng / mL (e.g., about 2.5 ng / mL) at least 2 hours after administration of a composition of about 0.1 mg or more and about 6 mg or less (e.g., about 0.5 mg or more and about 6 mg or less, about 0.75 mg or more and about 5 mg or less) per pound of subject.

[0193] 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 (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 0.5 milligrams or more of the composition per lesion (e.g., about 3 mg / lesion or more, about 3.5 mg / lesion or more, about 4 mg / lesion or more, about 4.5 mg / lesion or more, about 5 mg / lesion or more, about 5.5 mg / lesion or more, about 6 mg / lesion or more, about 6.5 mg / lesion or more, about 7 mg / lesion or more, about 7.5 mg / lesion or more, about 8 mg / lesion or more, about 8.5 mg / lesion or more, about 9 mg / lesion or more, about 9.5 mg / lesion or more). Illustratively, 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 3 mg / lesion or more and about 10 mg / lesion or less of the composition to the subject.

[0194] 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 milligrams 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). 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 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.

[0195] In some embodiments, the plasma concentration of cantharidin in a subject (for example, the concentration at a single time point, the concentration at all times, the maximum concentration) can be relatively low and uniform in a subject with a relatively low body weight and / or age.For example, the plasma concentration can be about 3.3ng / mL or less (for example, about 2.5ng / mL or less, about 1ng / mL or less) at least about 2 hours (for example, 2 hours±30 minutes, 6 hours±1 hour, 24 hours±3 hours) after administration of the composition in a subject with a body weight of about 200 lbs or less, about 175 lbs or less, about 150 lbs or less, about 125 lbs or less, about 100 lbs or less, about 90 lbs or less, about 80 lbs or less, about 70 lbs or less, about 60 lbs or less, about 50 lbs or less, about 40 lbs or less, or about 30 lbs or less. In some instances, 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 in a subject who is about 20 years of age or less, about 18 years of age or less, about 15 years of age or less, about 12 years of age or less, about 10 years of age or less, about 8 years of age or less, about 5 years of age or less, or about 3 years of age or less. 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 (e.g., 2 hours ± 30 minutes, 6 hours ± 1 hour, 24 hours ± 3 hours) after administration of the composition in a subject who has one or more skin lesions in the genital area.

[0196] As described above, in some embodiments, the composition may have beneficial properties that contribute, at least in part, to the efficacy and / or safety of the methods described herein. In some embodiments, the composition may include a relatively low concentration of cantharidin (e.g., about 1.2% (w / v) or 1.5% (w / v) or less), a non-aqueous solvent (e.g., ethanol and acetone having a vapor pressure of about 350 mmHg or less at 20°C), 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 include a dye (e.g., gentian violet) and / or a bittering agent (e.g., denatonium benzoate).

[0197] In one example, the composition may contain cantharidin (e.g., from about 0.1 to about 1.2 or 1.5 weight percent by volume, from about 0.7 to about 0.9 weight percent by volume, and from 0.7 weight percent by volume), acetone (e.g., from about 55 to about 65 weight percent by weight, from about 58 to about 62 weight percent by weight), ethanol (e.g., from about 25 to about 35 weight percent by weight, from about 28 to about 32 weight percent by weight), castor oil (e.g., from about 0.5 to about 2 weight percent by weight, from about 1.2 to about 1.6 weight percent by weight), nitrocellulose (e.g., from about 2 to about 10 weight percent by weight, from about 3 to about 6 weight percent by weight). and about 0.004 to about 0.008 weight percent), and / or gentian violet (e.g., in an amount of gentian violet from about 0.0001 to about 0.001 weight percent, and about 0.0002 to about 0.0008 weight percent).

[0198] In some embodiments, the solvent as a whole and / or the composition may have a certain vapor pressure that imparts beneficial properties to the composition. Illustratively, the solvent as a whole and / or the 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 the composition may be about 100 mmHg or more and about 210 mmHg or less (e.g., 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) at 20°C. In some embodiments, the solvent as a whole and / or the composition in the composition may have a flash point of about 4°C or more. In some embodiments, the solvent as a whole and / or the composition in the composition will not form peroxide radicals upon decomposition or will not otherwise have a tendency to form peroxide radicals.

[0199] In some embodiments, one or more solvent components in the total solvent (e.g., all solvent components), the total solvent, and / or the composition has a viscosity at 20° C. of about 350 mmHg or less, about 340 mmHg or less, about 330 mmHg or less, about 320 mmHg or less, about 310 mmHg or less, about 300 mmHg or less, about 290 mmHg or less, about 280 mmHg or less, about 270 mmHg or less, about 260 mmHg or less, about 250 mmHg or less, about 240 mmHg or less, about 230 mmHg or less. , about 220 mmHg or less, about 210 mmHg or less, about 200 mmHg or less, about 190 mmHg or less, about 180 mmHg or less, about 170 mmHg or less, about 160 mmHg or less, about 150 mmHg or less, about 140 mmHg or less, about 130 mmHg or less, about 120 mmHg or less, about 110 mmHg or less, about 100 mmHg or less, about 90 mmHg or less, about 80 mmHg or less, about 70 mmHg or less, about 60 mmHg or less, or about 50 mmHg or less. In some examples, one or more solvent components of the total solvent, the total solvent, and / or the composition 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 of the above-referenced ranges are possible. In some embodiments, one or more solvent components of the total solvent (e.g., all solvent components), the total solvent, and / or the composition may have a vapor pressure of about 210 mmHg or less (e.g., about 200 mmHg or less, 185 mmHg) at 20° C. In some embodiments, one or more solvent components of the total solvent (e.g., all solvent components) may have a flash point of about 4° C. or more. In some embodiments, the composition may be free of solvent components having a flash point of about 4° C. or less. In other embodiments, the composition may contain about 20 wt.% or less of solvent components having a flash point of about 4° C. or less.In some embodiments, one or more solvent components (e.g., all solvent components) in the overall solvent will not form peroxide radicals upon decomposition or will not otherwise have a tendency to form peroxide radicals.

[0200] In some embodiments, the composition will comprise 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 will be free of diethyl ether. In some embodiments, the composition will comprise 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 will be free of water.

[0201] In some embodiments, the composition will have a Reynolds number of less than about 1500 at 25°C. The composition may further comprise a gelling agent. The flavorant may be selected from the group consisting of denatonium, amarogentin, gentiopicrin, octaacetylsucrose, quercetin, brucine, and quassin. The colorant 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.

[0202] As used herein, the term "treatment" or "treating" generally refers to an approach for obtaining a beneficial, anticipated, or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or amelioration of the underlying disorder being treated, e.g., a skin disease or condition, such as a wart. A therapeutic benefit may also be achieved with the eradication or amelioration of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient may still be afflicted with the underlying disorder. Treatment may include the diagnosis of a health condition, e.g., warts.

[0203] As used herein, the term "cantharidin" generally refers to a compound of the following structure, or a derivative thereof having similar activity with respect to protein phosphatase inhibition. Compounds in which boron is substituted for carbon would also be considered cantharidins. Compounds with different ratios of carbon isotopes would also be considered cantharidins (e.g., C 14 ). Compounds with different ratios of oxygen isotopes would also be considered cantharidins (e.g., O 17 ). Compounds with different ratios of hydrogen isotopes would also be considered cantharidin (H 3 ). Compounds with different ratios of carbon, oxygen, and hydrogen isotopes, or combinations thereof, would also be considered cantharidin. Cantharidin may contain one or more unstable radioactive elements. Cantharidin may not contain one or more unstable radioactive elements. Cantharidin may include a pharmaceutically acceptable salt. Cantharidin may not include a pharmaceutically acceptable salt. [ka]

[0204] Non-limiting examples of cantharidin derivatives include cantharidin acid, norcantharidin, parasonin, endothal, fostriecin, and okadaic acid (see above). Other species that have exo,exo-diphenolic acid or that would be expected to be degraded or metabolized to a species containing exo,exo-diphenolic acid, whether substituted or not, would also be considered "cantharidin." Other compounds that serve as inhibitors of phosphoproteins 1, 2A, 4, or 5 would also be considered "cantharidin." A cantharidin composition may contain cantharidin alone or in addition to one or more other species, for example, one or more excipients. [ka]

[0205] Non-limiting examples of substituted exo,exo-diphenols include: 2,3-trimethylene anhydride; unsubstituted anhydride; 5,6-dehydro-anhydride; endo-5-methyl; mono-4-chloranilide; endo-5-carboxy; 5,6-dehydro; 2-bromo; and endo-5-hydroxymethyl.

[0206] Cantharidin may be produced by one or more Meloidae insects, including, but not limited to, Spanish fly, false blister beetle, red stag beetle, noctule, Chinese blister beetle, or combinations thereof. The amount of cantharidin produced per Meloidae 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 blister beetle may be greater than or equal to 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, 6 mg or more. The amount of cantharidin produced per blister beetle may be less than or equal to 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, 6 mg or less. Cantharidin may be produced biosynthetically. In some cases, the biosynthesis of cantharidin derivatives, norcantharidin, cantharidomide, or norcantharimide, produces similar therapeutic effects in users or patients. Alternatively, cantharidin may be produced entirely synthetically or semi-synthetically, for example, using naturally occurring raw materials.

[0207] In some embodiments, the present disclosure provides cantharidin compositions for treating skin conditions, diseases and / or disorders, such as, but not limited to, molluscum cantagiosum. The cantharidin compositions may comprise a therapeutically effective amount of cantharidin.

[0208] Generally, compositions containing cantharidin are administered locally using the applicator device described herein. For example, the composition can be administered to a specific location of a subject, such as the skin, rather than being administered systemically. In some such cases, the locally administered composition will be therapeutically effective at or around the site where the composition is administered, but will not be therapeutically effective in other locations. In some embodiments, the composition is administered locally to the skin, and after local administration, relatively little or no cantharidin is present systemically (e.g., a plasma concentration of about 3.3 ng / mL or less, a plasma concentration of about 2.5 ng / mL or less, or a plasma concentration of about 1 ng / mL or less).

[0209] The cantharidin used in the composition can be of sufficient purity to induce a therapeutic effect without toxicity.The purity of the cantharidin used in the composition can be between 50% and 100%.The purity of the cantharidin used can be about 70%, 80%, 90%, 95%, 98%, 99%, or 99.9% or more.

[0210] In some embodiments, cantharidin can be formulated into solid, semi-solid, gel or liquid form preparations suitable for local or topical administration, such as gel, water-soluble jelly, cream, lotion, suspension, solution, foam, powder, slurry, ointment, solution, oil, capsule, tablet, paste, suppository, spray, emulsion, saline solution, dimethyl sulfoxide (DMSO)-based solution, etc. High-density carriers can provide area with prolonged exposure to active ingredients.In contrast, solvent / solution compositions can provide more rapid exposure of cantharidin to selected area.

[0211] Cantharidin composition can also comprise suitable solid, semi-solid, gel or liquid phase carrier or excipient, which can provide the increased penetration of therapeutic molecules through the stratum corneum permeability barrier of skin or can change its delivery compound.The examples of such carrier and excipient include but are not limited to destructive agents (for example, base, acid, oxidizing agent), crosslinking agents (for example, formalin or formaldehyde), humectants (for example, urea), glycols (for example, propylene glycol), alcohols (for example, ethanol), fatty acids (for example, oleic acid), surfactants (for example, isopropyl myristate and sodium lauryl sulfate), pyrrolidone, glycerol monolaurate, sulfoxide, terpene (for example, menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycol.

[0212] The cantharidin composition may contain an acid or a combination of acids, including, but not limited to, salicylic acid, trichloroacetic acid, hydrochloric acid, formic acid, squaric acid, or nitric acid. The cantharidin composition may contain podophyllotoxin. The cantharidin composition may contain zinc oxide. The cantharidin composition may contain an immunotherapeutic agent such as imiquimod, 2,4-dinitrochlorobenzene, and / or a Candida antigen. The cantharidin composition may contain a chemotherapeutic agent such as bleomyosin, podophyllotoxin, and / or fluorouracil. The cantharidin composition may contain an oxidizing agent such as hydrogen peroxide.

[0213] The cantharidin composition can contain a solubilizer to ensure good solubilization and / or dissolution of cantharidin and minimize the precipitation of cantharidin in the composition.Solubilizer can be added to increase the solubility of cantharidin and / or maintain the composition as a stable or uniform solution, emulsion or dispersion.

[0214] Examples of suitable solubilizing agents 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, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose 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 (glycofurol) or methoxy PEG; 2-pyrrolyl Amides and other nitrogen-containing compounds such as methylpropionate, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl 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.

[0215] 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, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol, and propylene glycol.

[0216] The amount of a given solubilizer may be limited by its biotolerability. In some situations, for example, to maximize the drug concentration, it may be advantageous to include an amount of solubilizer that exceeds the biotolerability amount, and the excess solubilizer is removed using conventional techniques such as distillation or evaporation before providing the composition to a subject. When present, the solubilizer may be present in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight based on the combined weight of cantharidin and other excipients. Alternatively, substantially smaller amounts of solubilizer may be used, such as 5%, 2%, or 1% or less by weight of the cantharidin composition. In some examples, the solubilizer may be present in an amount of about 1% to about 100% by weight, or about 5% to about 25% by weight of the cantharidin composition. In some cases, the cantharidin composition contains less than the biotolerability amount.

[0217] The cantharidin composition may contain one or more film-forming agents. Examples of film-forming agents include, but are not limited to, nitrocellulose, nitrocellulose derivatives, polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethylcellulose, and other film-forming agents, or combinations thereof. The film-forming agent may be dissolved in a solvent. The film-forming agent may be dissolved in one or more solvents. The cantharidin composition may contain one or more solvents. The solvent may 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 a combination thereof, or other solvents. In some cases, the solvent is not or does not include diethyl ether. The solvent may be acetone and alcohol (e.g., ethanol). The cantharidin composition may contain one or more plasticizers. Examples of such plasticizers may include, but are not limited to, camphor and castor oil. The cantharidin composition may include one or more water-borne polymerization agents. The cantharidin composition may not include one or more water-borne polymerization agents. Examples of water-borne polymerization agents may include, but are not limited to, 2-octyl cyanoacrylate and butyl cyanoacrylate. In some cases, including a film-forming agent and a plasticizer provides viscosity, flexibility, durability, rigidity, toughness and / or film-forming properties to the final cantharidin composition.

[0218] The cantharidin composition may contain a dye. The cantharidin composition may contain one or more dyes. The cantharidin composition may not contain a dye. The dye may be an acridine, anthraquinone, arylmethane, azo, diazonium, nitro, phthalocyanine, quinoneimine, tetrazolium, thiazole, xanthene, acid, base, direct, mordant, natural, or solvent dye used in a concentration sufficient to adjust the color of the cantharidin composition.

[0219] The dyes include acridine orange, acriflavine, anthracene blue SWR, alizarin, alizarin red S (mordant red 3), nuclear fast red, auramine O, chromoxane cyanine R, pararosaniline, rosaniline, magenta II, new fuchsin, methyl violet 2B, methyl violet 6B, crystal violet, Hoffmann's 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, fulvorinate or diazonium benzenesulfonate, picric acid, Alcian Blue, Luxol Fast Blue, Toluidine Blue O, Thionin, Azure A, Azure B, Azure C, Neutral Red, Safranin O, Gallocyanine, Gallamine Blue, Iodonitrotetrazolium, Nitrobluetetrazolium, Thioflavin T, Pyronin Y, Pyronin Nin B, Rhodamine B, Martius Yellow (Acid Yellow 24), Eosin Y (Acid Red 87), Biebrich Scarlet (Acid Red 66), Sulfonated Pararosaniline (Basic Red 9), Pararosaniline (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), It may be romoxane cyanine R (mordant blue 3), celestine blue B (mordant blue 14), kermes (natural red 3), carmine (natural red 3), lac (natural red 25), hematein (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.

[0220] The dye may include a phase change dye. The dye may include multiple phase change dyes. The dye may not include a phase change pigment. Some examples of phase change dyes are D&C Orange, Neozapon Red 492, Orasol Red G, Direct Brilliant Pink B, Direct Red 3BL, Supranol Brilliant Red 3BW, Lemon Yellow 6G, Lightfast Yellow 3G, Eisenspiron Yellow C-GNH, Bemacrom Yellow GD Sub, Cultasol Brilliant Yellow 4GF, Sibanon Yellow 2G, Orasol Black RLI, Orasol Black CN, Savvinyl Black RLSN, Pyrazole Black BG, Morfast Black 101, Diazo The paint may include, but is not limited to, Luxol Black RN, Thermoplast Blue 670, Orasol Blue GN, Savrin Blue GLS, Luxol Fast Blue MBSN, Cebron Blue 5GMF, Bass Acid Blue 750, Keyplast Blue, Neozapon 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 Morplast Magenta 36, ​​or others.

[0221] The dye may serve as an indicator dye. The dye may include multiple indicator dyes. The dye may not include an indicator dye. 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, FD&C Green 3, FD&C Yellow 5, 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 demarcate the area treated with the cantharidin composition.

[0222] The cantharidin composition may include a fluorescent dye. The cantharidin composition may include multiple fluorescent dyes. The cantharidin composition may not include a fluorescent dye. The fluorescent dye may indicate the presence of a mineral (e.g., magnesium, calcium, zinc, copper, iron, lead, cadium, mercury, nickel, cobalt, aluminum, or a lanthanide). The fluorescent dye may indicate the presence of magnesium. The fluorescent dye may indicate the presence of intracellular magnesium. The cantharidin composition may include a fluorescent dye that fluoresces under ultraviolet light. Examples of fluorescent indicators that fluoresce under ultraviolet light include, but are not limited to, mag-indo-1 or mag-fura-2. The cantharidin composition may include a fluorescent dye that fluoresces under visible light. Examples of fluorescent indicators that fluoresce under visible light include, but are not limited to, magnesium green or mag-fluo-4.

[0223] The cantharidin composition 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 deter oral ingestion of the composition. Bittering agents or oral deterrents may be used to prevent or deter licking and / or ingestion of the composition 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 saccharide), amarogentin, gentiopicrin, sucrose octaacetate, quercetin, brucine, and quassin. The bittering agent denatonium benzoate may be added to the cantharidin composition.

[0224] The cantharidin composition may contain one or more pharmaceutically acceptable additives or excipients.Such additives or excipients may include, but are not limited to, anti-adherents, anti-foaming agents, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity adjusters, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0225] In some cases, the cantharidin composition may comprise at least one of the following: about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, about 10 The solution may have a pH of about 0.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.7, about 11.8, about 11.9, or about 12.0.Alternatively, the cantharidin composition may comprise at least about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6 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 The solution may have a pH of about 0.1, about 10.2, about 10.3, about 10.4, about 10.5, about 10.6, about 10.7, about 10.8, about 10.9, about 11.0, about 11.1, about 11.2, about 11.3, about 11.4, about 11.5, about 11.6, about 11.7, about 11.8, about 11.9, or about 12.0.

[0226] The cantharidin composition can be in liquid form.The liquid form can have resistance to fluid flow.The liquid form can have a Reynolds number of less than about 4000, 3000, 2000, 1500, 1000, 500, 400, 300, 200 or 100.The liquid form can have a Reynolds number of less than about 0.1, 1, 5, 10, 25, 50, 75, 100, 250, 500, 1000, 1250, 1500, 1750 or about 2000.The liquid form can have a Reynolds number of less than about 2000, 1750, 1500, 1250, 1000, 500, 400, 300, 250, 200, 150, 100, 75, 50, 25, 10, 5, 1 or 0.1 or less.

[0227] In some cases, the cantharidin composition may have a Reynolds number of less than about 4000, 3000, 2000, 1500, 1000, 500, 400, 300, 200, or 100 at a temperature of about 25° C. The liquid form may have a Reynolds number of about 1, 5, 10, 25, 50, 75, 100, 250, 500, 1000, 1250, 1500, 1750, or about 2000 at a temperature of about 25° C. The liquid form may have a Reynolds number of less than about 2000, 1750, 1500, 1250, 1000, 500, 400, 300, 250, 200, 150, 100, 75, 50, 25, 10, 5, or 1 or less at a temperature of about 25° C.

[0228] The liquid form may have a high viscosity. The liquid form may be substantially viscous so that the liquid cannot splash, drip, run, drain, leak, or aerosolize from the applicator unit. The liquid form may be substantially viscous so that the cantharidin composition remains at the patient or user's site where it is administered. The liquid form may be substantially viscous so that the cantharidin composition cannot run, splash, drip, run, drain, or leak from the patient or user's site where it is administered.

[0229] One or more gelling agents, such as dextran, nitrocellulose, hydroxypropyl cellulose, ethyl cellulose, or others, can be added to the liquid form to increase viscosity. The viscosity of the liquid form at ambient conditions (e.g., 25°C) can be about 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, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910 290, 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 ,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 about 2,000,000 centipoise.The viscosity of the liquid form at 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, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1 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, 6,000 It can be greater 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 2,000,000 centipoise or more.The viscosity of the liquid form at 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, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1 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, 6,000 It can be less than or equal to 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 2,000,000 centipoise. In some cases, the viscosity is between about 10 centipoise and 10,000 centipoise.

[0230] The cantharidin composition may have the following components: Table 1: Example cantharidin compositions [Table 1] Table 2: Example cantharidin compositions [Table 2]

[0231] The cantharidin solutions described in Tables 1 and 2 can be prepared in the following manner: Acetone, ethanol, and nitrocellulose are added to a glass vial to form a mixture. A polytetrafluoroethylene (PTFE)-coated stir bar is added, and the mixture can 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 of greater than 95% purity can be added to the glass vial. The mixture can be mixed until uniform. Hydroxypropyl cellulose is added, and the mixture can be mixed until completely gelled and uniform.

[0232] The composition, applicator device or system of the present disclosure can be used to deliver the cantharidin composition to the skin of a subject that is untreated, previously treated, or to be further treated.Some examples of previous treatments include, but are not limited to, the removal of scar tissue, scabs, or keratinized tissue by debridement, scrub, soaking, or surgical excision.Previous treatments can also include cryotherapy, cauterization, application of acid or base, application of salicylic acid, laser, surgical debridement, soaking, hydrogen peroxide, or immunotherapy.Previous treatments can also include adhesive tape, cream, ointment, solution, wax, or hydrophobic barrier to limit the area of ​​skin exposed to the cantharidin composition.The cantharidin composition can be used before or at the same time as surgical excision, cryotherapy, cauterization, application of acid or base, application of acid, laser, surgical debridement, soaking, hydrogen peroxide, immunotherapy, or covering the treatment area with occlusive tape or bandage.

[0233] In some embodiments, a cantharidin composition is applied to the skin, and an occlusive tape is placed over the treatment area. In some embodiments, the tape is left on the treatment area for at least 12 hours, at least 24 hours, at least 36 hours, or at least 48 hours. In some embodiments, the tape is left on the treatment area for 60 hours or less, 48 ​​hours or less, 36 hours or less, 24 hours or less, or 12 hours or less. Combinations of the above-referenced ranges are possible. For example, in some embodiments, the tape is left on the treatment area for about 12 hours to about 60 hours, or about 12 hours to about 48 hours, or about 12 hours to about 36 hours, or about 12 hours to about 24 hours. In some embodiments, such treatment may be used to treat warts, such as common warts and plantar warts.

[0234] Cantharidin compositions and associated applicator devices or systems may be used to treat the following: acrodermatitis, acrodermatitis enteropathica, acral keratoderma elastosis, actinic keratosis (solar keratosis), and cutaneous keratosis. keratoses), sebaceous adenoma, angiokeratoma, atopic dermatitis, basal cell carcinoma, benign fibrous histiocytoma, bladder cancer, Bowen's disease, breast cancer, Buschke-Ollendorff syndrome, cervical cancer, cervical dysplasia, senile hemangioma, chronic nodular chondrodermatitis, cutaneous endometriosis, leukemia cutis, cutaneous lymphoma, cutaneous meningioma, cutaneous mucomas, Darier's disease, dermal dendritic cell hamartoma, dermatofibroma, dermatofibrosarcoma protuberans, eccrine angiomatous hamartoma, ectodermal dysplasia, epidermal inclusion cyst, epidermal nevi (including, but not limited to, sebaceous nevus, comedonal nevus, and Proteus syndrome / Becker nevus), epithelioid cell histiocytoma, familial myxovascular fibromas, fungal skin diseases (including lobomycosis), granular cell tumor, glucagonoma syndrome syndrome), genital warts, ichthyosis (including but not limited to ichthyosis vulgaris, ichthyosis lamellaria, X-linked ichthyosis, epidermolytic hyperkeratosis, ichthyosis acquista, and palmoplantar keratosis), idiopathic guttate hypomelanosis, infantile acropustulosis, infantile fibromatosis, Kaposi's sarcoma, keloids, keratoacanthoma, keratocysts, knuckle pads, lentigines, melanoma, venular hemangiomas, Morton's neuroma, multifocal intralymphangiomatosis lymphangioendotheliomatosis, multinucleated angiohistiocytoma, multiple cutaneous leiomyomas, mycosis fungoides, cutaneous neuroma, neurocystoma, nevus flammeus, superficial lipomatous nevus, pachydermodactyly, palisade encapsulated neuroma, cutaneous infestations (including but not limited to scabies, pediculosis, sand fleas, hookworm-associated cutaneous larva migrans), pityriasis ruba pilaris, arrector piloleiomyomas, epidermal fibrohistiocytic tumor, pitted keratinized eccrine stomata and dermal duct nevus, progressive nodular histiocytoma psoriasisPsoriasis (including but not limited to psoriatic erythroderma, palmoplantar psoriasis, palmoplantar pustolosis, generalized pustular psoriasis of Thunbush, geographic tongue), porokeratosis, seborrheic dermatitis, seborrheic keratosis, rhinophyma, solitary cutaneous leiomyoma, spider angiomas, target hematoid angiomas, squamous cell carcinoma, tufted angiomas, venous lakes, pigmented urticaria, xanthelasmoidal mastocytosis, or herpetiform metastases.

[0235] Other skin conditions may also be treated with cantharidin compositions, including, but not limited to, acne, benign epidermal cysts, birthmarks, carbuncles, calluses, cellulitis, herpes simplex, corns, cutaneous candidiasis, eczema, freckles, hemangiomas, urticaria, lupus, measles, moles, necrotizing fasciitis, pigmentation disorders (drug-induced hyperpigmentation, hereditary symmetrical dyschromatosis, hereditary generalized dyschromatosis, familial progressive hyperpigmentation, Gari-Gari disease, hemosiderin hyperpigmentation, idiopathic guttate hypomelanosis, iron metallic discoloration, vitiligo, melasma, Mukamel syndrome, Venus necklace, anemic nevus, depigmented nevus, Pallister-Killian syndrome, phylloid hypomelanosis, mottling, reticular facial pigmentation). reticularis faciei et colli, hair cyst, pityriasis alba, poikiloderma of Civat, vascular poikiloderma, postinflammatory pigmentation, progressive macular hypomelanosis, pruritus, reticular pigmented anomaly, acropigmentation reticularis, Lille melanosis, Waardenburg-Schar syndrome, shiitake dermatitis, tar melanosis, titanium metallic discoloration, transient neonatal pustular melanosis, wanderer's leukoplakia, vasospastic macules, Wende-Bauckus syndrome, X-linked reticulate pigmentary disorder, Yemenite deaf-blind hypopigmentation syndrome), psoriasis, rosacea, scarring, skin cancer, skin tags, tattoo removal, vitiligo (non-segmental vitiligo and / or segmental vitiligo, trichome vitiligo, quadrichrome vitiligo, punctate vitiligo)eczema, warts, hypohidrosis, impetigo, cutis laxa, bedsores, erysipelas, diaper rash, dyshidrotic eczema, stomatitis, herpetic stomatitis, fungal nail infection, ichthyosis vulgaris, dermatomyositis, ingrown toenails, acrodermatitis, sebaceous cyst, seborrheic keratosis, pilonidal sinus, keloid, lichen planus, actinic keratosis, statis dermatitis, callus, verruca versicolor pemphigoid, mouth ulcers, or shingles.

[0236] There may also be use of cantharidin compositions in epidermal skin rejuvenation, such as peeling or flaking skin in those with sun damage or wrinkles.

[0237] Due to its chemotactic properties, ability to induce cell arrest and apoptosis, vesicant activity, and other therapeutic results, cantharidin compositions may be useful in combination with surgery, radiation, immunotherapy, small molecule-based, antibody-based, recombinant protein-based, nucleic acid-based, or chemotherapeutic agents. Cantharidin compositions may also be useful as second-, third-, or fourth-line therapeutic agents for treating patients who have failed previous therapies. Examples of the use of the cantharidin compositions, devices, and methods of the present disclosure include: immediately after Mohs micrographic surgery in the treatment of basal cell carcinoma, or after the failure of systemic chemotherapy in the treatment of mycosis fungoides, or in combination with destructive therapies such as cryotherapy, hydrogen peroxide, acid, or ingenol mebutate as first-line treatments in the treatment of actinic keratosis, or in the treatment of porokeratosis or seborrheic keratosis.

[0238] The composition, delivery device or system of the present disclosure can be used to treat warts, molluscum, actinic keratosis, seborrheic keratosis or other hyperproliferative disorders of the skin that have failed or are resistant to previous treatment.Alternatively, the composition, delivery device or system of the present disclosure can be used as first-line treatment.Alternatively, the composition, delivery device or system of the present disclosure can be used in combination with another first-line treatment.

[0239] Cantharidin compositions can be used to treat patients with cancer. For example, cantharidin compositions can be used to inhibit tumor growth and / or directly kill cancer cells. In some cases, cantharidin compositions can be used to kill cancer stem cells. In some cases, cantharidin compositions can be used to treat benign cancerous lesions. For example, cantharidin compositions can be used to kill cancer cells with multidrug-resistant phenotypes. In some situations, cantharidin, cantharidin, cantharidimide, or an analog of norcantharidimide or cantharidin can be used instead of cantharidin.

[0240] The cantharidin compositions, applicator devices, systems, and methods may be used for other purposes, such as, for example, 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 to removing residual cancer cells after surgery.

[0241] As used herein, the term "excipient" generally refers to an inactive ingredient 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, the excipient may be selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginic acid, tragacanth, gelatin, calcium silicate, crystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. In some embodiments, the excipient may be salicylic acid and / or podophyllotoxin.

[0242] As used herein, the term "user" generally refers to an individual who uses a delivery device or system to administer a composition to themselves or another individual, e.g., a subject.

[0243] As used herein, the term "subject" generally refers to an individual who is suspected of having a disease (e.g., a skin disease), who has been diagnosed with a disease, or who is undergoing treatment.For example, the subject may be under the treatment of another individual, or may be administered the composition of the present disclosure by himself or herself, or by another individual, such as a health care provider (e.g., a doctor, a treating doctor, a physician's assistant, a nurse) or a caregiver.Subjects may include asymptomatic individuals and symptomatic individuals, such as patients.In some cases, the subject may be diagnosed with a skin disease.

[0244] As used herein, the term "about" refers to within plus or minus (+ / -) 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the indicated amount.

[0245] In some embodiments using cantharidin as a pharmaceutical composition, the epidermal 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 after the cantharidin formulation is delivered to the subject. 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.

[0246] In some embodiments where cantharidin is used as a pharmaceutical composition, the amount of cantharidin delivered to a subject in a single administration can be between about 0.001 mg and 100 mg, about 0.1 mg and 50 mg, about 0.1 mg and 10 mg, about 0.5 mg and 10 mg, about 0.5 mg and 5 mg, about 1 mg and 5 mg, or about 1 mg and 2 mg.

[0247] In some embodiments where cantharidin is used as a pharmaceutical composition, the cantharidin formulation delivered to a subject can contain at least about 0.001% (weight / 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 a subject contains up to about 50% (w / v), 40%, 30%, 20%, or 10%, or 1% cantharidin.

[0248] In some embodiments in which cantharidin is used as a pharmaceutical composition, the cantharidin formulation delivered to a subject may contain about 50% (w / v), about 20% (w / v), about 10% (w / v), about 5% (w / v), about 1% (w / v), about 0.5% (w / v), or about 0.1% (w / v) or more of an excipient.

[0249] In some embodiments where cantharidin is used as a pharmaceutical composition, a delivery device or system is used to administer cantharidin in an amount of about 0.001 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, 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, a delivery device or system may be used to administer at least about 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, 5.5 mg / day, 6.0 mg / day, 7.0 mg / day, 8.0 mg / day, 9.0 mg / day, 10.0 mg / day, 11.0 mg / day, 12.0 mg / day, 13.0 mg / day, 14.0 mg / day, 15.0 mg / day, 16.0 mg / day, 17.0 mg / day, 18.0 mg / day, 19.0 mg / day, 20.0 mg / day, 21.0 mg / day, 22.0 mg / day, 23.0 mg / day, 24.0 mg / day, 25.0 mg / day, 26.0 mg / day, 27.0 mg / day, 28.0 mg / day, 29.0 mg / day, 30.0 mg / day, 31.0 mg / day, 32.0 mg / day, 33.0 mg / day, 34.0 mg / day, 35.0 mg / day, 36.0 mg / day, 37.0 mg / day, 38.0 mg / day, 39.0 mg / day, 40.0 mg / day, 41.0 mg / day, 42.0 mg / day, 43.0 mg / day, 44.0 mg / day, Cantharidin formulations may be delivered to a subject at 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.

[0250] Example 1 This example describes the results of a Phase II clinical trial for the treatment of skin lesions caused by molluscum contagiosum. Patients received four doses of the cantharidin composition shown in Table 2 over a 12-week period. When the cantharidin composition was administered via an applicator device, more patients had 75% clearance, 90% clearance, and complete clearance of skin lesions after 12 weeks than when the placebo was administered or when the same cantharidin composition was administered via a wooden stick. In addition, the mean percent reduction in skin lesions at 3, 6, 9, and 12 weeks was greater when the cantharidin composition was administered via an applicator device than when the same cantharidin composition was administered via a wooden stick. Placebo was evaluated from the placebo group (N=42 / 232) from two Phase 3 trials of ALDARA (imiquimod 5% cream), which was used as a placebo hypothesis.

[0251] Patients received one treatment every three weeks plus or minus four days (i.e., one treatment every 17 to 25 days): the first treatment at week 0, the second treatment at week 3, the third treatment at week 6, and the fourth treatment at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients received no treatment, but the amount of lesion clearance was measured and recorded.

[0252] The estimated placebo resulted in 18% of patients reaching complete clearance at 12 weeks with 4 treatments, while the cantharidin composition of Table 2 resulted in 46% of patients reaching complete clearance when administered via a traditional wooden stick applicator, with a P value of greater than 0.0015.

[0253] Patients receiving the cantharidin composition administered via an applicator device had a greater percent reduction in lesions than patients receiving the same cantharidin composition administered via a wooden stick and placebo.

[0254] Experiments have also shown that applying the pharmaceutical compositions of Table 2 using a device applicator similar to the embodiment shown in Figures 1-21 is significantly better than a conventional wood stick applicator when eliminating skin lesions resulting from molluscum contagiosum.

[0255] When using a conventional wood stick applicator, the pharmaceutical composition is held in a container with a lid. During treatment, the lid is removed, and the wood stick applicator is dipped into the container to coat the end of the wood stick applicator with the pharmaceutical composition. Finally, the wood stick applicator is moved toward each skin lesion on the patient to apply the pharmaceutical composition onto the lesion. The practitioner may dip the other end of the wood stick applicator into the container to obtain more pharmaceutical composition.

[0256] Patients received one treatment every three weeks plus or minus four days (i.e., one treatment every 17 to 25 days): the first treatment at week 0, the second treatment at week 3, the third treatment at week 6, and the fourth treatment at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients received no treatment, but the amount of lesion clearance was measured and recorded.

[0257] Data showing the percentage of patients with 100% lesion clearance with treatment using the wood stick applicator compared to the device applicator are shown in Figure 22. At week 12 with four treatments, the pharmaceutical composition with the wood stick applicator resulted in 46% of patients achieving complete clearance of skin lesions, while the pharmaceutical composition with the device applicator resulted in 75% of patients achieving complete clearance of skin lesions. In addition, at weeks 3 and 9, higher clearance of skin lesions was observed with the device applicator compared to the wood stick applicator.

[0258] Data showing the percentage of patients with at least 90% lesion clearance with treatment using the wood stick applicator compared to the device applicator are shown in Figure 23. At week 12 with four treatments, the pharmaceutical composition with the wood stick applicator resulted in 59% of patients reaching at least 90% lesion clearance, while the pharmaceutical composition with the device applicator resulted in 100% of patients reaching at least 90% lesion clearance. In addition, at weeks 6 and 9, higher clearance of skin lesions was observed with the device applicator compared to the wood stick applicator.

[0259] Data showing the percentage of patients with at least 75% lesion clearance with treatment using the wood stick applicator compared to the device applicator are shown in Figure 24. At 12 weeks with four treatments, the pharmaceutical composition with the wood stick applicator resulted in 59% of patients reaching at least 75% lesion clearance, while the pharmaceutical composition with the device applicator resulted in 100% of patients reaching at least 75% lesion clearance. In addition, at weeks 6 and 9, higher clearance of skin lesions was observed with the device applicator compared to the wood stick applicator.

[0260] Data showing the mean percent reduction in lesions for patients treated with the device applicator compared to patients treated with the traditional wood stick applicator are shown in Figure 25. At 12 weeks with four treatments, the pharmaceutical composition with the wood stick applicator resulted in a mean reduction in lesions of 76%, while the pharmaceutical composition with the device applicator resulted in a mean reduction in lesions of 97%, with a p-value equal to 0.002.

[0261] Additionally, a higher mean percent reduction in lesions was observed at 3, 6, and 9 weeks with the device applicator compared to the wood stick applicator.

[0262] Example 2 This example describes the results of a Phase II clinical trial for the treatment of skin lesions resulting from molluscum contagiosum.

[0263] Patients received one treatment every three weeks plus or minus four days (i.e., one treatment every 17 to 25 days): the first treatment at week 0, the second treatment at week 3, the third treatment at week 6, and the fourth treatment at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients received no treatment, but the amount of lesion clearance was measured and recorded.

[0264] Experiments have shown that applying the pharmaceutical compositions of Table 2 using a device applicator similar to the embodiment shown in Figures 1-21 is significantly better than a conventional wood stick applicator at eliminating skin lesions resulting from molluscum contagiosum.

[0265] When using a conventional wood stick applicator, the pharmaceutical composition is held in a container with a lid. During treatment, the lid is removed, and the wood stick applicator is dipped into the container to coat the end of the wood stick applicator with the pharmaceutical composition. Finally, the wood stick applicator is moved toward each skin lesion on the patient to apply the pharmaceutical composition onto the lesion. The practitioner may dip the other end of the wood stick applicator into the container to obtain more pharmaceutical composition.

[0266] Patients received one treatment every three weeks plus or minus four days (i.e., one treatment every 17 to 25 days): the first treatment at week 0, the second treatment at week 3, the third treatment at week 6, and the fourth treatment at week 9. At each visit, the amount of lesion clearance was measured and recorded. At the 12-week visit, patients received no treatment, but the amount of lesion clearance was measured and recorded.

[0267] Data showing the percentage of patients with 100% lesion clearance with treatment using the wood stick applicator compared to the device applicator is shown in Figure 26. At 12 weeks with four treatments, the pharmaceutical composition with the wood stick applicator resulted in approximately 46% of patients achieving complete clearance of skin lesions, while the pharmaceutical composition with the device applicator resulted in approximately 63% of patients achieving complete clearance of skin lesions. In addition, at 3 and 9 weeks, higher clearance of skin lesions was observed with the device applicator compared to the wood stick applicator.

[0268] Data showing the percentage of patients with at least 90% lesion clearance with treatment using the wood stick applicator compared to the device applicator are shown in Figure 27. At week 12 with four treatments, the pharmaceutical composition with the wood stick applicator resulted in approximately 67% of patients reaching at least 90% lesion clearance, while the pharmaceutical composition with the device applicator resulted in approximately 88% of patients reaching at least 90% lesion clearance. In addition, at week 9, greater clearance of skin lesions was observed with the device applicator compared to the wood stick applicator.

[0269] Data showing the percentage of patients with at least 75% lesion clearance with treatment using the wood stick applicator compared to the device applicator are shown in Figure 28. At 12 weeks with four treatments, the pharmaceutical composition with the wood stick applicator resulted in approximately 59% of patients reaching at least 75% lesion clearance, while the pharmaceutical composition with the device applicator resulted in approximately 92% of patients reaching at least 75% lesion clearance. In addition, at weeks 6 and 9, greater clearance of skin lesions was observed with the device applicator compared to the wood stick applicator.

[0270] Data showing the mean percent lesion reduction for patients treated with the device applicator compared to patients treated with the traditional wood stick applicator are shown in Figure 29. At 12 weeks with four treatments, the pharmaceutical composition with the wood stick applicator resulted in a 74% lesion reduction, while the pharmaceutical composition with the device applicator resulted in a 94% lesion reduction, with a p-value equal to 0.01.

[0271] In addition, a higher mean percent reduction in lesions was observed at 3, 6, and 9 weeks using the device applicator compared to the wood stick applicator.

[0272] Example 3 This example describes pharmacokinetic results from a Phase II clinical trial for the treatment of skin lesions caused by molluscum contagiosum. Patients received the cantharidin composition of Table 2 on their molluscum contagiosum lesions every 21 days for a maximum of four sessions or until complete clearance. Blood samples for systemic exposure assessment were collected on Day 1 prior to drug application and at 2 hours (±30 minutes), 6 hours (±1 hour), and 24 hours (±3 hours) after application. The mean age of subjects was 7±3.5 years. The mean weight of subjects was 58±34.6 lb. The mean number of lesions per subject was 43.7±24.2.

[0273] Only one of the 17 subjects had a cantharidin plasma concentration above the lower limit of quantitation (i.e., 2.5 ng / ml). For all subjects, cantharidin plasma concentrations were below 3.3 ng / ml at all sampled time points. Furthermore, subjects as young as (i) 2 years old, (ii) with more than 100 lesions, (iii) with genital lesions, and (iv) with as many as 2.26 lesions per lb had cantharidin plasma concentrations below the lower limit of quantitation. Table 10 shows the sex, age, weight, lesion count, genital involvement, 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 for the clinical trial subjects. Table 3: Subject demographic and pharmacokinetic data [Table 3-1] [Table 3-2] [Table 3-3]

[0274] While specific embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the present invention be limited by the specific examples provided herein. While the present invention has been described with reference to the above specification, the descriptions and illustrations of the embodiments herein are not intended to be construed in a limiting sense. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. Furthermore, it is to be understood that all aspects of the present invention are not limited to the specific depictions, configurations, or relative proportions set forth herein, which depend upon a variety of conditions and variables. It is to be understood that various alternatives to the embodiments of the present invention described herein may be used in practicing the invention. It is therefore contemplated that the present invention covers any such alternatives, modifications, variations, or equivalents. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0275] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each such variation and / or modification is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the particular application for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Accordingly, it is to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods is within the scope of the present invention, provided that such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent.

[0276] As used herein in the specification and claims, the indefinite articles "a" and "an" should be understood to mean "at least one," unless clearly indicated to the contrary.

[0277] As used herein and in the claims, the phrase "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., the elements present together in some instances, and the elements present separately in other instances. Other elements other than those specifically identified by the "and / or" clause may optionally be present, whether related to the specifically identified elements or not, unless otherwise stated. Thus, as a non-limiting example, a reference to "A and / or B" when used in combination with open-ended language such as "comprising" can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements), etc.

[0278] As used in this specification and 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, i.e., including at least one but also including a plurality of the number or list of elements, and optionally, including additional unlisted items. Only terms to the clear contrary, such as "only one" or "exactly one," or "consisting of," when used in the claims, will refer to the inclusion of exactly one element of the number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one," "only one," or "exactly one." "Consisting essentially of," when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0279] As used in this specification and claims, the phrase "at least one," in reference to a list of one or more elements, 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 every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related to the specifically identified elements or not. Thus, as a non-limiting 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") can refer, in one embodiment, to at least one (optionally multiple) A (and optionally including elements other than B) in the absence of B; in another embodiment, to at least one (optionally multiple) B (and optionally including elements other than A) in the absence of A; in yet another embodiment, to at least one (optionally multiple) A and at least one (optionally multiple) B (and optionally including other elements), etc.

[0280] In the claims, as well as in the foregoing specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and the like, are to be understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

1. 1. An applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, comprising: tube; an ampoule located within the tube; a pharmaceutical composition contained within the ampoule; a dispenser tip attached to the tube, the dispenser tip having a tapered tip; and a filter located within the tapered tip of the dispenser tip, constructed and arranged to permit the passage of fluid and to prevent the passage of broken ampoule fragments having a particle size of at least 150 μm; The applicator device comprising:

2. 10. The applicator device of claim 1, wherein the filter is retained within the dispenser tip via an interference fit between the filter and an interior surface of the tapered tip.

3. 3. The applicator device of claim 2, wherein the distal end of the filter is more compressed than the proximal end of the filter.

4. 4. The applicator device of any one of claims 1 to 3, wherein the dispenser tip comprises an inner surface and an outer surface, wherein at least a portion of the inner surface is tapered at a first taper angle and at least a portion of the outer surface is tapered at a second taper angle.

5. The applicator device of claim 4 , wherein the second taper angle is different from the first taper angle.

6. The applicator device of claim 4, wherein the first taper angle is between 2.5 and 5.5 degrees.

7. The applicator device of claim 4, wherein the second taper angle is between 2.5 and 5.5 degrees.

8. The applicator device of claim 4 , wherein the second taper angle is equal to the first taper angle.

9. 9. The applicator device of any one of claims 1 to 8, wherein the dispenser tip comprises a first portion and a second portion, wherein the first portion has a tapering internal diameter and the second portion has a constant internal diameter.

10. The applicator device of claim 5 , wherein the second portion is distal to the first portion.

11. An applicator device according to any preceding claim, wherein the dispenser tip comprises a drip guard comprising a groove configured to receive fluid that runs down the outer surface of the tapered tip.

12. The applicator device of claim 11 , wherein the drip guard is distal to at least a portion of the tapered tip.

13. The applicator device of claim 11 , wherein the drip guard comprises an annular ring.

14. The applicator device of claim 13 , wherein the drip guard comprises an annular groove.

15. The applicator device of claim 11 , wherein the drip guard surrounds at least a portion of the tapered tip.

16. 16. The applicator device of any one of claims 1 to 15, wherein at least a portion of the dispenser tip is attached to the tube, forming a fluid-tight seal between the dispenser tip and the tube.

17. The applicator device of any one of claims 1 to 16, wherein the dispenser tip has a distal opening with an inner diameter of less than about 0.02 inches and an outer diameter of less than about 0.05 inches.

18. The applicator device of any one of claims 1 to 17, wherein the dispenser tip has a distal opening with an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches.

19. 19. An applicator device according to any preceding claim, wherein the applicator device is constructed and arranged to produce droplets of less than 10 uL from the tip.

20. 20. An applicator device according to any preceding claim, wherein the applicator device is constructed and arranged to produce droplets of less than 5 uL from the tip.

21. 21. The applicator device of any one of claims 1 to 20, wherein the applicator device is constructed and arranged to generate more than 5 separate droplets from 450 ul or less of the pharmaceutical composition contained within the ampoule.

22. 22. The applicator device of any one of claims 1 to 21, wherein the applicator device is constructed and arranged to generate more than 50 separate droplets from 450 ul or less of the pharmaceutical composition contained within the ampoule.

23. An applicator device according to any preceding claim, wherein the filter is smaller than 0.045 cubic centimeters.

24. 24. An applicator device according to any preceding claim, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to drying skin, the droplets being less than 10 mm in diameter.

25. 25. The applicator device of claim 24, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition less than 5 mm in diameter to drying skin.

26. 26. The applicator device of claim 25, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition less than 4 mm in diameter to drying skin.

27. 27. An applicator device according to any preceding claim, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition, less than 3 mm in diameter, to drying skin.

28. An applicator device according to any preceding claim, wherein the applicator device is constructed and arranged to create a vacuum within the tube when the tube is squeezed and then released.

29. 29. An applicator device according to any preceding claim, wherein the applicator device is constructed and arranged to seal the tip for a period of between 5 and 60 minutes while the cap is in the open position.

30. 30. The applicator device of any one of claims 1 to 29, wherein the pharmaceutical composition comprises a composition selected from the group consisting of cantharidin, antifungals, antibacterials, antivirals, corticosteroids, steroids, immunostimulants, chemotherapeutics, keratolytics, antihistamines, and anti-inflammatory agents.

31. 31. The applicator device of any one of claims 1 to 30, wherein the filter has a density of 3 grams per cubic inch.

32. The applicator device of claim 1 , wherein the pharmaceutical composition has a viscosity of about 30 cps to about 110 cps.

33. The applicator device of claim 1 , wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent.

34. 34. The applicator device of claim 33, wherein the composition further comprises hydroxypropyl cellulose, nitrocellulose, castor oil, camphor, denatonium benzoate, and gentian violet.

35. 35. The applicator device of claim 34, wherein the pharmaceutical composition comprises 31.5 weights per weight percent of ethanol, 60 weights per weight percent of acetone, 0.88 weights per weight percent of hydroxypropyl cellulose, 4.5 weights per weight percent of nitrocellulose, 1.4 weights per weight percent of castor oil, 0.92 weights per weight percent of camphor, 0.88 weights per weight percent of cantharidin, 0.006 weights per weight percent of denatonium benzoate, and 0.0005 weights per weight percent of gentian violet.

36. 35. The applicator device of claim 34, wherein the composition further comprises an ether.

37. The pharmaceutical composition comprises: greater than or equal to about 25 and less than or equal to about 35 weight percent per weight percent of ethanol; greater than or equal to about 55 and less than or equal to about 65 weight percent per weight percent of acetone; about 10 or less weight per weight percent of ether; greater than or equal to about 0.1 and less than or equal to about 2 weight percent per weight percent of hydroxypropyl cellulose; greater than or equal to about 2.0 and less than or equal to about 10 weight percent per weight percent of nitrocellulose; a weight percent of castor oil of about 0.5 or more and about 2 or less; greater than or equal to about 0.1 and less than or equal to about 1.5 weight per weight percent of cantharidin; greater than or equal to about 0.001 and less than or equal to about 0.01 weight percent per weight percent of denatonium benzoate; and greater than or equal to about 0.0001 and less than or equal to about 0.001 weight percent per weight percent of gentian violet 35. The applicator device of claim 34, comprising:

38. The applicator device of claim 1 , wherein the pharmaceutical composition is ether-free.

39. 2. The applicator device of claim 1, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less cantharidin and a non-aqueous solvent for application to at least a portion of the skin lesion, and wherein the vapor pressure of the composition is about 210 mg Hg or less at 20 degrees Celsius.

40. The applicator device of claim 1, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less of cantharidin and a non-aqueous solvent for at least a portion of the skin lesion, wherein the composition comprises about 20% (w / w) or less of diethyl ether.

41. 10. The applicator device of claim 1, wherein the pharmaceutical composition comprises a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

42. 10. The applicator device of claim 1, wherein the filter is constructed and arranged to prevent the passage of broken ampoule fragments having a particle size of at least 100 μm.

43. 10. The applicator device of claim 1, wherein the filter is constructed and arranged to prevent the passage of broken ampoule fragments having a particle size of at least 130 μm.

44. The applicator device of claim 1 , further comprising a sleeve around the tube.

45. 45. The applicator device of claim 44, wherein the sleeve is made from paperboard or cardboard.

46. 1. An applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, comprising: tube; a pharmaceutical composition contained within the tube; a dispenser tip connected to the tube; and a cap having an opening for receiving a dispenser tip, wherein the cap has a closed position in which at least a portion of the dispenser tip passes through the opening, wherein the cap is coupled to and overlies at least a portion of the dispenser tip; wherein when the cap is in the closed position, ventilation of the dispenser tip is permitted through the opening in the cap; The applicator device comprising:

47. 47. The applicator device of claim 46, wherein ventilation of the dispenser tip occurs only through the opening in the cap.

48. 47. The applicator device of claim 46, further comprising grooves on a surface of the dispenser tip, wherein ventilation of the dispenser tip occurs through the grooves.

49. 49. The applicator device of claim 48, wherein at least a portion of the groove is received within the cap when the cap is in the closed position.

50. 50. An applicator device according to any one of claims 46 to 49, wherein the cap comprises an exterior surface having flat sides configured to prevent rotation of the applicator device.

51. 51. An applicator device according to any one of claims 46 to 50, wherein the cap comprises an outer surface having six flat sides forming a hexagon, wherein the flat sides are configured to prevent rotation of the applicator device.

52. 52. The applicator device of any one of claims 46 to 51, wherein the pharmaceutical composition comprises cantharidin.

53. 53. The applicator device of any one of claims 51 to 52, wherein the pharmaceutical composition comprises about 10% (w / v) or less diethyl ether.

54. 54. The applicator device of any one of claims 51 to 53, wherein the pharmaceutical composition comprises no more than about 1.2% (w / v) cantharidin.

55. The applicator device of any one of claims 51 to 54, wherein the pharmaceutical composition does not contain diethyl ether.

56. 56. The applicator device of any one of claims 51 to 55, wherein the pharmaceutical composition has a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

57. The applicator device of any one of claims 51 to 56, wherein the pharmaceutical composition comprises a film-forming agent.

58. 58. The applicator device of claim 57, wherein the film-forming agent comprises one or more polymers.

59. 59. The applicator device of claim 58, wherein the film-forming agent comprises nitrocellulose, hydroxypropyl cellulose, or a combination thereof.

60. 52. The applicator device of claim 51, wherein the pharmaceutical composition comprises a non-aqueous solvent.

61. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises a composition selected from the group consisting of cantharidin, antifungals, antibacterials, antivirals, corticosteroids, steroids, antibiotics, immunostimulants, antifungal agents, chemotherapeutics, keratolytics, antihistamines, and anti-inflammatory agents.

62. 47. The applicator device of claim 46, wherein the pharmaceutical composition does not include diethyl ether.

63. 47. The applicator device of claim 46, wherein the pharmaceutical composition has a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

64. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises a film-forming agent.

65. 65. The applicator device of claim 64, wherein the film-forming agent comprises one or more polymers.

66. 65. The applicator device of claim 64, wherein the film-forming agent comprises nitrocellulose, hydroxypropyl cellulose, or a combination thereof.

67. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises a non-aqueous solvent.

68. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises a nitrocellulose solution that solidifies in a time period between 5 and 60 minutes.

69. 47. The applicator device of claim 46, wherein the dispenser tip comprises grooves through which ventilation occurs.

70. 47. The applicator device of claim 46, wherein the pharmaceutical composition has a viscosity of about 30 cps to about 110 cps.

71. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent.

72. 72. The applicator device of claim 71, wherein the composition further comprises hydroxypropyl cellulose, nitrocellulose, castor oil, camphor, denatonium benzoate, and gentian violet.

73. 73. The applicator device of claim 72, wherein the pharmaceutical composition comprises 31.5 weights per weight percent of ethanol, 60 weights per weight percent of acetone, 0.88 weights per weight percent of hydroxypropyl cellulose, 4.5 weights per weight percent of nitrocellulose, 1.4 weights per weight percent of castor oil, 0.92 weights per weight percent of camphor, 0.88 weights per weight percent of cantharidin, 0.006 weights per weight percent of denatonium benzoate, and 0.0005 weights per weight percent of gentian violet.

74. 73. The applicator device of claim 72, wherein the composition further comprises an ether.

75. The pharmaceutical composition comprises: greater than or equal to about 25 and less than or equal to about 35 weight percent per weight percent of ethanol; greater than or equal to about 55 and less than or equal to about 65 weight percent per weight percent of acetone; about 10 or less weight per weight percent of ether; greater than or equal to about 0.1 and less than or equal to about 2 weight percent per weight percent of hydroxypropyl cellulose; greater than or equal to about 2.0 and less than or equal to about 10 weight percent per weight percent of nitrocellulose; a weight percent of castor oil of about 0.5 or more and about 2 or less; greater than or equal to about 0.1 and less than or equal to about 1.5 weight per weight percent of cantharidin; greater than or equal to about 0.001 and less than or equal to about 0.01 weight percent per weight percent of denatonium benzoate; and greater than or equal to about 0.0001 and less than or equal to about 0.001 weight percent per weight percent of gentian violet 73. The applicator device of claim 72, comprising:

76. 47. The applicator device of claim 46, wherein the pharmaceutical composition is ether-free.

77. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less cantharidin and a non-aqueous solvent for application to at least a portion of the skin lesion, wherein the vapor pressure of the composition is about 210 mg Hg or less at 20 degrees Celsius.

78. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less of cantharidin and a non-aqueous solvent for application to at least a portion of the skin lesion, wherein the composition comprises about 20% (w / w) or less of diethyl ether.

79. 47. The applicator device of claim 46, wherein the pharmaceutical composition comprises a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

80. 47. The applicator device of claim 46, further comprising a container located within the tube, wherein the pharmaceutical composition is contained within the container.

81. 81. The applicator device of claim 80, wherein the container comprises an ampoule.

82. 81. The applicator device of claim 80, wherein the container comprises a pouch.

83. 1. A method of topically administering a pharmaceutical composition to a subject, comprising: squeezing the tube of the applicator device while the cap is in a closed position covering at least a portion of the dispenser tip of the applicator device to break the ampoule within the tube and release the pharmaceutical composition contained within the ampoule; moving the dispenser tip toward the object; and Dispensing the pharmaceutical composition from the dispenser tip to a subject; The method comprising:

84. 84. The method of claim 83, further comprising removing the cap from the closed position prior to dispensing the pharmaceutical composition from the dispenser tip to the subject.

85. 84. The method of claim 83, wherein the pharmaceutical composition is a composition comprising cantharidin.

86. 86. The method of claim 85, wherein the composition comprises about 10% (w / v) or less diethyl ether.

87. 87. The method of claim 86, wherein the composition does not include diethyl ether.

88. 84. The method of claim 83, wherein dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to a skin lesion of the subject.

89. 89. The method of claim 88, further comprising allowing at least a portion of the pharmaceutical composition to remain on the skin lesion for more than about 6 hours.

90. 89. The method of claim 88, wherein the skin lesion is not caused by human papillomavirus.

91. 91. The method of any one of claims 88 to 90, wherein the composition remains on the skin lesion for about 12 hours or more.

92. 92. The method of any one of claims 88 to 91, wherein the composition remains on the skin lesion for about 18 hours or more.

93. 93. The method of any one of claims 88 to 92, wherein the composition remains on the skin lesion for about 24 hours or more.

94. 94. The method of any one of claims 88 to 93, wherein the composition remains on the skin lesion until removal of the composition.

95. 95. The method of any one of claims 88-94, wherein the composition remains on the skin lesion for at least about 6 hours and not more than about 72 hours.

96. 96. The method of any one of claims 88-95, wherein the composition remains on the skin lesion for not less than about 12 hours and not more than about 48 hours.

97. 97. The method of any one of claims 88-96, wherein the composition remains on the skin lesion for not less than about 18 hours and not more than about 24 hours.

98. 98. The method of any one of claims 88 to 97, further comprising allowing at least a portion of the epidermal tissue of the skin lesion to separate from at least a portion of the outer dermal tissue of the skin lesion.

99. 99. The method of any one of claims 88 to 98, wherein outer skin tissue is not substantially removed and / or damaged during said enabling step.

100. 100. The method of any one of claims 88-99, wherein the skin lesion is from molluscum contagiosum, seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer.

101. 101. The method of any one of claims 88 to 100, wherein the skin lesion is caused by a molluscum contagiosum infection.

102. 102. The method of any one of claims 88-101, further comprising applying at least 5 drops of the pharmaceutical composition with an applicator device in less than 5 minutes.

103. 103. The method of any one of claims 88-102, further comprising applying at least 10 drops of the pharmaceutical composition with an applicator device in less than 1 minute.

104. 84. The method of claim 83, wherein the cap comprises an opening for receiving the dispenser tip, and when the cap is in the closed position, the cap allows ventilation of the dispenser tip through the opening in the cap.

105. 84. The method of claim 83, wherein dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the skin of the subject.

106. 84. The method of claim 83, wherein dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to a mucosa of the subject.

107. 84. The method of claim 83, wherein the step of dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to an eye of the subject.

108. 84. The method of claim 83, wherein dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the ear of the subject.

109. 84. The method of claim 83, wherein dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the subject's mouth.

110. 110. The method of claim 109, wherein the step of dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the lips of the subject.

111. 110. The method of claim 109, wherein the step of dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to a tooth of the subject.

112. 110. The method of claim 109, wherein the step of dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the tongue of the subject.

113. 110. The method of claim 109, wherein the step of dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the gums of the subject.

114. 108. The method of claim 107, wherein the step of dispensing the pharmaceutical composition from the dispenser tip to the subject comprises administering the pharmaceutical composition to the eyelid of the subject.

115. 85. The method of claim 84, wherein the pharmaceutical composition comprises a composition selected from the group consisting of cantharidin, antifungals, antibacterials, antivirals, corticosteroids, steroids, immunostimulants, chemotherapeutics, keratolytics, antihistamines, and anti-inflammatory agents.

116. 85. The method of claim 84, wherein squeezing the tube expels air from the tube prior to dispensing the pharmaceutical composition, resulting in the creation of an internal vacuum within the tube that allows for controlled administration of the pharmaceutical composition.

117. 84. The method of claim 83, further comprising applying an occlusive tape to the location on the subject where the pharmaceutical composition has been dispensed.

118. 118. The method of claim 117, wherein the occlusive tape is retained on the subject for at least 24 hours.

119. 84. The method of claim 83, wherein the pharmaceutical composition dispensed from the applicator has a viscosity of about 30 cps to about 110 cps upon contact with the subject.

120. 84. The method of claim 83, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent.

121. 121. The method of claim 120, wherein the composition further comprises hydroxypropyl cellulose, nitrocellulose, castor oil, camphor, denatonium benzoate, and gentian violet.

122. 122. The method of claim 121, wherein the pharmaceutical composition comprises 31.5 weights per weight percent of ethanol, 60 weights per weight percent of acetone, 0.88 weights per weight percent of hydroxypropyl cellulose, 4.5 weights per weight percent of nitrocellulose, 1.4 weights per weight percent of castor oil, 0.92 weights per weight percent of camphor, 0.88 weights per weight percent of cantharidin, 0.006 weights per weight percent of denatonium benzoate, and 0.0005 weights per weight percent of gentian violet.

123. 122. The method of claim 121, wherein the composition further comprises an ether.

124. The pharmaceutical composition comprises: greater than or equal to about 25 and less than or equal to about 35 weight percent per weight percent of ethanol; greater than or equal to about 55 and less than or equal to about 65 weight percent per weight percent of acetone; about 10 or less weight per weight percent of ether; greater than or equal to about 0.1 and less than or equal to about 2 weight percent per weight percent of hydroxypropyl cellulose; greater than or equal to about 2.0 and less than or equal to about 10 weight percent per weight percent of nitrocellulose; a weight percent of castor oil of about 0.5 or more and about 2 or less; greater than or equal to about 0.1 and less than or equal to about 1.5 weight per weight percent of cantharidin; greater than or equal to about 0.001 and less than or equal to about 0.01 weight percent per weight percent of denatonium benzoate; and greater than or equal to about 0.0001 and less than or equal to about 0.001 weight percent per weight percent of gentian violet 122. The method of claim 121, comprising:

125. 84. The method of claim 83, wherein the pharmaceutical composition is ether-free.

126. 84. The method of claim 83, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less cantharidin and a non-aqueous solvent for at least a portion of the skin lesion, wherein the vapor pressure of the composition is about 210 mg Hg or less at 20 degrees Celsius.

127. 84. The method of claim 83, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less of cantharidin and a non-aqueous solvent for at least a portion of the skin lesion, wherein the composition comprises about 20% (w / w) or less of diethyl ether.

128. 84. The method of claim 83, wherein the pharmaceutical composition comprises a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

129. 84. The method of claim 83, wherein the step of squeezing the tube of the applicator device comprises squeezing a sleeve surrounding the tube.

130. 130. The method of claim 129, wherein the sleeve is made from paperboard or cardboard.

131. 1. A kit for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, comprising: a plurality of applicator devices, wherein each applicator device comprises: tube; an ampoule located within the tube; a pharmaceutical composition contained within an ampoule; a dispenser tip attached to the tube, wherein the dispenser tip has a tapered tip; and a filter located within the tapered tip of the dispenser tip, the filter constructed and arranged to allow the passage of fluid and to prevent the passage of broken ampoule fragments having a particle size of at least 150 μm; and Instructions for use The kit comprises:

132. 132. The kit of claim 131, further comprising prescribing information.

133. 133. The kit of any one of claims 131 to 132, wherein the pharmaceutical composition comprises cantharidin.

134. 134. The kit of any one of claims 131 to 133, wherein the pharmaceutical composition comprises about 10% (w / v) or less diethyl ether.

135. 135. The kit of any one of claims 131 to 134, wherein the pharmaceutical composition comprises no more than about 1.2% (w / v) cantharidin.

136. 136. The kit of any one of claims 131 to 135, wherein the pharmaceutical composition does not contain diethyl ether.

137. 137. The kit of any one of claims 131 to 136, wherein the pharmaceutical composition has a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

138. 138. The kit of any one of claims 131 to 137, wherein the pharmaceutical composition comprises a film-forming agent.

139. The kit of any one of claims 131 to 138, wherein the film-forming agent comprises one or more polymers.

140. 140. The kit of any one of claims 131-139, wherein the film-forming agent comprises nitrocellulose, hydroxypropyl cellulose, or a combination thereof.

141. 141. The kit of any one of claims 131 to 140, wherein the pharmaceutical composition comprises a non-aqueous solvent.

142. 132. The kit of claim 131, wherein the pharmaceutical composition comprises a composition selected from the group consisting of antimicrobial agents, corticosteroids, steroids, antibiotics, antifungal agents, antihistamines, and anti-inflammatory agents.

143. 132. The kit of claim 131, wherein the pharmaceutical composition has a viscosity of about 30 cps to about 110 cps.

144. 132. The kit of claim 131, wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent.

145. 145. The kit of claim 144, wherein the composition further comprises hydroxypropyl cellulose, nitrocellulose, castor oil, camphor, denatonium benzoate, and gentian violet.

146. 146. The kit of claim 145, wherein the pharmaceutical composition comprises 31.5 weights per weight percent of ethanol, 60 weights per weight percent of acetone, 0.88 weights per weight percent of hydroxypropyl cellulose, 4.5 weights per weight percent of nitrocellulose, 1.4 weights per weight percent of castor oil, 0.92 weights per weight percent of camphor, 0.88 weights per weight percent of cantharidin, 0.006 weights per weight percent of denatonium benzoate, and 0.0005 weights per weight percent of gentian violet.

147. 146. The kit of claim 145, wherein the composition further comprises an ether.

148. The pharmaceutical composition comprises: greater than or equal to about 25 and less than or equal to about 35 weight percent per weight percent of ethanol; greater than or equal to about 55 and less than or equal to about 65 weight percent per weight percent of acetone; about 10 or less weight per weight percent of ether; greater than or equal to about 0.1 and less than or equal to about 2 weight percent per weight percent of hydroxypropyl cellulose; greater than or equal to about 2.0 and less than or equal to about 10 weight percent per weight percent of nitrocellulose; a weight percent of castor oil of about 0.5 or more and about 2 or less; greater than or equal to about 0.1 and less than or equal to about 1.5 weight per weight percent of cantharidin; greater than or equal to about 0.001 and less than or equal to about 0.01 weight percent per weight percent of denatonium benzoate; and greater than or equal to about 0.0001 and less than or equal to about 0.001 weight percent per weight percent of gentian violet 146. The kit of claim 145, comprising:

149. 132. The kit of claim 131, wherein the pharmaceutical composition does not contain an ether.

150. 132. The kit of claim 131, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less cantharidin and a non-aqueous solvent for application to at least a portion of a skin lesion, wherein the vapor pressure of the composition is about 210 mg Hg or less at 20 degrees Celsius.

151. The kit of claim 131, wherein the pharmaceutical composition comprises about 1.2% (w / v) or less of cantharidin and a non-aqueous solvent for at least a portion of the skin lesion, wherein the composition comprises about 20% (w / w) or less of diethyl ether.

152. 132. The kit of claim 131, wherein the pharmaceutical composition comprises a vapor pressure of about 200 mg Hg or less at 20 degrees Celsius.

153. 1. A method of treating a skin condition, comprising: applying to a subject a pharmaceutical composition comprising: squeezing the tube of the applicator device to break the ampoule within the tube and release the pharmaceutical composition contained within the ampoule; dispensing the pharmaceutical composition from the dispenser tip onto multiple skin lesions of the subject; applying the pharmaceutical composition once every 17 to 25 days up to four times; wherein the pharmaceutical composition comprises cantharidin, acetone, ethanol, a plasticizer, and a film-forming agent; The method comprising:

154. 154. The method of claim 153, wherein the skin condition is molluscum contagiosum.

155. 154. The method of claim 153, wherein the skin condition is seborrheic keratosis, actinic keratosis, milia, age spots, porokeratosis, or skin cancer.

156. 154. The method of claim 153, further comprising removing the cap of the applicator device from the closed position prior to dispensing the pharmaceutical composition from the dispenser tip onto the skin lesion.

157. 154. The method of claim 153, further comprising allowing at least a portion of the pharmaceutical composition to remain on the skin lesion for more than about 6 hours.

158. 154. The method of claim 153, wherein the skin condition is not caused by human papillomavirus.

159. 154. The method of claim 153, wherein the skin condition is caused by human papillomavirus.

160. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion for about 12 hours or more.

161. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion for about 18 hours or more.

162. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion for about 24 hours or more.

163. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion until removal of the pharmaceutical composition.

164. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion for at least about 6 hours and not more than about 72 hours.

165. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion for about 12 hours or more and about 48 hours or less.

166. 154. The method of claim 153, wherein the pharmaceutical composition remains on the skin lesion for about 18 hours or more and about 24 hours or less.

167. 154. The method of claim 153, further comprising applying 50 drops of the pharmaceutical composition with an applicator device in less than 5 minutes.

168. 154. The method of claim 153, further comprising applying 10 drops of the pharmaceutical composition with an applicator device in less than 1 minute.

169. 154. The method of claim 153, wherein the dispenser tip has a tapered tip and the applicator device comprises a filter located within the tapered tip of the dispenser tip, wherein the filter is constructed and arranged to allow the passage of fluid and to prevent the passage of broken ampoule fragments having a particle size of at least 150 μm.

170. 170. The method of claim 169, wherein the filter is retained within the dispenser tip via an interference fit between the filter and the interior surface of the tapered tip.

171. 171. The method of claim 170, wherein the distal end of the filter is more compressed than the proximal end of the filter.

172. 154. The method of claim 153, wherein the dispenser tip comprises an inner surface and an outer surface, wherein at least a portion of the inner surface is tapered at a first taper angle and at least a portion of the outer surface is tapered at a second taper angle different from the first taper angle.

173. 154. The method of claim 153, wherein the dispenser tip comprises a first portion and a second portion, wherein the first portion has a tapering internal diameter and the second portion has a constant internal diameter.

174. 174. The method of claim 173, wherein the second portion is distal to the first portion.

175. 174. The method of claim 173, wherein the outer diameter of the first portion has a taper angle and the outer diameter of the second portion has a taper angle equal to the taper angle of the outer diameter of the first portion.

176. 154. The method of claim 153, wherein at least a portion of the dispenser tip is attached to the tube so as to form a fluid-tight seal between the dispenser tip and the tube.

177. 154. The method of claim 153, wherein the dispenser tip has an inner diameter of less than about 0.02 inches and an outer diameter of less than about 0.05 inches.

178. 154. The method of claim 153, wherein the dispenser tip has an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches.

179. 154. The method of claim 153, wherein the applicator device is constructed and arranged to produce droplets of less than 10 uL from the tip.

180. 154. The method of claim 153, wherein the applicator device is constructed and arranged to produce droplets of less than 5 uL from the tip.

181. 154. The method of claim 153, wherein the applicator device is constructed and arranged to generate more than 50 separate droplets from 450 ul or less of the pharmaceutical composition contained within the ampoule.

182. 170. The method of claim 169, wherein the filter is smaller than 0.045 cubic centimeters.

183. 154. The method of claim 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to drying skin in diameters of less than 10 mm.

184. 154. The method of claim 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition less than 5 mm in diameter to drying skin.

185. 154. The method of claim 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition to drying skin in diameters of less than 4 mm.

186. 154. The method of claim 153, wherein the applicator device is constructed and arranged to repeatedly apply droplets of the pharmaceutical composition less than 3 mm in diameter to drying skin.

187. 154. The method of claim 153, wherein the applicator device is constructed and arranged to create a vacuum within the tube when the tube is squeezed and then released.

188. 154. The method of claim 153, wherein the applicator device is constructed and arranged to seal the tip for a period of between 5 minutes and 60 minutes while the cap of the applicator device is in the open position.

189. a cap of the applicator device having an opening for receiving the dispenser tip, and the cap having a closed position in which at least a portion of the dispenser tip passes through the opening, wherein the cap is coupled to and positioned over at least a portion of the dispenser tip; and 154. The method of claim 153, wherein when the cap is in the closed position, ventilation of the dispenser tip is permitted through an opening in the cap.

190. 190. The method of claim 189, wherein ventilation of the dispenser tip occurs only through the opening in the cap.

191. 190. The method of claim 189, wherein the applicator device further comprises grooves on the surface of the dispenser tip, wherein ventilation of the dispenser tip occurs through the grooves.

192. 192. The applicator device of claim 191, wherein at least a portion of the groove is received within the cap when the cap is in the closed position.

193. 193. The method of any one of claims 153 to 192, wherein the composition comprises from about 0.1 to about 1.5 weight per volume percent of cantharidin.

194. 194. The method of any one of claims 153 to 193, wherein the composition comprises greater than or equal to about 55 and less than or equal to about 65 weight per weight percent of acetone.

195. 195. The method of any one of claims 153 to 194, wherein the composition comprises greater than or equal to about 25 and less than or equal to about 35 weight per weight percent of ethanol.

196. 196. The method of any one of claims 153 to 195, wherein the plasticizer comprises castor oil and / or camphor.

197. 197. The method of claim 196, wherein the composition comprises greater than or equal to about 0.5 and less than or equal to about 2 weight percent of castor oil.

198. 198. The method of claim 196 or 197, wherein the composition comprises greater than or equal to about 0.1 and less than or equal to about 2 weight per weight percent of camphor.

199. 199. The method of any one of claims 153 to 198, wherein the film-forming agent comprises nitrocellulose and / or hydroxypropylcellulose.

200. 200. The method of claim 199, wherein the composition comprises about 2 or more and about 10 or less weight per weight percent of nitrocellulose.

201. 201. The method of claim 199 or 200, wherein the composition comprises greater than or equal to about 0.1 and less than or equal to about 2 weight per weight percent of hydroxypropyl cellulose.

202. The method of any one of claims 153 to 201, wherein the composition further comprises a bittering agent.

203. 203. The method of any one of claims 153-202, wherein the composition comprises about 0.001 or more and about 0.01 or less weight per weight percent of bittering agent.

204. The method of any one of claims 153 to 203, wherein the composition further comprises a dye.

205. The method of any one of claims 153 to 204, wherein the composition comprises from about 0.0001 or more and from about 0.001 or less weight per weight percent of dye.

206. 206. The method of any one of claims 153 to 205, wherein the composition comprises from about 0.7 to about 0.9 weight per volume percent of cantharidin.

207. 207. The method of any one of claims 153 to 206, wherein the composition comprises greater than or equal to about 58 and less than or equal to about 62 weight per weight percent of acetone.

208. 208. The method of any one of claims 153 to 207, wherein the composition comprises greater than or equal to about 28 and less than or equal to about 32 weight per weight percent of ethanol.

209. 209. The method of any one of claims 153 to 208, wherein the composition comprises from about 1.2 to about 1.6 weight per weight percent of castor oil.

210. 210. The method of any one of claims 153 to 209, wherein the composition comprises about 3 or more and about 6 or less weight per weight percent of nitrocellulose.

211. 211. The method of any one of claims 153-210, wherein the composition comprises from about 0.1 to about 2 weight per weight percent of hydroxypropyl cellulose.

212. 212. The method of any one of claims 153-211, wherein the composition comprises about 0.5 or more and about 1.5 or less weight per weight percent of camphor.

213. 213. The method of any one of claims 153-212, wherein the composition comprises about 0.004 or more and about 0.008 or less weight per weight percent of the bittering agent.

214. The method of any one of claims 153 to 213, wherein the composition comprises from about 0.0002 to about 0.0008 weight per weight percent of dye.

215. 215. The method of any one of claims 153 to 214, wherein the composition comprises about 10% (w / v) or less diethyl ether.

216. The method of any one of claims 153 to 215, wherein the composition does not include diethyl ether.

217. The method of any one of claims 153 to 216, wherein the composition does not include a solvent having a flash point below 4 degrees Celsius.

218. The method of any one of claims 153 to 217, wherein the composition is free of solvents that tend to form peroxides.

219. The method of any one of claims 153 to 218, wherein the composition does not include a solvent having a vapor pressure of about 185 mm Hg or greater at 20 degrees Celsius.

220. 220. The method of any one of claims 153 to 219, wherein the composition comprises no more than about 10% (w / v) water.

221. 221. The method of any one of claims 153 to 220, wherein the skin condition is from a skin disorder that primarily affects the epidermis of the skin.

222. The composition comprises: greater than or equal to about 0.1 and less than or equal to about 1.5 weight per volume percent of cantharidin; greater than or equal to about 55 and less than or equal to about 65 weight percent per weight percent of acetone; greater than or equal to about 25 and less than or equal to about 35 weight percent per weight percent of ethanol; a weight percent of the plasticizer of about 0.5 or more and about 4 or less; and greater than or equal to about 2 and less than or equal to about 12 weight percent per weight percent of the film-forming agent The method of any one of claims 153 to 221, comprising:

223. The composition comprises: greater than or equal to about 0.1 and less than or equal to about 1.5 weight per volume percent of cantharidin; greater than or equal to about 55 and less than or equal to about 65 weight percent per weight percent of acetone; greater than or equal to about 25 and less than or equal to about 35 weight percent per weight percent of ethanol; a weight percent of castor oil of about 0.5 or more and about 2 or less; greater than or equal to about 2 and less than or equal to about 10 weight percent per weight percent of nitrocellulose; greater than or equal to about 0.1 and less than or equal to about 2 weight percent per weight percent of hydroxypropyl cellulose; greater than or equal to about 0.1 and less than or equal to about 2 weight percent per weight percent of camphor; a weight percent of the bittering agent of about 0.001 or more and about 0.01 or less; and greater than or equal to about 0.0001 and less than or equal to about 0.001 weight percent per weight percent of dye 223. The method of any one of claims 153 to 222, comprising:

224. 224. The method of any one of claims 153 to 223, wherein the bittering agent comprises denatonium benzoate.

225. 225. The method of any one of claims 153 to 224, wherein the dye comprises gentian violet.

226. 154. The method of claim 153, further comprising applying the pharmaceutical composition five times.

227. 154. The method of claim 153, wherein the step of squeezing the tube of the applicator device occurs while the applicator cap is in a closed position covering at least a portion of the dispenser tip of the applicator device.

228. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in complete clearance of the skin lesion in 75% of all patients.

229. 229. The method of claim 228, wherein all clearance of skin lesions occurs within 15 weeks in 75% of all patients.

230. 230. The method of claim 229, wherein total clearance of skin lesions occurs within 12 weeks in 75% of all patients.

231. 230. The method of claim 229, wherein total elimination of skin lesions occurs within 12 weeks and with four or fewer treatments in 75% of all patients.

232. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in at least 90% clearance of the skin lesion in 100% of all patients.

233. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in clearance of at least 75% of the skin lesion in 100% of all patients.

234. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in an average 97% reduction in the skin lesion.

235. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in total clearance of the skin lesion in 50% or more of all patients.

236. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in total clearance of the skin lesion in 60% or more of all patients.

237. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in total clearance of the skin lesion in 70% or more of all patients.

238. 154. The method of claim 153, wherein treating the skin lesion with the applicator device results in total clearance of the skin lesion in 75% or more of all patients.

239. 1. A method of treating a skin condition, comprising: Treating multiple skin lesions in a subject by dispensing the pharmaceutical composition from the applicator device onto the skin lesions; wherein the pharmaceutical composition comprises cantharidin and one or more excipients; and treating the skin lesion with the applicator device eliminates more of the skin lesion than treating the skin lesion with the stick applicator in the same amount of time. The method comprising:

240. 240. The method of claim 239, wherein the step of treating the skin lesion comprises dispensing the pharmaceutical composition from the applicator device onto the skin lesion four times, once every 17 to 25 days.

241. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in complete elimination of the skin lesion in 75% of all patients.

242. 242. The method of claim 241, wherein total elimination of skin lesions occurs in 75% of all patients with five or fewer treatments.

243. 242. The method of claim 241, wherein total elimination of skin lesions occurs in 75% of all patients with four or fewer treatments.

244. 242. The method of claim 241, wherein total clearance of skin lesions occurs in 75% of all patients within 15 weeks.

245. 245. The method of claim 244, wherein total clearance of skin lesions occurs in 75% of all patients within 12 weeks.

246. 245. The method of claim 244, wherein total clearance of skin lesions occurs in 75% of all patients within 12 weeks and with no more than four treatments.

247. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in at least 90% clearance of the skin lesion in 100% of all patients.

248. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in clearance of at least 75% of the skin lesion in 100% of all patients.

249. 240. The method of claim 239, wherein treating skin lesions with the applicator device results in an average 97% reduction in skin lesions.

250. 240. The method of claim 239, wherein the applicator device results in complete elimination of skin lesions in 63% more patients than the stick applicator.

251. 240. The method of claim 239, wherein the applicator device results in complete elimination of skin lesions in 50% more patients than the stick applicator.

252. 240. The method of claim 239, wherein the applicator device results in complete elimination of skin lesions in 25% more patients than the stick applicator.

253. 240. The method of claim 239, wherein the applicator device results in complete elimination of skin lesions in 10% more patients than the stick applicator.

254. 240. The method of claim 239, wherein the applicator device results in complete elimination of skin lesions in 5% more patients than the stick applicator.

255. 240. The method of claim 239, wherein the pharmaceutical composition comprises acetone, ethanol, a plasticizer, and a film-forming agent.

256. The method of any one of claims 239 to 255, wherein the composition further comprises a bittering agent.

257. The method of any one of claims 239 to 256, wherein the composition further comprises a dye.

258. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in complete elimination of the skin lesion in 50% or more of all patients.

259. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in complete elimination of the skin lesion in 60% or more of all patients.

260. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in complete elimination of the skin lesion in 70% or more of all patients.

261. 240. The method of claim 239, wherein treating the skin lesion with the applicator device results in complete elimination of the skin lesion in 75% or more of all patients.

262. 1. An applicator device for dispensing a pharmaceutical composition for topical administration of the pharmaceutical composition to a subject, comprising: tube; a pharmaceutical composition contained within the tube; a dispenser tip attached to the tube, wherein the dispenser tip has a tapered tip terminating in a distal opening having an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches; The applicator device comprising:

263. 263. The applicator device of claim 262, wherein the dispenser tip has an inner surface and an outer surface, wherein at least a portion of the inner surface is tapered at a first taper angle and at least a portion of the outer surface is tapered at a second taper angle different from the first taper angle.

264. 263. The applicator device of claim 262, wherein the dispenser tip comprises a first portion and a second portion, wherein the first portion has a tapering inner diameter and the second portion has a constant inner diameter.

265. 265. The applicator device of claim 264, wherein the second portion is distal to the first portion.

266. 265. The applicator device of claim 264, wherein the outer diameter of the first portion has a taper angle, and the outer diameter of the second portion has a taper angle equal to the taper angle of the outer diameter of the first portion.

267. 1. A method of treating a skin condition, comprising: applying to a subject a pharmaceutical composition comprising: squeezing a tube of an applicator device having a dispenser tip with a tapered tip at a distal opening having an inner diameter of less than about 0.013 inches and an outer diameter of less than about 0.034 inches; Dispensing the pharmaceutical composition from the dispenser tip onto multiple skin lesions of the subject. The method comprising:

268. 268. The method of claim 267, wherein the dispenser tip has an inner surface and an outer surface, wherein at least a portion of the inner surface is tapered at a first taper angle and at least a portion of the outer surface is tapered at a second taper angle different from the first taper angle.

269. 268. The method of claim 267, wherein the dispenser tip comprises a first portion and a second portion, wherein the first portion has a tapering inner diameter and the second portion has a constant inner diameter.

270. 270. The method of claim 269, wherein the second portion is distal to the first portion.

271. 270. The method of claim 269, wherein the outer diameter of the first portion has a taper angle, and the outer diameter of the second portion has a taper angle equal to the taper angle of the outer diameter of the first portion.

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